Exercise To Counteract Alzheimer's Disease What Do Fluid Biomarkers Say?

International Journal of
Molecular Sciences
Review
Exercise to Counteract Alzheimer’s Disease: What Do Fluid
Biomarkers Say?
Roberto Bonanni 1,† , Ida Cariati 2,† , Pierangelo Cifelli 3 , Claudio Frank 4 , Giuseppe Annino 2,5,6, * ,
Virginia Tancredi 2,5 and Giovanna D’Arcangelo 2,5
1 Department of Biomedicine and Prevention, “Tor Vergata” University of Rome, 00133 Rome, Italy;
[email protected]
2 Department of Systems Medicine, “Tor Vergata” University of Rome, 00133 Rome, Italy;
[email protected] (I.C.); [email protected] (V.T.); [email protected] (G.D.)
3 Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila,
67100 L’Aquila, Italy; [email protected]
4 UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy;
[email protected]
5 Centre of Space Bio-Medicine, “Tor Vergata” University of Rome, 00133 Rome, Italy
6 Sports Engineering Laboratory, Department of Industrial Engineering, “Tor Vergata” University of Rome,
00133 Rome, Italy
* Correspondence: [email protected] or [email protected]
† These authors contributed equally to this work.
Abstract: Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-
increasing population incidence. Particularly, Alzheimer’s disease (AD) is the most widespread ND
characterized by an accumulation of amyloid aggregates of beta-amyloid (Aβ) and Tau proteins
that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques
are needed to diagnose AD, the investigation of biomarkers within body fluids could provide
important information on neurodegeneration. Indeed, as there is no definitive solution for AD, the
monitoring of these biomarkers is of strategic importance as they are useful for both diagnosing
AD and assessing the progression of the neurodegenerative state. In this context, exercise is known
to be an effective non-pharmacological management strategy for AD that can counteract cognitive
decline and neurodegeneration. However, investigation of the concentration of fluid biomarkers in
Citation: Bonanni, R.; Cariati, I.;
AD patients undergoing exercise protocols has led to unclear and often conflicting results, suggesting
Cifelli, P.; Frank, C.; Annino, G.;
the need to clarify the role of exercise in modulating fluid biomarkers in AD. Therefore, this critical
Tancredi, V.; D’Arcangelo, G. Exercise
to Counteract Alzheimer’s Disease:
literature review aims to gather evidence on the main fluid biomarkers of AD and the modulatory
What Do Fluid Biomarkers Say? Int. J. effects of exercise to clarify the efficacy and usefulness of this non-pharmacological strategy in
Mol. Sci. 2024, 25, 6951. https:// counteracting neurodegeneration in AD.
doi.org/10.3390/ijms25136951
Keywords: neurodegeneration; Alzheimer’s disease; amyloid aggregates; fluid biomarkers; physiology;
Academic Editor: Amal Kaddoumi
exercise; performance; cognitive function
Received: 14 May 2024
Revised: 14 June 2024
Accepted: 22 June 2024
Published: 25 June 2024 1. Introduction
Neurodegenerative diseases (NDs) represent a major cause of disability and mortality
worldwide, with an economic and social impact, especially in the elderly population that is
Copyright: © 2024 by the authors.
constantly growing [1]. These cognitive disorders are characterized by extremely complex
Licensee MDPI, Basel, Switzerland. pathological mechanisms that are not yet fully understood. Nevertheless, all NDs share some
This article is an open access article common events, including progressive neuronal death and altered synaptic transmission
distributed under the terms and and plasticity, with severe repercussions on higher cognitive functions, such as memory and
conditions of the Creative Commons learning, and an individual’s motor skills [2–5].
Attribution (CC BY) license (https:// NDs are caused by a group of unrelated proteins with some common characteristics,
creativecommons.org/licenses/by/ such as the tendency to form insoluble aggregates of different sizes, and neurotoxicity [6].
4.0/). Between them, Alzheimer’s disease (AD) is undoubtedly the best-known and most widespread
Int. J. Mol. Sci. 2024, 25, 6951. https://doi.org/10.3390/ijms25136951 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2024, 25, 6951 2 of 28
ND disease, in which amyloid aggregates formed by the beta-amyloid (Aβ) protein and
the hyperphosphorylated Tau protein result in an initial short-term memory loss that then
progresses into typical dementia that characterizes this disease [7]. In a recent report published
in the Lancet, Scheltens et al. reported that, by 2050, the prevalence of AD-related dementia
will double in Europe and triple worldwide, highlighting the need to develop strategies to
counter its progression [8].
Interestingly, numerous synaptic and neuronal integrity proteins can be detected in the
body fluids of AD and other ND patients, highlighting their potential role as biomarkers of
neurodegeneration [9–11]. Early detection of such biomarkers in cerebrospinal fluid (CSF)
and plasma could facilitate both the early diagnosis of neurodegenerative disorders and the
initiation of pharmacological treatment, which will be more effective if undertaken in the early
stages of the diseases [12]. Furthermore, such fluid biomarkers in patients’ CSF could provide
valuable information on disease progression and actual treatment efficacy, thus acquiring
diagnostic and prognostic value [13]. However, despite the enormous efforts of research in
this field, to date, there is still no solution capable of definitively defeating neurodegenerative
disorders, highlighting the need to adopt strategies to slow down the ND’s progression,
attenuating both cognitive and motor symptoms [14].
In this context, exercise is an excellent tool for preventing the onset of NDs and counter-
acting its progression [15]. Indeed, numerous studies have demonstrated the effectiveness of
exercise in limiting cognitive decline in AD patients [16]. However, investigations on fluid
biomarkers of neurodegeneration often report conflicting results, suggesting the need for
further knowledge on the ability of exercise to counteract neurodegeneration in AD. Therefore,
this literature review aims to i) examine the role of biomarkers of synaptic and neuronal
integrity as potential diagnostic factors of AD and ii) collect evidence to evaluate the effi-
cacy of exercise as a valid tool to counteract neurodegeneration in AD by modulating the
concentrations of these biomarkers in body fluids.
2. AD: A Brief Overview of Pathogenesis

Some biochemical and biophysical events are underlying the pathogenesis of several
NDs [17]. Particularly, the formation of pores in neuronal membranes leading to an imbal-
ance in calcium homeostasis has been suggested as a common mechanism in many amyloid
storage neurodegenerative disorders. The result is vesicular depletion with neurotrans-
mitter reduction, impaired synaptic transmission, and neuronal death [18]. Although this
sequence of events is common to several diseases, the molecular mechanisms and genetic
determinants leading to the onset of AD require special discussion.
AD
Most cases of AD are sporadic and late-onset, making it extremely difficult to identify the
underlying causes of the genesis of AD-related dementia [19]. In fact, more than 20 genetic risk
factors have been identified as being responsible for the onset of AD [20]. Among these, the
APOE gene represents the largest single risk factor, as demonstrated by the increased likelihood
of developing AD in carriers of the ε4 allele, particularly homozygotes [21]. On the other hand,
mutations in the genes encoding for amyloid precursor protein (APP), presenilin 1 (PSEN1),
and presenilin 2 (PSEN2) have been associated with a rare familial form and early onset of
AD [22]. Specifically, under non-amylogenic conditions, APP, a transmembrane protein with
extracellular domains, undergoes cleavage by the enzyme α-secretase, producing soluble, non-
pathogenic peptide fragments that undergo further cleavage by the enzyme γ-secretase. In AD,
the so-called amyloidogenic pathway is active, in which APP is first cleaved by the β-secretase
enzyme (BACE) and then by γ-secretase, with the formation of Aβ peptides that aggregate,
leading to the formation of neurotoxic prefibrillar oligomers (PFOs) [23]. It is noteworthy that
the neurotoxicity of Aβ peptides varies considerably depending on the fragment formed by the
action of γ-secretase, as the Aβ1–40 peptide is characterized by significantly lower toxicity than
the Aβ1–42 fragment, which is associated with early-onset familial AD [24].
Int. J. Mol. Sci. 2024, 25, 6951 3 of 28
Importantly, AD is characterized by the deregulation of several kinases and phosphatases

that act on the Tau protein, resulting in its hyperphosphorylation [25]. The Tau protein has a
microtubule-binding domain that allows it to co-assemble with tubulin to form mature, stable
microtubules [26]. In AD, the altered action of both proline-directed kinases, such as glycogen
synthase kinase-3 (GSK3) and cyclin-dependent protein kinase-5 (CDK5), and mitogen-activated
kinases (MAPKs), results in hyperphosphorylation of Tau, which dissociates from the micro-
tubule and tends to aggregate to form characteristic neurofibrillary tangles (NFTs) [27]. As a
result, microtubules become unstable and disassemble, leading to cytoskeletal degeneration
with a deficit in vesicular transport [28]. The impairment of this process, which is fundamental
for the proper functioning of neurons, leads to the formation of Aβ accumulations in the axon
terminal, causing the failure of synaptic transmission [23]. Furthermore, in axon terminals,
calcium deregulation induced by the amyloid pores formed by Aβ oligomers promotes consti-
tutive neurotransmitter release in the inter-synaptic cleft and inevitable vesicular depletion. All
these events, combined with the alteration of the intracellular redox state due to mitochondrial
dysfunction by Aβ, result in apoptotic neuronal death [29].
It is noteworthy that autophagy and mitophagy, evolutionarily conserved cellular events
in eukaryotes, are found to be defective in AD and promote the accumulation of Aβ and Tau
aggregates, with dramatic consequences on neuronal health [30,31]. Indeed, these processes
represent the main pathway by which cells degrade dysfunctional organelles and protein ag-
gregates and play an essential role in neuronal homeostasis, being terminally differentiated
and non-substitutable cells [32]. In this context, Reddy and colleagues reported that the ac-
cumulation of mutated Aβ and APP in the hippocampal cell line HT22 drastically impairs
mitochondrial function and biogenesis, reducing the expression of the dendritic proteins, includ-
ing microtubule-associated protein 2 (MAP2), and synaptic proteins, including synaptophysin
and postsynaptic density protein 95 (PSD-95), as well as altering autophagy and mitophagy
processes, resulting in neuronal dysfunction and impaired cell viability [33]. Thus, the accumu-
lation of amyloid deposits in AD is responsible for cognitive impairment by altering several
fundamental cellular processes.
The presence of cognitive and behavioral symptoms is the basis for the diagnosis of AD,
as it has been reported that among individuals aged 70 years or older, only 20–40% have
biomarkers typical of AD, highlighting the inadequacy of autopsy findings for its diagnosis [34].
However, detecting neuronal and synaptic integrity proteins in body fluids could facilitate an
accurate and timely diagnosis, which is crucial for the optimal management of AD patients.
Furthermore, monitoring the concentrations of such biomarkers in body fluids could provide
valuable information regarding the staging of AD and the efficacy of therapeutic interventions.
Finally, although the extraordinary therapeutic power of exercise in AD patients is widely
known and well documented, the analysis of biomarkers detected in the fluids of AD patients
undergoing exercise programs needs further investigation to verify both the efficacy of specific
exercise protocols and the diagnostic and/or prognostic power of individual biomarkers.
3. Fluid Biomarkers as Diagnostic and Prognostic Factors of AD

Generally, by the time neurodegenerative diseases are diagnosed, the damage caused
by neurodegeneration is already severe [34]. To date, the most widely used approach
for diagnosing AD involves the use of neuroimaging techniques such as magnetic reso-
nance imaging (MRI), positron emission tomography (PET), and single-photon emission
computed tomography (SPECT). These techniques can provide valuable information on
structural and functional changes in affected brain areas, helping to diagnose neurodegener-
ative disorders in the prodromal stages [35]. However, although neuroimaging techniques
represent the gold standard for diagnosing AD, a good deal of biological research in this
field is focused on identifying biomarkers, detectable in body fluids, as potential diagnostic
and prognostic factors of AD.
Figure 1 summarizes the main fluid biomarkers discussed below, focusing on location
and function.
computed tomography (SPECT). These techniques can provide valuable information on
structural and functional changes in affected brain areas, helping to diagnose
neurodegenerative disorders in the prodromal stages [35]. However, although
neuroimaging techniques represent the gold standard for diagnosing AD, a good deal of
Int. J. Mol. Sci. 2024, 25, 6951 biological research in this field is focused on identifying biomarkers, detectable in body
4 of 28
fluids, as potential diagnostic and prognostic factors of AD.
Figure 1 summarizes the main fluid biomarkers discussed below, focusing on
location and function.
Figure 1. A schematic representation of the main fluid biomarkers involved in Alzheimer’s disease
Figure 1. A schematic(AD). representation of the
In the cytoplasm of neurons, main fluid
neuron-specific enolase biomarkers
(NSE) with glycolyticinvolved in Alzheimer’s disease
enzymatic action
and visinin-like protein 1 (VILIP-1), which regulates membrane transport, synaptic plasticity, as
(AD). In the cytoplasm
well asof neurons,
neuronal growth neuron-specific
and survival, are localized. enolase (NSE)
Neurofilament lightwith
chain glycolytic
(Nfl) is an enzymatic action
intermediate filament protein localized in the axon, which controls the maintenance of the neuronal
and visinin-like protein
caliber. 1 (VILIP-1),
Other which
proteins are in regulates
the cytoplasm membrane
of the presynaptic transport, synaptic
neuron: growth-associated protein plasticity, as well
as neuronal growth43 (GAP-43), involved in axonal growth, neuroplasticity, and memory formation; neuregulin 1
and survival, are localized. Neurofilament light chain
(NRG1) regulates neuronal development and survival, synaptic plasticity, and memory modulation;
(Nfl) is an intermediate
synaptosomal-associated protein 25 (SNAP-25) is responsible for synaptic and neuroendocrine
filament protein localized in the axon, which controls the maintenance of the
exocytosis. At the level of the postsynaptic membrane, postsynaptic density protein 95 (PSD-95),
neuronal caliber. Other
proteins are in the which
cytoplasm of the
increases synaptic presynaptic
plasticity neuron:
and reduces long-term growth-associated
depression (LTD), and neurogranin (Ng),protein 43 (GAP-43),
which promotes synaptic plasticity and long-term potentiation (LTP), are localized. Other fluid
involved in axonal biomarkers
growth,associated
neuroplasticity, and
with the pathogenesis memory
of AD, formation;
but not localized neuregulin
in neurons, include chitinase 1 (NRG1) regulates
3-like protein 1 or human cartilage glycoprotein 39 (YKL-40) secreted mainly by astrocytes, heart
neuronal development fatty acidand survival,
binding synaptic
protein (HFABP) with a role plasticity, and
in lipid metabolism, andmemory
apolipoproteinmodulation;
A1 (ApoA- synaptosomal-
1) that influences neuronal lipid homeostasis.
associated protein 25 (SNAP-25) is responsible for synaptic and neuroendocrine exocytosis. At
3.1. Biomarkers of Neurodegeneration in the CSF of AD Patients
the level of the postsynaptic membrane, postsynaptic density protein 95 (PSD-95), which increases
Although numerous molecular actors are involved in AD pathogenesis that could
synaptic plasticity and
provide reduces long-term
valuable information depression
on the (LTD), of
diagnosis or progression and neurogranin
the disease, some of these(Ng), which promotes
indicate a condition of neuronal and/or synaptic damage, thus acting as indicators of
synaptic plasticity and long-term
neurodegeneration [36].
potentiation (LTP), are localized. Other fluid biomarkers associated
with the pathogenesis of AD, but not localized in neurons, include chitinase 3-like protein 1 or human
cartilage glycoprotein 39 (YKL-40) secreted mainly by astrocytes, heart fatty acid binding protein
(HFABP) with a role in lipid metabolism, and apolipoprotein A1 (ApoA-1) that influences neuronal
lipid homeostasis.
3.1. Biomarkers of Neurodegeneration in the CSF of AD Patients

Although numerous molecular actors are involved in AD pathogenesis that could
provide valuable information on the diagnosis or progression of the disease, some of these
indicate a condition of neuronal and/or synaptic damage, thus acting as indicators of
neurodegeneration [36].
The finding of Aβ in CSF dates to 1992, when Seubert and colleagues demonstrated that
the peptide responsible for AD was produced and released both in vivo and in vitro, laying
the foundation for the development of diagnostic tests based on the presence of amyloid in
CSF [37]. Following the identification of the peptide Aβ42 as the main peptide responsible for
neurodegeneration in AD, numerous scientists attempted to positively correlate the amount
of this peptide in CSF with cognitive impairment, but with poor results. Indeed, numerous
reports have shown that the CSF of AD patients is characterized by low levels of Aβ42 [38,39].
This reduction could be explained by the aggregative behavior of this peptide, as Fagan
et al. demonstrated the existence of an inverse relationship between low Aβ42 levels and
the presence of amyloid plaques in AD patients [40]. This association has been confirmed
by several studies, with a concordance value of 90%, emerging as a potential preclinical
biomarker of AD [41]. Other Aβ species have also been found in the CSF of AD patients, such
as the peptide Aβ40 . Particularly, the Aβ42 /Aβ40 ratio, besides offering higher performance
in the identification of AD, shows better concordance with PET positivity for amyloid [42].
The presence of the Tau protein in the CSF is also considered a biomarker of AD. Par-
ticularly, the total Tau (T-Tau) protein has been proposed as a marker of the severity of
neurodegeneration, while the phosphorylated Tau (P-Tau) protein in residues 231, 181, or 199
can discriminate AD from other NDs [43]. Furthermore, P-Tau217 has been proposed as a
Int. J. Mol. Sci. 2024, 25, 6951 5 of 28
potential diagnostic and prognostic biomarker of AD, with a higher sensitivity than P-Tau181,
as its levels are significantly increased in PET-positive Aβ mild cognitive impairment (MCI)
patients [44]. In general, in the context of AD, the presence of T-Tau and P-Tau in the CSF can
predict faster disease progression, highlighting their role as biomarkers of AD [45–47].
Neurogranin (Ng) is a postsynaptic protein involved in synaptic plasticity and long-term
potentiation (LTP), processes underlying memory formation, whose increases in the CSF
could reflect marked synaptic loss and profound structural alterations [48]. In this regard,
Mavroudis et al. conducted a systematic literature review with a meta-analysis comparing the
results of studies that analyzed the presence of Ng in the CSF in different NDs. Significantly
higher levels of Ng were found in AD patients compared to patients with MCI, frontotemporal
dementia (FTD), and other NDs, suggesting its role as a reliable diagnostic biomarker for the
diagnosis of AD as well as for discrimination against other disorders [49]. On the other hand,
Willemse et al. evaluated Ng levels in the CSF of a dementia cohort consisting of AD patients,
AD patients with high T-Tau, Creutzfeldt–Jakob disease (CJD) patients, and non-AD subjects
and controls, concluding that Ng in the CSF represents a biomarker of synaptic degeneration,
closely related to Tau but not specific to AD [50].
Neuron-specific enolase (NSE) is a neuronal glycolytic enzyme that indicates the presence
of acute or prolonged neuronal damage [51]. Its role as a biomarker of AD dates back to
1995 when Parnetti and colleagues found a correlation between NSE levels in the CSF and
the severity of cognitive deficits [52]. Subsequently, Palumbo et al. conducted a comparative
study of AD patients and healthy controls to measure concentrations of NSE, Aβ42, and T-Tau
in CSF, finding a significant increase in NSE and T-Tau and a significant decrease in Aβ42 .
Interestingly, a direct correlation of NSE with T-Tau and an inverse correlation with Aβ42 was
found, suggesting NSE as a specific marker of AD being correlated with major biomarkers [53].
In agreement, Schmidt and colleagues found significantly elevated levels of NSE in the CSF of
AD patients compared to the control group, confirming its role as a biomarker of cognitive
impairment and its direct correlation with T-Tau and P-Tau [51]. Finally, Katayama et al.
conducted a systematic review with a meta-analysis to investigate the utility of NSE levels in
CSF as a biomarker of some NDs. Significantly elevated levels of NSE were observed in the
CSF of AD patients, although this biomarker can also be found in the CSF of patients with
Parkinson’s disease (PD), concluding that NSE may be a useful indicator of neurodegeneration
in these disorders [54].
The neurofilament light chain (Nfl) is a neuronal cytoplasmic protein that is highly
expressed in myelinated large-caliber axons, the levels of which increase in the CSF propor-
tionally to the degree of axonal damage. Therefore, this protein could reliably play the role
of a biomarker of neurodegeneration in a wide variety of neurological disorders, including
inflammatory, neurodegenerative, traumatic, and cerebrovascular diseases [55]. In this regard,
in 2019, Bridel and colleagues published in JAMA the results of a systematic literature review
with a meta-analysis on the diagnostic value of Nfl in certain neurological disorders. The au-
thors found that Nfl levels in the CSF were significantly higher in almost all neurodegenerative
disorders studied, indicating its potential role as a marker in neuroaxonal degeneration [56].
More recently, Leckey and colleagues found no significant changes in Nfl levels in the CSF
of AD patients, behavioral variant of FTD (bvFTD) patients, corticobasal syndrome (CBS)
patients, dementia with Lewy Bodies (DLB) patients, Huntington’s disease (HD) patients,
multiple sclerosis patients, and patients with semantic dementia, confirming its non-specificity
for neurodegeneration in AD [57].
Visinin-like protein 1 (VILIP-1), which belongs to the group of neuronal calcium sensor
proteins (NCS), performs several crucial functions in the central nervous system (CNS),
regulating ion channels, membrane trafficking, synaptic plasticity, neuronal growth, and
survival [58]. This protein is considered an emerging biomarker that can aid in the early
diagnosis of AD, as deregulation of calcium homeostasis results in axonal degeneration and
release of VILIP-1 into the CSF [59]. Indeed, a comparison of VILIP-1 levels in the CFS of
AD patients with those of healthy subjects and MCI patients showed that this protein was
significantly more represented in AD patients. In addition, VILIP-1 levels correlated with
Int. J. Mol. Sci. 2024, 25, 6951 6 of 28
elevated T-Tau levels and reduced Aβ42 levels, confirming its role as an effective diagnostic
biomarker of AD [59,60].
Interestingly, altered lipid metabolism is an event that characterizes AD and leads to
changes in membrane composition and fluidity, contributing to neuronal dysfunction [61].
Therefore, lipid-binding proteins could play an important role in the pathogenesis of AD as
predictors of neuronal plasma membrane modifications leading to neuronal deterioration [62,63].
In this context, heart fatty acid binding protein (HFABP) has been suggested as a diagnostic
and prognostic biomarker in the early stages of AD [64]. Indeed, in 2013, Desikan et al.
demonstrated that high levels of HFABP in CSF, concomitantly with low levels of Aβ42 ,
were associated with brain atrophy of selectively affected areas in the early stages of AD.
Importantly, the authors reported that HFABP is not simply a generalized marker of neuronal
damage, but high levels of HFABP in CSF may reflect the deregulation of lipid homeostasis in
the CNS [65]. This observation suggests a crucial role of CNS lipids in AD pathogenesis that
could reflect the involvement of proteins responsible for lipid metabolism. Indeed, reduced
levels of apolipoprotein A1 (ApoA-1) have been observed in the CSF of AD patients compared
to MCI patients and healthy controls, suggesting its potential role as a fluid biomarker for
AD diagnosis [66]. Moreover, this protein does not contribute to neuronal integrity as it is
synthesized in the liver and intestine and is responsible for transporting excess cholesterol
from peripheral tissues to the liver. However, ApoA-1 has been suggested to enter the brain
and influence neuronal lipid homeostasis [67]. Particularly, Slot et al. measured ApoA-1
levels in the CSF of elderly people with cognitive decline (SCD) and MCI, detecting increased
levels of the protein in APOE ε4 carriers with cognitive decline and confirming its role as
a biomarker in the early stages of AD [68]. Other evidence has shown that reduced levels
of ApoA-1 in the CSF are associated with AD, although it is not entirely clear whether this
biomarker can be considered specific for AD or whether it signals the presence of neuronal
damage [67].
Growth-associated protein 43 (GAP-43) is a protein found on the cytoplasmic side of the
presynaptic membrane [65] and is involved in axonal growth, neuroplasticity, and memory
formation [69]. This protein is abundantly expressed in the cerebellum, neocortex, entorhinal
cortex, hippocampus, olfactory bulb, and retinal cells and has been suggested as a biomarker of
synaptic dysfunction, being abundantly present in the CSF of AD patients [70–73]. Specifically,
Franzmeier and colleagues observed that GAP-43 levels in the CSF of AD patients were
associated with a more rapid accumulation of Aβ-related Tau. In other words, the effect of Aβ
on Tau deposition was greater in the presence of high levels of GAP-43 in the CSF, highlighting
the role of this presynaptic protein as a biomarker of synaptic dysfunction in AD [74].
Chitinase 3-like protein 1 or human cartilage glycoprotein 39 (YKL-40) is a chitin-
binding lectin and belongs to the glycosyl hydrolase 18 family [75]. It has been indicated as a
marker of neuroinflammation that can facilitate the diagnosis of AD, as demonstrated by in-
creased levels of this protein in the CSF of AD patients compared to healthy controls [76,77].
Interestingly, YKL-40 could represent a valid tool for predicting the conversion of MCI to
AD, as differences were found in CSF between the two patient cohorts [78].
Another protein that could play the role of a biomarker of neurodegeneration is PSD-
95, which is known to bind to the C-terminal domain of glutamate N-Methyl-D-Aspartate
Receptors (NMDARs), affecting synaptic transmission and plasticity. Indeed, up-regulation
of PSD-95 has been reported to enhance synaptic transmission and inhibit long-term depres-
sion (LTD) [79]. Furthermore, the brain tissue of AD patients is known to be characterized
by reduced expression of PSD-95, suggesting its potential to signal neural damage in AD
pathogenesis [80]. In this context, Kivisäkk and colleagues investigated the role of PSD-95
as a potential fluid biomarker of AD by comparing protein levels in the CSF of AD patients
with those of other patients with different neurological conditions. The authors found high
levels of PSD-95 in all types of patients, suggesting that this protein may be a valid marker of
non-highly specific synaptic damage in AD [81].
Synaptosomal-associated protein 25 (SNAP-25) is widely distributed in the brain, per-
forming crucial functions such as synaptic and neuroendocrine exocytosis [82]. Several authors
Int. J. Mol. Sci. 2024, 25, 6951 7 of 28
have investigated the role of SNAP-25 as a fluid biomarker, finding the existence of a positive
relationship with Aβ pathology [83,84]. Notably, in 2018, Wang and colleagues published
results of a comparison of SNAP-25 levels in the CSF of patients with MCI, dementia, mild
AD, and normal cognition, in carriers and non-carriers of APOE ε4. The authors showed
that SNAP-25 was more abundant in the CSF of AD and MCI patients and that, among MCI
patients, SNAP-25 levels were higher in APOE ε4 carriers than non-carriers, suggesting the
ability of this protein to indicate presynaptic degeneration preceding AD [85]. It is noteworthy
that SNAP-25 levels were also increased in the CSF of cognitively normal elderly patients
who were APOE ε4 carriers, indicating the existence of selective synaptic damage in these
subjects compared to their non-carriers [86]. Finally, in 2022, Kivisäkk and colleagues detected
significantly increased levels of SNAP-25 in AD patients compared to other NDs, suggesting
its role as a potential AD-specific biomarker [81].
Neuregulin 1 (NRG1) is a neurotrophic factor that stimulates the release of gamma-
aminobutyric acid (GABA) [87]. This pre-synaptic protein is cleaved by the enzyme BACE-1
and can activate the postsynaptic receptor tyrosine-protein kinase erbB4 (ErbB4), regulating
neuronal processes such as development, synaptic plasticity, neuronal survival, and modula-
tion of memory [88]. In the retrospective study by Mouton-Liger et al., which included a total
of 162 subjects, NRG1 levels in the CSF of AD patients were significantly increased compared
to controls and subjects with other neurological disorders, underlining the specificity of NRG1
to signal synaptic impairment typical of AD [88].
Overall, changes in the levels of these biomarkers in the CSF of AD patients could
provide valuable support for early diagnosis, facilitating the identification of AD patients
in the prodromal phase and the timely initiation of the treatment pathway.
Table 1 summarizes the main scientific evidence on the levels of biomarkers discussed
in the text in the CSF of AD patients or patients with other NDs.
Table 1. A schematic representation of the main evidence on AD biomarkers in the CSF.
Biomarker Study Population Biomarker Levels Evidence References

n = 24, age (years): 48–83 - Aβ42 reduction is
- CN subjects: 483–1071 in
- 18 CN subjects; age (years): 15 subjects and 326–443 in associated with the
Aβ42 48–83 3 subjects presence of amyloid
- 4 patients with AD-type - Patients with AD-type deposits in AD brains [40]
(pg/mL)
dementia; age (years): 73–81 dementia: 230–426 - Preclinical AD
- 2 patients with non-AD type - Patients with non-AD type biomarker potential
dementia; age (years): 77 dementia: 572–588
n = 206 - AD patients: 667.5 for
- 108 AD patients; age (years): P-Tau231, 20.5 for P-Tau181,
54–84; 65 females and 1.7 for P-Tau199
43 males - DLB patients: 213.5 for
- 22 DLB patients; age (years): P-Tau231, 11.3 for P-Tau181,
65–87; 7 females and 1.1 for P-Tau199
P-Tau231 15 males - FTD patients: 86.5 for
(pg/mL) - 24 FTD patients; age (years): - Discriminates AD
P-Tau231, 10.7 for P-Tau181,
P-Tau181 46–79; 15 females and from other NDs
1.1 for P-Tau199 [43]
(pmol/L) 9 males - Predicts faster
- VaD patients: 201.0 for
P-Tau199 - 7 VaD patients; age (years): disease progression
P-Tau231, 13.6 for P-Tau181,
(fmol/mL) 65–77; 4 females and 3 males 1.3 for P-Tau199
- 22 OND patients; age (years): - OND patients: 54.0 for
49–81; 16 females and P-Tau231, 11.3 for P-Tau181,
6 males 0.8 for P-Tau199
- 23 controls; age (years): - Controls: 35.0 for P-Tau231,
44–77; 14 females and 11.0 for P-Tau181, 0.8 for
19 males P-Tau199
Int. J. Mol. Sci. 2024, 25, 6951 8 of 28
Table 1. Cont.

n = 753
- 290 CU Aβ+ patients; age
(years): 63.8–77.9; 121
females and 169 males; 38.3%
APOE ε4 carriers
- 34 MCI Aβ− patients; age
(years): 69.1–81.7; 12 females - CU Aβ+ patients: 41.3–183.0
and 22 males; 20.6% APOE - MCI Aβ− patients: - Higher diagnostic
ε4 carriers 52.8–114.6 sensitivity than
- 47 MCI Aβ+ patients; age - MCI Aβ+ patients: P-Tau181
P-Tau217
(years): 74.5–84.6; 24 females 98.3–484.8 - Potential prognostic [44]
(pg/mL)
and 23 males; 46.8% APOE - Patients with Aβ+ dementia: marker in MCI Aβ+
ε4 carriers 201.7–558.4 patients
- 6 patients with Aβ+ - CU Aβ− subjects: 48.3–90.5
dementia; age (years):
80.4–85.7; 6 males; 33.3%
APOE ε4 carriers
- 376 CU Aβ− subjects; age
(years): 62.9–78.7; 169
APOE ε4 carriers
Clinical cohort: n = 116
- 30 AD patients; age (years):
78 ± 9; 15 females and
15 males
- 32 AD patients with high
T-Tau; age (years): 77 ± 9; 21
females and 11 males
- 13 CJD patients; age (years): Clinical cohort:
68 ± 14; 8 females and - AD patients: 315–499
5 males - AD patients with high T-Tau: - Increases in AD
- 11 non-AD individuals; age 716–1148 patients and with
(years): 68 ± 6; 7 females - CJD patients: 703–1373 other NDs
Ng and 4 males - non-AD patients: 319–699 - Closely associated
- 30 controls; age (years): 65 ± - Controls: 193–306 with T-Tau and P-Tau [50]
(pg/mL)
12; 10 females and 20 males Cohort confirmed by autopsy: 181 in slowly
Cohort autopsy-confirmed: n = 147 progressive dementia,
- AD patients: 249–470
but not in CJD
- 50 AD patients; age (years): - non-AD patients: 137–416
76 ± 9; 22 females and 28 - Controls: 193–370
males; 34% APOE ε4 carriers
- 47 non-AD individuals; age
(years): 67 ± 11; 15 females
and 32 males; 26% APOE ε4
carriers
- 50 controls; age (years): 60 ±
6; 32 females and 18 males;
34% APOE ε4 carriers
n = 63
- 32 AD patients; mean age - Indicates the
(years): 74.37 ± 6.64; 21 presence of cognitive
NSE - AD patients: 18.12
females and 11 males impairment [51]
(ng/mL) - Controls: 8.46
- 32 controls; mean age (years): - Direct correlation
50.75 ± 16.50; 14 females and with T-Tau and P-Tau
18 males
Int. J. Mol. Sci. 2024, 25, 6951 9 of 28
Table 1. Cont.

Clinical cohort: n = 85
60–69; 7 females and 8 males
- 11 bvFTD patients; age
(years): 60–67; 2 females and
9 males - AD patients: 700.0–1317.1
- 4 CBS patients; age (years): - bvFTD patients: 476.9–3714.2
57–66; 1 female and 3 males - CBS patients: 1071.5–2698.5
- 19 DLB patients; age (years): - DLB patients: 703.3–1099.9
61–70; 5 females and - HD patients: 2108.8–3218.4
Nfl Indicates non-AD-specific
14 males - Multiple sclerosis patients: [57]
(pg/mL) axonal damage
- 10 HD patients; age (years): 523.3–932.3
44–60; 3 females and 7 males - Semantic dementia patients:
- 10 multiple sclerosis patients; 1046.9–2039.4
age (years): 49–61; 6 females - Controls: 417.9–735.6
and 4 males
- 6 semantic dementia patients;
age (years): 56–68; 1 female
and 5 males
- 10 controls; age (years):
n = 234
- 73 AD patients; mean age
and 26 males
- 18 FTD patients; mean age
and 9 males - Positive correlation
- AD patients: 119–220
- 26 PD patients; mean age with T-Tau and
- FTD patients: 81–134
(years): 70 ± 8; 11 females negative correlation
VILIP-1 - PD patients: 62–166
and 15 males with Aβ42 [59]
(pg/mL) - ALS patients: 64–141
- 20 ALS patients; mean age - High in AD patients
- CJD patients: 326–1173
(years): 64 ± 13; 8 females compared to controls
- Controls: 72–119
and 12 males - High in CJD patients
- 22 CJD patients; mean age
and 8 males
- 75 controls; mean age (years):
30 males
n = 295
(years): 75.4 ± 0.9; 41%
females and 59% males; 71% - Reports brain
APOE ε4 carriers atrophy in patients
- 139 MCI patients; mean age - AD patients: 0.58 ± 0.03
HFABP with low Aβ42 levels
(years): 75.1 ± 0.7; 33% - MCI patients: 0.54 ± 0.02 [65]
(ng/mL) - Associated with
females and 67% males; 54% - Controls: 0.38 ± 0.03
neuronal lipid
APOE ε4 carriers deregulation
76.0 ± 0.6; 51% females and
49% males; 24% APOE ε4
carriers
Int. J. Mol. Sci. 2024, 25, 6951 10 of 28
Table 1. Cont.

n = 429
- 206 SCD patients; mean age
(years): 61.0 ± 8.8; 42%
females and 58% males; 42% - SCD patients: 3.4 ± 1.6 High levels in patients
ApoA-1
APOE ε4 carriers - MCI patients: 3.6 ± 1.9 with cognitive decline and [68]
(mg/L)
- 223 MCI patients; mean age APOE ε4 carriers
(years): 67.1 ± 8.2; 42%
females and 58% males; 58%
APOE ε4 carriers
n = 93
- 39 CN Aβ- subjects; mean age
- CN Aβ-
(years): 72.8 ± 5.06; 29 females - Abundant in the CSF
subjects: 4780 ± 2220
and 19 males of AD patients
GAP-43 - 33 CN Aβ+ subjects; mean - CN Aβ+ subjects:
- Predicts rapid [74]
(pg/mL) age (years): 76.6 ± 6.36; 5570 ± 3820
accumulation of
23 females and 10 males - MCI patients or with Aβ+
Aβ-related tau
- 21 MCI patients or with Aβ+ dementia: 5560 ± 3070
dementia; mean age (years): 77.9
± 7.06; 13 females and 8 males
n = 109
(years): 73.6 ± 5.6; 7 females
and 4 males; 72.7% APOE ε4
carriers - AD: patients 467.1 Discriminates MCI patients
YKL-40 - 63 MCI patients; mean age - MCI patients: 374.2 from AD patients and
[78]
(ng/mL) (years): 73.8 ± 6.4; 18 - Controls: 335.0 predicts the conversion of
females and 45 males; 54% MCI to AD
APOE ε4 carriers
75.9 ± 5.2; 20 females and
15 males; 22.9%
APOE ε4 carriers
Initial cohort: n = 178
- 37 AD patients; 56–84;
16 females and 21 males
- 62 patients with another Initial cohort:
neurodegeneration; age
- AD patients: 452.6 ± 176.2
(years): 40–89; 34 females
- Patients with another
and 28 males
neurodegeneration:
- 59 neurocontrol patients; age
316.1 ± 270.6
- Neurocontrol
and 26 males
patients: 308.4 ± 267.9
- 20 healthy controls; age
- Healthy controls:
(years): 23–77; 9 females and
212.6 ± 70.1
PSD-95 11 males Identifies the presence of
Validation cohort: [81]
(pg/mL) Validation cohort: n = 165 synaptic neuronal damage
- 105 AD patients; age (years): - AD patients: 279.1 ± 137.9
51–89; 45 females and 60 males - Patients with another
- 6 patients with another neurodegeneration:
neurodegeneration; age 129 ± 53.2
(years): 46–79; 2 females and - Neurocontrol patients:
4 males 109.6 ± 37.3
- 33 neurocontrol patients; age - Healthy controls:
(years): 25–84; 18 females 130.3 ± 67.7
and 15 males
and 11 males
Int. J. Mol. Sci. 2024, 25, 6951 11 of 28
Table 1. Cont.

Initial cohort: n = 178
- 37 AD patients; 56–84;
- 62 patients with another
neurodegeneration; age
(years): 40–89; 34 females Initial cohort:
and 28 males - AD patients: 113.9 ± 30.3
- 59 neurocontrol patients; age - Patients with another
(years): 20–85; 33 females neurodegeneration:
and 26 males 71.3 ± 24.1
- 20 healthy controls; age - Neurocontrol patients: - Increases in AD
(years): 23–77; 9 females and 91.0 ± 53.0 patients compared to
11 males - Healthy controls: 83.2 ± 21.2 other
SNAP-25
Validation cohort: n = 165 Validation cohort: neurodegenerations [81]
(pg/mL)
- 105 AD patients; age (years): - AD patients: 163.4 ± 61.6 - AD-specific
51–89; 45 females and - Patients with another biomarker potential
60 males neurodegeneration:
- 6 patients with another 78.8 ± 29.5
neurodegeneration; age - Neurocontrol patients:
(years): 46–79; 2 females and 88.3 ± 28.7
4 males - Healthy controls: 96.9 ± 36.1
- 33 neurocontrol patients; age
and 15 males
and 11 males
n = 162
(years): 69.4 ± 7.9; 33
APOE ε4 carriers
- 20 MCI-AD patients; mean
age (years): 70.2 ± 8.0;
12 females and 8 males; - AD patients: 364.7 ± 149.2
- MCI-AD patients:
38.9% APOE ε4 carriers
- 31 patients with other MCI; 342.6 ± 161.5
NRG1 mean age (years): 61.5 ± 9.6; - Patients with other MCI: Increases in AD patients
304.9 ± 113.0 [88]
(pg/mL) 11 females and 20 males; and with other NDs
30.8% APOE ε4 carriers - Patients with other
- 30 patients with other dementias: 287.5 ± 106.5
dementias; mean age (years): - Controls: 267.7 ± 104.2
68.7 ± 7.6; 11 females and
20 males; 46.4% APOE ε4
carriers
62.0 ± 11.3; 23 females and
carriers
Aβ42 : beta-amyloid 42; P-Tau: phosphorylated tau; Ng: neurogranin; NSE: neuron-specific enolase; Nfl: neurofila-
ment light chain; VILIP-1: visinin-like protein 1; HFABP: heart fatty acid binding protein; ApoA-1: apolipoprotein
A1; GAP-43: growth-associated protein 43; YKL-40: chitinase 3-like protein 1 or human cartilage glycoprotein
39; PSD-95: postsynaptic density protein 95; SNAP-25: synaptosomal-associated protein 25; NRG1: neuregulin
1; CN: cognitively normal; AD: Alzheimer’s disease; DLB: dementia with Lewy Bodies; FTD: frontotemporal
dementia; VaD: vascular dementia; OND: other neurodegenerative disorders; CU Aβ+: cognitively normal
beta-amyloid positive; MCI Aβ-: mild cognitive impairment beta-amyloid negative; MCI Aβ+: mild cognitive
impairment beta-amyloid positive; CU Aβ-: cognitively normal beta-amyloid negative; CJD: Creutzfeldt–Jakob
disease; bvFTD: behavioral variant of frontotemporal dementia; CBS: corticobasal syndrome; HD: Huntington’s
disease; PD: Parkinson’s disease; ALS: amyotrophic lateral sclerosis; SCD: cognitive decline.
Int. J. Mol. Sci. 2024, 25, 6951 12 of 28
3.2. Plasma Biomarkers in AD

Although the diagnostic relevance of Aβ40 and Aβ42 in the CSF of AD patients has
been documented, their presence at the plasma level would not appear as useful for diagnos-
ing AD [89]. However, Nakamura et al. reported in Nature that APP/Aβ42 and Aβ40 /Aβ42
ratios, detected in plasma through immunoprecipitation coupled to mass spectrometry,
can predict amyloid accumulation in the brain, suggesting the diagnostic importance of
these biomarkers in the AD pathogenesis [90]. In agreement, Cai and colleagues monitored
the plasma concentration of Aβ42 in control subjects and in patients with preclinical AD,
finding a slight reduction between the two cohorts. Importantly, plasma levels of the
protein were significantly reduced in AD patients at follow-up, confirming Aβ42 ’s ability
to predict the AD development 8 to 10 years before disease onset [91].
Regarding the role of tau in blood, Moscoso and colleagues reported that the presence
of P-Tau in the plasma of AD patients is closely associated with Aβ deposition, neurodegen-
eration, cognitive decline, and disease progression [92]. Interestingly, plasma brain-derived
tau (BD-Tau) level, rather than T-Tau, has been suggested to represent an AD-specific
neurodegenerative biomarker associated with clinical disease severity, as demonstrated by
the strong association between BD-Tau concentrations in plasma and CSF [93]. The high
sensitivity of P-Tau, and particularly the phosphorylated form at residue 181, has also been
documented by other authors, to the point of being considered an easy biomarker capa-
ble of predicting pathologies characterized by tau and Aβ accumulation, discriminating
between AD and other NDs, as well as identifying AD in the clinical continuum [94,95].
Particularly, Janelizde and colleagues investigated the role of P-Tau181 in the plasma of
AD patients, MCI patients, non-AD patients, and cognitively normal subjects, concluding
that high plasma P-Tau181 can discriminate AD from other NDs. Therefore, the authors
suggested a role for P-Tau181 as a non-invasive diagnostic and prognostic biomarker of
AD [96]. In addition, Milà-Alomà et al. highlighted the prognostic importance of P-Tau231
and P-Tau217 being able to detect early brain changes associated with the presence of Aβ
before the appearance of clinical signs of AD [97].
To test the utility of plasma Ng, De Vos and colleagues measured, by enzyme-linked
immunosorbent assay (ELISA), the C-terminal portion of Ng in paired CSF and plasma
samples of 29 controls compared to 29 MCI patients or those with dementia due to AD.
Although the presence of Ng in the CSF confirmed its diagnostic power, as the increased
concentration correlated positively with Tau levels, no differences were found at the plasma
level between controls and AD patients, suggesting the unreliability of plasmatic Ng for
diagnosing AD [98,99].
In 2023, Chatterjee et al. evaluated the presence of plasma AD biomarkers in corre-
lation to PET positivity for Aβ, investigating, in a transversal manner, the variations in
Aβ1–42 /Aβ1–40 , P-Tau181, glial fibrillary acidic protein (GFAP), and Nfl along the contin-
uum of AD [100]. The authors found that Aβ-PET-positive patients with cognitive decline
were characterized, compared to Aβ-PET-negative patients, by a lower Aβ42 /Aβ40 ratio,
an elevated P-Tau181 concentration, as well as increased Nfl levels. It is noteworthy that
plasma Nfl levels were elevated in AD patients and patients with prodromal AD but not
in those with preclinical AD, highlighting the prognostic potential of Nfl to predict AD
progression [100]. This evidence agrees with what was previously shown by Baiardi et al.,
who analyzed the presence of biomarkers in plasma and CSF samples from patients with
AD and other NDs. In addition to confirming the high diagnostic value of P-Tau181, the
authors found that Nfl was more highly represented in the body fluids of ND patients
compared to healthy controls, suggesting the ability of this biomarker to signal neuronal
damage not specific to AD [101]. Importantly, although Cai and colleagues reported that
increased plasma Nfl predicts the development of AD 8 to 10 years before the disease, it is
unclear whether or not this biomarker is specific for AD [91].
Int. J. Mol. Sci. 2024, 25, 6951 13 of 28
A detailed investigation into the emerging AD marker role of serum VILIP-1 was
conducted by Halbgebauer et al., who analyzed paired CSF and serum samples from
patients with AD or other NDs. The concentration of VILIP-1 in CSF and serum was higher
in AD patients than in controls, although higher concentrations were found in the fluids of
CJD patients, suggesting a useful role of VILIP-1 in the differential diagnosis of AD [59].
Similar results were obtained by Steinacker and colleagues studying the potential of
HFABP in the differential diagnosis of NDs [102]. The authors measured the concentration
of this biomarker in the CSF and plasma of AD patients, CJD patients, DLB patients, and
controls, finding increased levels in all groups with NDs compared to healthy controls.
Interestingly, HFABP was more represented in the CSF of CJD patients and in the serum of
DLB patients, suggesting the usefulness of this biomarker in the differential diagnosis of
neurodegenerative disorders [102].
In agreement with observations conducted by analyzing CSF, reduced levels of ApoA-
1 were also found in the plasma of AD patients compared to controls. It is noteworthy that
such reduction appears to be associated with a greater risk of clinical progression to MCI
and AD, probably because ApoA-1 appears to play a neuroprotective role on neurons by
counteracting Aβ-induced neurodegeneration [68,103,104]. However, Slot et al. observed
that the risk of clinical progression in subjects carrying APOE ε4 is associated with elevated
levels of ApoA-1 in CSF but reduced levels in plasma, suggesting the need to clarify the
role of ApoA-1 in the development of AD [68].
An important result was provided by Jia and colleagues, who investigated the presence
of synaptic proteins in the CSF and in neuronal-derived exosomes isolated in the blood of
AD patients, MCI patients, and healthy subjects. Interestingly, GAP-43, Ng, and SNAP-25
were increased in CSF and decreased in exosomes isolated from the blood of AD and MCI
patients, suggesting a role for such exosomal biomarkers in distinguishing AD from MCI
patients and in predicting AD 5 to 7 years before cognitive deterioration [99].
Choi et al. reported the importance of YKL-40 in plasma as a biomarker of AD
and analyzed its levels in samples taken from AD patients, MCI patients, and control
subjects [105]. A significant increase in the plasma concentration of YKL-40 was observed
in patients with early AD, compared to the other experimental groups, suggesting the
ability of this marker to highlight the severity of AD. Interestingly, plasma YKL-40 levels in
patients with mild AD, but not in those with moderate or severe AD, correlated positively
with cognitive assessment test results, highlighting its potential to signal the onset of
cognitive symptoms of AD [105].
Regarding the role of NRG1 as a plasma biomarker of AD, Chang et al. found a
higher concentration in samples taken from AD patients than in healthy individuals. It is
noteworthy that AD patients were stratified into mild and moderate AD groups based on
mini-mental status exam (MMSE) scores. A significant relationship was found between
NRG1 levels and disease severity, as plasma concentrations of this biomarker were higher
in the group with lower MMSE scores [106]. In agreement, Vrillon and colleagues reported
the existence of a close association between increased plasma levels of NRG1, cognitive
decline, and synaptic dysfunction, suggesting its role as a potential non-invasive biomarker
for monitoring neuronal damage in AD [107].
Overall, this evidence suggests a salient role of plasma biomarkers in signaling neu-
ronal damage associated with cognitive decline. Furthermore, investigating AD character-
istics, in terms of disease severity and evolution, by means of a blood sample offers
the possibility of acquiring relevant information on AD patients in a rapid and non-
invasive manner. Importantly, plasma-level concentrations of fluid biomarkers could
reflect the effect of a management course, highlighting the usefulness or ineffectiveness of
a particular treatment.
Table 2 summarizes the main scientific evidence on the levels of biomarkers dis-cussed
in the text in the plasma of AD patients or patients with other NDs.
Int. J. Mol. Sci. 2024, 25, 6951 14 of 28
Table 2. A schematic representation of the main evidence on AD biomarkers in plasma.

n = 249
Baseline:
- 123 controls; mean age
(years): 60.0 ± 7.1;
62 females and 61 males;
17.9% APOE ε4 carriers Baseline:
- 126 pre-AD patients; mean - Controls: 16.69 ± 3.84
age (years): 59.0 ± 6.3; - Aβ42 reduction
- Pre-AD patients: predicts the
63 females and 63 males; 14.43 ± 3.96
Aβ42 development of AD 8
41.3% APOE ε4 carriers [91]
(pg/mL) Follow-up: to 10 years before
Follow-up
- Controls: 15.33 ± 3.25 disease onset
- AD patients: 9.59 ± 2.53
(years): 70.0 ± 7.1;
(years): 69.0 ± 6.3;
- Strong association
n = 397 P-Tau231 with Aβ positivity
- 262 Aβ− subjects; mean age - Aβ− subjects: 9.62 ± 4.33 detected by PET
P-Tau231 (years): 60.6 ± 4.45; - Aβ+ subjects: 15.0 ± 7.49 - P-Tau231 and
(pg/mL) 162 females and 100 males; P-Tau217 detect early
P-Tau181
P-Tau181 42.4% APOE ε4 carriers brain changes
- Aβ− subjects: 8.83 ± 3.21 [97]
(pg/mL) - 135 Aβ+ subjects; mean age associated with the
- Aβ+ subjects: 11.0 ± 4.60
P-Tau217 (years): 62.2 ± 4.91; presence of Aβ before
(pg/mL) 81 females and 54 males; P-Tau217
- Aβ− subjects: 0.13 ± 0.055 the clinical
76.3% APOE ε4 carriers manifestations of the
- Aβ+ subjects: 0.18 ± 0.086
disease
n = 298
Discovery cohort:
and 12 males; 39.2% APOE
ε4 carriers
- 25 MCI patients; mean age
ε4 carriers Discovery cohort:
- 29 controls; mean age (years): - AD patients: 250 ± 67
63 ± 5; 15 females and - MCI patients: 1567 ± 445
14 males; 17.2% APOE ε4 - Controls: 2010 ± 530 Reduction in exosomes
Ng
carriers Validation cohort: isolated from the blood of [99]
(pg/mL)
Validation cohort: - AD patients: 254 ± 69 AD and MCI patients
- 73 AD patients; mean age - MCI patients: 1511 ± 390
(years): 65 ± 6; 42 females - Controls: 2099 ± 540
ε4 carriers
ε4 carriers
carriers
Int. J. Mol. Sci. 2024, 25, 6951 15 of 28
Table 2. Cont.

n = 249
Baseline:
(years): 60.0 ± 7.1;
- 126 pre-AD patients; mean Baseline:
- Controls: 10.71 ± 3.88
age (years): 59.0 ± 6.3; - Increased Nfl predicts
- Pre-AD patients:
63 females and 63 males; the development of
Nfl 41.3% APOE ε4 carriers 13.24 ± 5.00
AD 8 to 10 years [91]
(pg/mL) - Follow-up:
Follow-up before disease onset
- Controls: 11.90 ± 3.58
- AD patients: 16.17 ± 4.70
(years): 70.0 ± 7.1;
(years): 69.0 ± 6.3;
n = 234
and 26 males
- 18 FTD patients; mean age
and 9 males - AD patients: 24–36
- 26 PD patients; mean age - FTD patients: 21–42
(years): 70 ± 8; 11 females - High in AD patients
VILIP-1 - PD patients: 18–32
and 15 males compared to controls [59]
(pg/mL) - ALS patients: 20–46
- 20 ALS patients; mean age - High in CJD patients
- CJD patients: 52–142
(years): 64 ± 13; 8 females - Controls: 18–31
and 12 males
- 22 CJD patients; mean age
and 8 males
30 males
n = 64
47–85; 13 females and 5 males - AD patients: 581–9029
- 14 CJD patients; age (years): - CJD patients: 1836–25,000
HFABP Increases in all NDs,
57–78; 8 females and 6 males - DLB patients: 1292–25,000 [102]
(pg/mL) especially in DLB patients
- 16 DLB patients; age (years): - Controls: 445–3543
- 16 controls; age (years):
Int. J. Mol. Sci. 2024, 25, 6951 16 of 28
Table 2. Cont.

n = 429
- 206 SCD patients; mean age
(years): 61.0 ± 8.8; 42% - Low levels in patients
females and 58% males; 42% - SCD patients: 1.4 ± 0.4 with cognitive
ApoA-1
APOE ε4 carriers - MCI patients: 1.3 ± 0.3 decline and APOE ε4 [68]
(g/L)
- 223 MCI patients; mean age carriers
(years): 67.1 ± 8.2; 42%
females and 58% males; 58%
APOE ε4 carriers
n = 298
Discovery cohort:
ε4 carriers
GAP-43 carriers Validation cohort: isolated from the blood of [99]
(pg/mL)
ε4 carriers
ε4 carriers
64 ± 5; 37 females and 35
males; 19.4% APOE ε4
carriers
n = 145
- 41 mild AD patients; mean
age (years): 75.04 ± 0.91;
- 20 moderate/severe AD - Mild AD patients: - Increases in patients
patients; mean age (years): 407.81 ± 73.25 with early AD
YKL-40 74.55 ± 1.56; 16 females and - Moderate/severe AD - Positive correlation
patients: 313.43 ± 68.72 with cognitive [105]
(ng/mL) 4 males
- 49 MCI patients; mean age - MCI patients: 176.49 ± 25.68 function in patients
(years): 68 ± 1.00; 30 females - Controls: 96.91 ± 11.02 with mild AD
and 19 males
63.88 ± 0.96; 22 females and
13 males
Int. J. Mol. Sci. 2024, 25, 6951 17 of 28
Table 2. Cont.

n = 298
Discovery cohort:
ε4 carriers
- 25 MCI patients mean age
SNAP-25
carriers Validation cohort: isolated from the blood of [99]
(pg/mL)
ε4 carriers
ε4 carriers
64 ± 5; 37 females and 35
males; 19.4% APOE ε4
carriers
n = 127
- 20 neurological controls;
mean age (years): 60.6 ± 9.6;
14 females and 6 males - Neurological controls:
- 19 non-AD MCI patients; 378.9 ± 400.7
61.1 ± 8.4; 12 females and - non-AD MCI patients:
- High concentration in
7 males 488.4 ± 392.2
AD patients
NRG1 - 25 AD-MCI patients; - AD-MCI patients:
correlates with [107]
(pg/mL) 70.3 ± 5.8; 17 females and 707.6 ± 562.7
cognitive decline and
8 males - AD dementia patients:
synaptic damage
- 37 AD dementia patients; 940.3 ± 737.5
67.7 ± 7.9; 23 females and - non-AD dementia patients:
14 males 615.5 ± 486.3
- 26 non-AD dementia
patients; 68.1 ± 7.0;
Aβ42 : beta-amyloid 42; P-Tau: phosphorylated tau; Ng: neurogranin; Nfl: neurofilament light chain; VILIP-
1: visinin-like protein 1; HFABP: heart fatty acid binding protein; ApoA-1: apolipoprotein A1; GAP-43:
growth-associated protein 43; YKL-40: chitinase 3-like protein 1 or human cartilage glycoprotein 39; SNAP-
25: synaptosomal-associated protein 25; NRG1: neuregulin 1; AD: Alzheimer’s disease; PET: positron emis-
sion tomography; MCI: mild cognitive impairment; FTD: frontotemporal dementia; PD: Parkinson’s disease;
ALS: amyotrophic lateral sclerosis; CJD: Creutzfeldt–Jakob disease; DLB: dementia with Lewy Bodies; SCD:
cognitive decline.
4. Exercise in AD to Counteract Neurodegeneration

Exercise is a recommended non-pharmacological strategy for AD patients, but the effects
of such an intervention on fluid biomarker concentrations are poorly supported. For this
reason, we report below the main evidence in which the role of exercise in modulating AD fluid
biomarker concentrations has been documented.
Int. J. Mol. Sci. 2024, 25, 6951 18 of 28
Several pieces of evidence have shown the benefits of exercise in AD patients, particularly
on cognitive function and physical performance, facilitating the performance of activities of
daily living [108–110]. From a molecular perspective, exercise can counteract AD progression by
regulating processes such as neuronal apoptosis, intercellular communication, oxidative stress,
mitochondrial autophagy, synaptic plasticity, and neurotoxicity [111]. The multiple benefits of
exercise on the CNS make it an ideal strategy to prevent and/or counteract the cognitive decline
and neurodegeneration that characterize NDs. However, current evidence points to the need
for further studies both to determine the efficacy of exercise in modulating the expression of
neurodegeneration biomarkers and to establish which type and exercise programs are most
effective for the well-being of AD patients. Indeed, in 2017, Jensen and colleagues published
the results of a randomized controlled trial (RCT) aimed at assessing the effects of exercise
on biomarkers of neuronal and synaptic integrity [112]. In this trial, 51 AD patients were
randomized into two groups, one undergoing 16 weeks of moderate-to-high aerobic exercise
and one undergoing usual care as a control group. Before and after the intervention, CSF was
taken to analyze the levels of Nfl, Ng, VILIP-1, and YKL-40 to compare the mean change from
baseline between the exercise and control groups. The authors found no significant differences
in the concentrations of the investigated biomarkers, concluding that moderate or high-intensity
exercise does not modulate the concentration of neuronal integrity biomarkers in the CSF of
AD patients [112]. However, in 2018, Law et al. examined the relationship between physical
activity levels and the concentration of Aβ42 and tau in CSF in asymptomatic middle-aged
adults at risk for AD [113]. In this study, 85 cognitively healthy middle-aged adults wore an
accelerometer for one week to measure daily physical activity level and underwent lumbar
puncture for CSF sampling. Neither light nor vigorous physical activity produced relevant
changes in the concentration of Aβ42 and Tau. However, moderate-intensity physical activity
promoted marked changes in the investigated biomarkers, as it was associated with increased
levels of Aβ42 and a reduced ratio of both T-Tau/Aβ42 and P-Tau/Aβ42, indicating a favorable
AD biomarker profile [113]. On the other hand, Sewell et al. studied the effects of 6 months of
moderate- or high-intensity exercise in 99 cognitively normal older adults to assess possible
changes in plasma levels of potential AD biomarkers, including Aβ42, P-Tau181, and Nfl.
The authors observed no significant changes in the plasma levels of the biomarkers analyzed,
suggesting the need for studies with longer follow-up periods to highlight any exercise-induced
effects [114]. In contrast, Hou et al. evaluated the self-reported lifestyle of 1108 cognitively
normal adults, of whom 161 were APOE ε4 carriers, and found an association between the daily
practice of moderate-intensity physical activity and a significant reduction in P-Tau181 in the
CSF [115]. In agreement, Yu and colleagues conducted a randomized trial of 26 older adults who
were APOE ε4 carriers with mild-to-moderate AD dementia. Of these, 18 performed cycling
exercises on a recumbent stationary cycle at moderate intensity 3 days/week for 6 months, while
the other 8 older adults performed low-intensity stretching exercises for the same period. The
authors observed a reduction in plasma P-Tau181 levels in the cycling group only, confirming
the effectiveness of moderate-intensity aerobic exercise in counteracting P-Tau181 accumulation
in AD [116].
Noteworthily, Di Battista et al. subjected eleven healthy, active men to interval and high-
intensity training on a cycle ergometer three times a week for 2 weeks, for a total of six training
sessions [117]. Blood samples were collected before and after the intervention to assess the
change in the concentration of plasma biomarkers, including Ng, NSE, T-Tau, VILIP-1, and
brain-derived neurotrophic factor (BDNF). An increase in the plasma concentration of NSE,
Ng, and BDNF was detected both after the first training session and after the last, highlighting
the ability of exercise to influence their expression. Interestingly, T-Tau increased after the first
training session, whereas no significant changes were found between the pre-and post-exercise
phase of the last session [117].
Contrasting results were obtained by de Farias and colleagues by studying exercise-
induced serum NSE changes in AD patients [118]. Specifically, 15 women diagnosed with AD
underwent 22 physical/functional training sessions, including coordination, agility, balance,
strength, and endurance activities, lasting 60 min per session, twice a week. In addition to im-
Int. J. Mol. Sci. 2024, 25, 6951 19 of 28
proved judgment, problem-solving, and memory, the exercise programs significantly reduced
serum NSE levels, demonstrating the efficacy of exercise in counteracting neurodegeneration
and cognitive decline in AD [118]. Overall, although Olsson et al.’s meta-analysis found no
significant plasma changes in NSE in AD patients, the studies by Di Battista and de Farias
showed exercise-induced modulation, highlighting the need for further clarification.
The extraordinary power of exercise to regulate the expression of biomarkers of neuronal
damage was confirmed by Desai et al. and Casaletto et al., who investigated the association
between physical activity levels, Nfl concentrations, and cognitive decline in elderly subjects
and subjects with frontotemporal lobar degeneration, respectively. Both studies reported that
serum Nfl concentration was strongly influenced by physical activity, being lower in more
active subjects. Furthermore, more active individuals were characterized by slower cognitive
decline, demonstrating that greater physical activity leads to slower axonal degeneration [119,
120]. However, these results are in contrast to more recent findings by Sewell et al., who found
no exercise-induced modulation in plasma Nfl levels [114].
As suggested by Stojanovic and colleagues, a potential moderating factor of the effects of
exercise in AD patients could be cardiovascular risk [121]. To test this hypothesis, the authors
compared the levels of Ng, VILIP-1, SNAP-25, and Nfl in the CSF of clinically healthy subjects
enrolled at the Knight Alzheimer Disease Research Center at Washington University with the
aim of identifying and validating AD biomarkers. The study’s results claimed that neither Nfl
nor SNAP-25 was modulated by exercise, while VILIP-1 and Ng were lower in subjects who
engaged in exercise programs [121].
Finally, Yang et al. evaluated the effect of moderate-intensity aerobic exercise on elderly
people with mild AD, dividing five volunteers with mild cognitive impairment into two
groups: an aerobic exercise group subjected to cycling training at 70% of maximum intensity
for 40 min a day, 3 days a week, for 3 months, and a control group. In addition to a marked
cognitive improvement, a significant increase in Apo-A1 in the plasma of subjects in the
aerobic exercise group after 3 months of intervention was detected, demonstrating the ability
of this form of training to modulate the expression of this AD biomarker [122].
Unfortunately, evidence regarding the effects of exercise on the regulation of fluid
biomarkers is still rather limited, suggesting the need for high-quality studies to confirm the
efficacy of exercise in AD patients as well as the real diagnostic and/or prognostic power of
fluid biomarkers.
Table 3 summarizes the main scientific evidence on the modulatory effects of exercise
on biomarker levels in the CSF and plasma of patients with AD or other NDs.
Table 3. A schematic representation of the main evidence for the influence of exercise on fluid
biomarker levels.
Biomarker Study Population Exercise Protocol CSF Plasma References

- Subjects wore an accelerometer
for a week
n = 85 cognitively normal adults; High Aβ42 levels have
- The data collected were
mean age (years): 64.31 ± 5.44; been associated with
processed to calculate the time / [113]
52 females and 33 males; 42.4% moderate-intensity
spent in light-, moderate-, or
APOE ε4 carriers physical activity
vigorous-intensity physical
activity
n = 99 cognitively unimpaired
older adults - Control group: 2-h information
- 32 control group: mean session on the benefits of
age (years): 68.7 ± 5.9; exercise
Aβ42
19 females and 13 males; - Moderate-intensity group:
28.1% APOE ε4 carriers cycling at constant intensity for
- 34 moderate intensity 50 min (50–60% aerobic
group: mean age (years): capacity; 13.0 Borg Scale) No exercise-induced
- High-intensity group: 10 min / [114]
68.4 ± 4.2; 18 females and modulation
16 males; 23.5% APOE ε4 warm-up, 11 1 min intervals of
carriers intense exercise cycling at 18.0
- 33 high intensity group: Borg Scale, 80% aerobic
mean age (years): capacity, interspersed with
70.2 ± 5.3; 17 females and 2 min of active recovery, and a
16 males; 27.3% APOE ε4 9 min cool-down
carriers
Int. J. Mol. Sci. 2024, 25, 6951 20 of 28
Table 3. Cont.

Moderate daily physical
n = 1108 cognitively normal Of the total, 275 individuals
activity is associated
adults; mean age (years): self-reported via questionnaire that
with a significant / [115]
61.1 ± 11.0; 461 females and 647 they practice regular physical activity
reduction in P-Tau181
males; 161 APOE ε4 carriers at moderate intensity every day
levels
n = 26 older adults with
- Cycling group: cycling on
mild-to-moderate AD dementia
P-Tau181 recumbent stationary cycles for
- 18 cycling group; mean 20–50 min at moderate intensity
age (years): 76.8 ± 7.6; 6 months of cycling
(50–75% of HRR), 3 days/week slows down the plasma
7 females and 11 males; for 6 months / increase in P-Tau181 [116]
100% APOE ε4 carriers - Stretching group: seated compared to the
- 8 stretching group; mean movements and low-intensity stretching group
age (years): 79.3 ± 5.5; static stretching (<20% of HRR),
2 females and 6 males; 3 days/week for 6 months
100% APOE ε4 carriers
n = 51 AD patients
- 26 control group: mean
age (years): 68.9 ± 8.05; Aerobic exercise on treadmill,
No modulation induced
7 females and 19 males stationary bike, and cross-trainer for
by moderate-to-high / [112]
- 25 intervention group; 60 min/day, 3 days/week for 16
aerobic exercise
mean age (years): weeks, with moderate to high intensity
Ng 68.2 ± 6.94; 12 females and
13 males
HIIT on a bicycle ergometer (8–12 × 60
n = 11 physically active adults; Significant increase in
sec intervals at 100% of peak power
mean age (years): 28.8 ± 5.3; / plasma Ng levels after a [117]
output, interspersed by 75 sec recovery
11 males single HIIT session
at 50 W) for 3 days/week for 2 weeks
HIIT on a bicycle ergometer (8–12 × 60
n = 11 physically active adults; Significant increase in
sec intervals at 100% of peak power
mean age (years): 28.8 ± 5.3; / plasma NSE levels after [117]
output, interspersed by 75 sec recovery
11 males a single HIIT session
at 50 W) for 3 days/week for 2 weeks
NSE 22 training sessions (coordination,
agility, balance, strength, and Exercise decreased
n = 15 AD patients, mean age endurance activities), 60 min a day, plasma levels of NSE,
/ [118]
(years): 68.3 ± 13.8; 15 females 2 days a week, with a target effort reversing neuronal
intensity of 40–60% of the target heart damage
rate
n = 51 AD patients
Aerobic exercise on treadmill,
age (years): 68.9 ± 8.05;
stationary bike, and cross-trainer for No modulation induced
60 min/day, 3 days/week for 16 by moderate-to-high / [112]
- 25 intervention group;
weeks, with moderate-to-high aerobic exercise
mean age (years):
intensity
68.2 ± 6.94; 12 females and
13 males
- Self-reported measure of
physical activity by PASE over
the last 7 days
n = 160 individuals with Strong association
- Assessment of the weekly
autosomal dominant variants for between higher reported
frequency and daily duration of
FTLD; mean age (years): / physical activity and [120]
the following recreational
50.7 ± 14.7; 84 females and reduced plasma Nfl
activities: walking; light,
76 males levels
moderate, and strenuous sports;
housework; gardening work;
Nfl strength training
n = 99 cognitively unimpaired
older adults - Control group: 2-h information
- 32 control group: mean session on the benefits of
age (years): 68.7 ± 5.9; exercise
19 females and 13 males; - Moderate-intensity group:
28.1% APOE ε4 carriers cycling at constant intensity for
- 34 moderate intensity 50 min (50–60% aerobic
group: mean age (years): capacity; 13.0 Borg Scale) No exercise-induced
- High-intensity group: 10 min / [114]
68.4 ± 4.2; 18 females and modulation
16 males; 23.5% APOE ε4 warm-up, 11 1 min intervals of
carriers intense exercise cycling at
- 33 high intensity group: 18.0 Borg Scale, 80% aerobic
mean age (years): capacity, interspersed with
70.2 ± 5.3; 17 females and 2 min of active recovery, and a
16 males; 27.3% APOE ε4 9 min cool-down
carriers
Int. J. Mol. Sci. 2024, 25, 6951 21 of 28
Table 3. Cont.

n = 51 AD patients
- 26 control group: mean Aerobic exercise on treadmill,
age (years): 68.9 ± 8.05; stationary bike, and cross-trainer for No modulation induced
7 females and 19 males 60 min/day, 3 days/week for by moderate-to-high / [112]
- 25 intervention group; 16 weeks, with moderate-to-high aerobic exercise
mean age (years): intensity
VILIP-1
68.2 ± 6.94; 12 females and
13 males
HIIT on a bicycle ergometer (8–12 × 60 No modulation in
n = 11 physically active adults;
sec intervals at 100% of peak power plasma VILIP-1 levels
mean age (years): 28.8 ± 5.3; / [117]
output, interspersed by 75 sec recovery after a single HIIT
11 males
at 50 W) for 3 days/week for 2 weeks session
Aerobic exercise
n = 50 mild AD patients: promoted a significant
- Control group: no intervention, increase in plasma
- 25 control group; mean age health education for 3 months ApoA-1 levels in
(years): 71.92 ± 7.28; - Aerobic group: cycling training association with an
ApoA-1 18 females and 7 males at 70% of maximal intensity for / [122]
improvement in
- 25 aerobic group; mean 40 min/day, 3 day/week for cognitive function,
age (years): 72.00 ± 6.69; 3 months mental state, and quality
15 females and 10 males of life in mild AD
patients
n = 51 AD patients
age (years): 68.9 ± 8.05; Aerobic exercise on treadmill,
No modulation induced
7 females and 19 males stationary bike, and cross-trainer for 60
YKL-40 by moderate-to-high / [112]
- 25 intervention group; min/day, 3 days/week for 16 weeks,
aerobic exercise
mean age (years): with moderate-to-high intensity
68.2 ± 6.94; 12 females and
13 males
Aβ42 : beta-amyloid 42; P-Tau: phosphorylated tau; Ng: neurogranin; NSE: neuron-specific enolase; Nfl: neurofila-
ment light chain; VILIP-1: visinin-like protein 1; ApoA-1: apolipoprotein A1; YKL-40: chitinase 3-like protein 1 or
human cartilage glycoprotein 39; AD: Alzheimer’s disease; HRR: reserve heart rate; HIIT: high-intensity interval
training; FTLD: frontotemporal lobar degeneration; PASE: physical activity scale for the elderly.
5. Conclusions
Based on current knowledge, exercise emerges as the best non-pharmacological
strategy to prevent and/or treat AD, counteracting neurodegeneration and cognitive
decline [123–125]. Indeed, numerous RCTs have been conducted to determine the effects
of exercise in AD patients, and although there is often considerable variability in the re-
sults obtained from the different studies, exercise overall seems to positively influence
both physical and cognitive function [16]. Nevertheless, the full picture of the molecular
mechanisms involved in brain adaptations to exercise in AD patients remains unclear and
difficult to understand due to its complexity. Indeed, exercise is known to promote the
expression of a wide variety of neurotrophic factors that regulate the function and vitality
of neurons by promoting neurogenesis, but numerous other mechanisms are regulated
by exercise [126,127]. Among these, autophagy and mitophagy may be partly responsible
for the beneficial effects of exercise in AD patients, as they may promote Aβ turnover by
limiting its accumulation in the brain [128,129]. Furthermore, the modulatory effects of
exercise are known to include reducing oxidative stress and improving cerebral blood flow,
two phenomena that play a crucial role in the development and progression of AD [130].
It is noteworthy thjat inflammation is also known to be associated with AD and
undergoes exercise-induced regulation with beneficial effects in AD patients. Indeed, pro-
inflammatory factors such as tumor necrosis factor α (TNF-α), caspase-1, and interleukin 1β
(IL-β) have been linked to neurodegeneration in AD and their expression is increased in the
brains of AD and MCI patients [131,132]. Interestingly, a crucial role of neuroinflammation
in AD seems to be played by the conversion of microglia from the M1 phenotype, which is
involved in pro-inflammatory processes and contributes to neurodegeneration, into the
M2 phenotype, which has an anti-inflammatory function [133]. Not surprisingly, studies
in different rodent models have shown that exercise can promote the polarization of mi-
croglia, in favor of the M2 phenotype, and ensure the development of an anti-inflammatory
Int. J. Mol. Sci. 2024, 25, 6951 22 of 28
environment in the hippocampus by inducing the production of anti-inflammatory cy-

tokines [15]. Taken together, all these exercise-regulated processes can establish a favorable
environment for neuronal survival in AD patients and counteract neurodegeneration by
modulating biomarker concentrations in body fluids accordingly. Indeed, the results of
a systematic review with a meta-analysis conducted by Stigger and colleagues in 2019
showed how exercise can significantly reduce serum levels of interleukin-6 (IL-6) and
TNF-α and positively modulate BDNF expression, overall suggesting a beneficial effect on
neuronal viability [134].
Nevertheless, numerous unknowns still make it impossible to determine which form
of exercise produces the best effects in AD patients. Indeed, the complexity of this pathol-
ogy makes it necessary to consider numerous confounding variables when designing a
study on the effects of exercise in AD patients. As suggested by Stojanovic and colleagues
and described above, cardiovascular risk is a potential moderating factor in the effects of
exercise in AD patients [121]. Furthermore, adequate social support from family members
can significantly influence the patient’s psychological well-being and emotional state and
provide the right individual motivation for rigorous exercise programs. Importantly, as sug-
gested by Butt et al., APOE ε4 carriers, although cognitively intact, could be characterized
by selective synaptic damage compared to non-carriers that could affect cognitive abilities
and, consequently, the way such individuals cope with exercise programs [86]. Therefore,
a successful strategy could be the design of individual exercise protocols, appropriately
designed on the basis of the patients’ physical, psychic, emotional, and cognitive needs and
characteristics, to identify the best forms and modes of exercise for a specific individual.
However, the need for further investigation to define the modulatory function of exercise
on biomarkers of neuronal damage is imperative, both to clarify its diagnostic and/or
prognostic role and to determine its efficacy on neuronal and synaptic health.
One of the main limitations found in studies included in this critical review concerns
the size of the study sample. Indeed, the difficulty of recruiting AD patients who meet the
eligibility criteria of the study and who can exercise at a certain intensity and with regular
frequency may result in the study population being narrowed down, with a consequent
increase in effects due to variability. Another limitation found in some studies concerns
the time of administration of the exercise program. Particularly, some studies evaluated
the effects of a 6-month exercise program, which may not be sufficient to modulate the
expression of the neuronal biomarkers addressed in this review. Finally, all the exercise
protocols administered were significantly different from each other, not allowing for a
comparison of the results obtained.
Author Contributions: Conceptualization, R.B. and I.C.; investigation, R.B., I.C., P.C. and C.F.; data
curation, R.B. and I.C.; writing—original draft preparation, R.B. and I.C.; writing—review and editing,
P.C., G.A., V.T. and G.D.; supervision, G.D. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Acknowledgments: The authors acknowledge the Centre of Space Bio-medicine, “Tor Vergata”
University of Rome, for their support. This work was supported by #NEXTGENERATIONEU
(NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and
Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale integrated approach to the
study of the nervous system in health and disease (DN. 1553 11.10.2022).
Conflicts of Interest: The authors declare no conflicts of interest.
Int. J. Mol. Sci. 2024, 25, 6951 23 of 28
References
1. Ding, C.; Wu, Y.; Chen, X.; Chen, Y.; Wu, Z.; Lin, Z.; Kang, D.; Fang, W.; Chen, F. Global, regional, and national burden and
attributable risk factors of neurological disorders: The Global Burden of Disease study 1990–2019. Front. Public Health 2022, 10,
952161. [CrossRef] [PubMed]
2. Chi, H.; Chang, H.-Y.; Sang, T.-K. Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases. Int. J. Mol. Sci. 2018,
19, 3082. [CrossRef] [PubMed]
3. Assogna, M.; Di Lorenzo, F.; Martorana, A.; Koch, G. Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders.
Biomolecules 2022, 12, 1161. [CrossRef] [PubMed]
4. Skaper, S.D.; Facci, L.; Zusso, M.; Giusti, P. Synaptic Plasticity, Dementia and Alzheimer Disease. CNS Neurol. Disord.-Drug Targets
2017, 16, 220–233. [CrossRef] [PubMed]
5. Chu, H.-Y. Synaptic and cellular plasticity in Parkinson’s disease. Acta Pharmacol. Sin. 2020, 41, 447–452. [CrossRef] [PubMed]
6. Ross, C.A.; Poirier, M.A. Protein aggregation and neurodegenerative disease. Nat. Med. 2004, 10, S10–S17. [CrossRef] [PubMed]
7. Gallardo, G.; Holtzman, D.M. Amyloid-β and Tau at the Crossroads of Alzheimer’s Disease. Adv. Exp. Med. Biol. 2019, 1184,
187–203. [CrossRef] [PubMed]
8. Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M.
Alzheimer’s disease. Lancet 2021, 397, 1577–1590. [CrossRef] [PubMed]
9. Prasad, A.; Bharathi, V.; Sivalingam, V.; Girdhar, A.; Patel, B.K. Molecular Mechanisms of TDP-43 Misfolding and Pathology in
Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci. 2019, 12, 25. [CrossRef]
10. Matlahov, I.; van der Wel, P.C. Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s
disease. Exp. Biol. Med. 2019, 244, 1584–1595. [CrossRef]
11. Diociaiuti, M.; Bonanni, R.; Cariati, I.; Frank, C.; D’arcangelo, G. Amyloid Prefibrillar Oligomers: The Surprising Commonalities
in Their Structure and Activity. Int. J. Mol. Sci. 2021, 22, 6435. [CrossRef] [PubMed]
12. Barve, K.H.; Kumar, M.S. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr.
Neuropharmacol. 2020, 18, 1106–1125. [CrossRef]
13. Hansson, O.; Edelmayer, R.M.; Boxer, A.L.; Carrillo, M.C.; Mielke, M.M.; Rabinovici, G.D.; Salloway, S.; Sperling, R.; Zetterberg,
H.; Teunissen, C.E. The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease.
Alzheimer’s Dement. 2022, 18, 2669–2686. [CrossRef] [PubMed]
14. Breijyeh, Z.; Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 2020, 25, 5789.
[CrossRef] [PubMed]
15. Valenzuela, P.L.; Castillo-García, A.; Morales, J.S.; de la Villa, P.; Hampel, H.; Emanuele, E.; Lista, S.; Lucia, A. Exercise benefits on
Alzheimer’s disease: State-of-the-science. Ageing Res. Rev. 2020, 62, 101108. [CrossRef] [PubMed]
16. López-Ortiz, S.; Valenzuela, P.L.; Seisdedos, M.M.; Morales, J.S.; Vega, T.; Castillo-García, A.; Nisticò, R.; Mercuri, N.B.; Lista, S.;
Lucia, A.; et al. Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled
trials. Ageing Res. Rev. 2021, 72, 101479. [CrossRef] [PubMed]
17. Maity, D. Inhibition of Amyloid Protein Aggregation Using Selected Peptidomimetics. ChemMedChem 2023, 18, e202200499.
[CrossRef] [PubMed]
18. Belfiore, M.; Cariati, I.; Matteucci, A.; Gaddini, L.; Macchia, G.; Fioravanti, R.; Frank, C.; Tancredi, V.; D’arcangelo, G.; Diociaiuti, M.
Calcitonin native prefibrillar oligomers but not monomers induce membrane damage that triggers NMDA-mediated Ca2+ -influx,
LTP impairment and neurotoxicity. Sci. Rep. 2019, 9, 5144. [CrossRef] [PubMed]
19. Dorszewska, J.; Prendecki, M.; Oczkowska, A.; Dezor, M.; Kozubski, W. Molecular Basis of Familial and Sporadic Alzheimer’s
Disease. Curr. Alzheimer Res. 2016, 13, 952–963. [CrossRef]
20. Armstrong, R.A. Risk factors for Alzheimer’s disease. Folia Neuropathol. 2019, 57, 87–105. [CrossRef]
21. Lane, C.A.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol. 2017, 25, 59–70. [CrossRef] [PubMed]
22. Bateman, R.J.; Aisen, P.S.; De Strooper, B.; Fox, N.C.; Lemere, C.A.; Ringman, J.M.; Salloway, S.; Sperling, R.A.; Windisch,
M.; Xiong, C. Autosomal-dominant Alzheimer’s disease: A review and proposal for the prevention of Alzheimer’s disease.
Alzheimer’s Res. Ther. 2011, 3, 1. [CrossRef] [PubMed]
23. Querfurth, H.W.; LaFerla, F.M. Alzheimer’s Disease. N. Engl. J. Med. 2010, 362, 329–344. [CrossRef] [PubMed]
24. Tiwari, S.; Atluri, V.; Kaushik, A.; Yndart, A.; Nair, M. Alzheimer’s disease: Pathogenesis, diagnostics, and therapeutics. Int. J.
Nanomed. 2019, 14, 5541–5554. [CrossRef] [PubMed]
25. Gao, Y.; Tan, L.; Yu, J.-T.; Tan, L. Tau in Alzheimer’s Disease: Mechanisms and Therapeutic Strategies. Curr. Alzheimer Res. 2018,
15, 283–300. [CrossRef] [PubMed]
26. Avila, J.; Lucas, J.J.; Pérez, M.; Hernández, F. Role of Tau Protein in Both Physiological and Pathological Conditions. Physiol. Rev.
2004, 84, 361–384. [CrossRef] [PubMed]
27. Naseri, N.N.; Wang, H.; Guo, J.; Sharma, M.; Luo, W. The complexity of tau in Alzheimer’s disease. Neurosci. Lett. 2019, 705,
28. Jouanne, M.; Rault, S.; Voisin-Chiret, A.-S. Tau protein aggregation in Alzheimer’s disease: An attractive target for the develop-
ment of novel therapeutic agents. Eur. J. Med. Chem. 2017, 139, 153–167. [CrossRef]
29. Kumari, S.; Dhapola, R.; Reddy, D.H. Apoptosis in Alzheimer’s disease: Insight into the signaling pathways and therapeutic
avenues. Apoptosis 2023, 28, 943–957. [CrossRef]
Int. J. Mol. Sci. 2024, 25, 6951 24 of 28
30. Zhang, Z.; Yang, X.; Song, Y.-Q.; Tu, J. Autophagy in Alzheimer’s disease pathogenesis: Therapeutic potential and future
perspectives. Ageing Res. Rev. 2021, 72, 101464. [CrossRef]
31. Reddy, P.H.; Oliver, D.M. Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s
Disease. Cells 2019, 8, 488. [CrossRef] [PubMed]
32. Stavoe, A.K.; Holzbaur, E.L. Autophagy in Neurons. Annu. Rev. Cell Dev. Biol. 2018, 35, 477–500. [CrossRef] [PubMed]
33. Reddy, P.H.; Yin, X.; Manczak, M.; Kumar, S.; Pradeepkiran, J.A.; Vijayan, M.; Reddy, A.P. Mutant APP and amyloid beta-induced
defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons
from Alzheimer’s disease. Hum. Mol. Genet. 2018, 27, 2502–2516. [CrossRef] [PubMed]
34. Atri, A. The Alzheimer’s Disease Clinical Spectrum. Med. Clin. N. Am. 2019, 103, 263–293. [CrossRef] [PubMed]
35. Domínguez-Fernández, C.; Egiguren-Ortiz, J.; Razquin, J.; Gómez-Galán, M.; Heras-García, L.D.L.; Paredes-Rodríguez, E.;
Astigarraga, E.; Miguélez, C.; Barreda-Gómez, G. Review of Technological Challenges in Personalised Medicine and Early
Diagnosis of Neurodegenerative Disorders. Int. J. Mol. Sci. 2023, 24, 3321. [CrossRef] [PubMed]
36. Tan, C.-C.; Yu, J.-T.; Tan, L. Biomarkers for Preclinical Alzheimer’s Disease. J. Alzheimer’s Dis. 2014, 42, 1051–1069. [CrossRef]
[PubMed]
37. Seubert, P.; Vigo-Pelfrey, C.; Esch, F.; Lee, M.; Dovey, H.; Davis, D.; Sinha, S.; Schiossmacher, M.; Whaley, J.; Swindlehurst, C.;
et al. Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 1992, 359, 325–327. [CrossRef]
[PubMed]
38. Motter, R.; Vigopelfrey, C.; Kholodenko, D.; Barbour, R.; Johnsonwood, K.; Galasko, D.; Chang, L.; Miller, B.A.; Clark, C.M.; Green,
R.H.; et al. Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann. Neurol. 1995,
39. Olsson, B.; Lautner, R.; Andreasson, U.; Öhrfelt, A.; Portelius, E.; Bjerke, M.; Hölttä, M.; Rosén, C.; Olsson, C.; Strobel, G.; et al.
CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet Neurol. 2016,
15, 673–684. [CrossRef]
40. Fagan, A.M.; Mintun, M.A.; Mach, R.H.; Lee, S.; Dence, C.S.; Shah, A.R.; LaRossa, G.N.; Spinner, M.L.; Klunk, W.E.; Mathis, C.A.;
et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 2006, 59,
512–519. [CrossRef]
41. Blennow, K.; Mattsson, N.; Schöll, M.; Hansson, O.; Zetterberg, H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol.
Sci. 2015, 36, 297–309. [CrossRef]
42. Blennow, K.; Zetterberg, H. Biomarkers for Alzheimer’s disease: Current status and prospects for the future. J. Intern. Med. 2018,
43. Hampel, H.; Buerger, K.; Zinkowski, R.; Teipel, S.J.; Goernitz, A.; Andreasen, N.; Sjoegren, M.; DeBernardis, J.; Kerkman, D.;
Ishiguro, K.; et al. Measurement of Phosphorylated Tau Epitopes in the Differential Diagnosisof Alzheimer Disease. Arch. Gen.
Psychiatry 2004, 61, 95–102. [CrossRef]
44. Mielke, M.M.; Aakre, J.A.; Algeciras-Schimnich, A.; Proctor, N.K.; Machulda, M.M.; Eichenlaub, U.; Knopman, D.S.; Vemuri,
P.; Graff-Radford, J.; Jack, C.R., Jr.; et al. Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline. Alzheimer’s
Dement. 2021, 18, 602–611. [CrossRef]
45. Hertze, J.; Minthon, L.; Zetterberg, H.; Vanmechelen, E.; Blennow, K.; Hansson, O. Evaluation of CSF Biomarkers as Predictors of
Alzheimer’s Disease: A Clinical Follow-Up Study of 4.7 Years. J. Alzheimer’s Dis. 2009, 21, 1119–1128. [CrossRef] [PubMed]
46. Wallin, A.; Blennow, K.; Zetterberg, H.; Londos, E.; Minthon, L.; Hansson, O. CSF biomarkers predict a more malignant outcome
in Alzheimer disease. Neurology 2010, 74, 1531–1537. [CrossRef]
47. Hansson, O.; Seibyl, J.; Stomrud, E.; Zetterberg, H.; Trojanowski, J.Q.; Bittner, T.; Lifke, V.; Corradini, V.; Eichenlaub, U.; Batrla, R.;
et al. CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully
automated immunoassays in BioFINDER and ADNI cohorts. Alzheimer’s Dement. 2018, 14, 1470–1481. [CrossRef]
48. Saunders, T.; Gunn, C.; Blennow, K.; Kvartsberg, H.; Zetterberg, H.; Shenkin, S.D.; Cox, S.R.; Deary, I.J.; Smith, C.; King, D.; et al.
Neurogranin in Alzheimer’s disease and ageing: A human post-mortem study. Neurobiol. Dis. 2023, 177, 105991. [CrossRef]
[PubMed]
49. Mavroudis, I.A.; Petridis, F.; Chatzikonstantinou, S.; Kazis, D. A meta-analysis on CSF neurogranin levels for the diagnosis of
Alzheimer’s disease and mild cognitive impairment. Aging Clin. Exp. Res. 2020, 32, 1639–1646. [CrossRef]
50. Willemse, E.A.; Sieben, A.; Somers, C.; Vermeiren, Y.; De Roeck, N.; Timmers, M.; Van Broeckhoven, C.; De Vil, B.; Cras, P.; De
Deyn, P.P.; et al. Neurogranin as biomarker in CSF is non-specific to Alzheimer’s disease dementia. Neurobiol. Aging 2021, 108,
51. Schmidt, F.M.; Mergl, R.; Stach, B.; Jahn, I.; Gertz, H.-J.; Schönknecht, P. Elevated levels of cerebrospinal fluid neuron-specific
enolase (NSE) in Alzheimer’s disease. Neurosci. Lett. 2014, 570, 81–85. [CrossRef]
52. Pametti, L.; Palumbo, B.; Cardinali, L.; Loreti, F.; Chionne, F.; Cecchetti, R.; Senin, U. Cerebrospinal fluid neuron-specific enolase
in Alzheimer’s disease and vascular dementia. Neurosci. Lett. 1995, 183, 43–45. [CrossRef]
53. Palumbo, B.; Siepi, D.; Sabalich, I.; Tranfaglia, C.; Parnetti, L. Cerebrospinal fluid neuron-specific enolase: A further marker of
Alzheimer’s disease? Funct. Neurol. 2008, 23, 93–96. [PubMed]
Int. J. Mol. Sci. 2024, 25, 6951 25 of 28
54. Katayama, T.; Sawada, J.; Takahashi, K.; Yahara, O.; Hasebe, N. Meta-analysis of cerebrospinal fluid neuron-specific enolase levels
in Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Alzheimer’s Res. Ther.
2021, 13, 163. [CrossRef]
55. Gaetani, L.; Blennow, K.; Calabresi, P.; Di Filippo, M.; Parnetti, L.; Zetterberg, H. Neurofilament light chain as a biomarker in
neurological disorders. J. Neurol. Neurosurg. Psychiatry 2019, 90, 870–881. [CrossRef]
56. Bridel, C.; van Wieringen, W.N.; Zetterberg, H.; Tijms, B.M.; Teunissen, C.E.; Alvarez-Cermeño, J.C.; Andreasson, U.; Axelsson,
M.; Bäckström, D.C.; Bartos, A.; et al. Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology. JAMA
Neurol. 2019, 76, 1035–1048. [CrossRef] [PubMed]
57. Leckey, C.A.; Coulton, J.B.; Giovannucci, T.A.; He, Y.; Aslanyan, A.; Laban, R.; Heslegrave, A.; Doykov, I.; Ammoscato, F.;
Chataway, J.; et al. CSF neurofilament light chain profiling and quantitation in neurological diseases. Brain Commun. 2024, 6,
fcae132. [CrossRef] [PubMed]
58. Groblewska, M.; Muszyński, P.; Wojtulewska-Supron, A.; Kulczyńska-Przybik, A.; Mroczko, B. The Role of Visinin-Like Protein-1
in the Pathophysiology of Alzheimer’s Disease. J. Alzheimer’s Dis. 2015, 47, 17–32. [CrossRef] [PubMed]
59. Halbgebauer, S.; Steinacker, P.; Riedel, D.; Oeckl, P.; Anderl-Straub, S.; Lombardi, J.; von Arnim, C.A.F.; Nagl, M.; Giese,
A.; Ludolph, A.C.; et al. Visinin-like protein 1 levels in blood and CSF as emerging markers for Alzheimer’s and other
neurodegenerative diseases. Alzheimer’s Res. Ther. 2022, 14, 175. [CrossRef]
60. Hu, X.; Yang, Y.; Gong, D. A meta-analysis of cerebrospinal fluid visinin-like protein-1 in alzheimer’s disease patients relative to
healthy controls and mild cognitive impairment patients. Neurosciences 2017, 22, 94–101. [CrossRef]
61. Yin, F. Lipid metabolism and Alzheimer’s disease: Clinical evidence, mechanistic link and therapeutic promise. FEBS J. 2022, 290,
62. Huang, Y.; Mahley, R.W. Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases.
Neurobiol. Dis. 2014, 72 Pt A, 3–12. [CrossRef]
63. Yang, L.G.; March, Z.M.; Stephenson, R.A.; Narayan, P.S. Apolipoprotein E in lipid metabolism and neurodegenerative disease.
Trends Endocrinol. Metab. 2023, 34, 430–445. [CrossRef] [PubMed]
64. Rosén, C.; Mattsson, N.; Johansson, P.M.; Andreasson, U.; Wallin, A.; Hansson, O.; Johansson, J.-O.; Lamont, J.; Svensson,
J.; Blennow, K.; et al. Discriminatory Analysis of Biochip-Derived Protein Patterns in CSF and Plasma in Neurodegenerative
Diseases. Front. Aging Neurosci. 2011, 3, 1. [CrossRef] [PubMed]
65. Desikan, R.S.; Thompson, W.K.; Holland, D.; Hess, C.P.; Brewer, J.B.; Zetterberg, H.; Blennow, K.; Andreassen, O.A.; McEvoy, L.K.;
Hyman, B.T.; et al. Heart fatty acid binding protein and Aβ-associated Alzheimer’s neurodegeneration. Mol. Neurodegener. 2013,
8, 39. [CrossRef] [PubMed]
66. Johansson, P.; Almqvist, E.G.; Bjerke, M.; Wallin, A.; Johansson, J.-O.; Andreasson, U.; Blennow, K.; Zetterberg, H.; Svensson, J.
Reduced Cerebrospinal Fluid Concentration of Apolipoprotein A-I in Patients with Alzheimer’s Disease. J. Alzheimer’s Dis. 2017,
67. Endres, K. Apolipoprotein A1, the neglected relative of Apolipoprotein E and its potential role in Alzheimer’s disease. Neural
Regen. Res. 2021, 16, 2141–2148. [CrossRef] [PubMed]
68. Slot, R.E.; Van Harten, A.C.; Kester, M.I.; Jongbloed, W.; Bouwman, F.H.; Teunissen, C.E.; Scheltens, P.; Veerhuis, R.; van der Flier,
W.M. Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer’s Disease in Non-Demented Elderly. J.
Alzheimer’s Dis. 2017, 56, 687–697. [CrossRef] [PubMed]
69. Mascaro, A.L.A.; Cesare, P.; Sacconi, L.; Grasselli, G.; Mandolesi, G.; Maco, B.; Knott, G.W.; Huang, L.; De Paola, V.; Strata, P.; et al.
In vivo single branch axotomy induces GAP-43–dependent sprouting and synaptic remodeling in cerebellar cortex. Proc. Natl.
Acad. Sci. USA 2013, 110, 10824–10829. [CrossRef]
70. Holahan, M.R. A Shift from a Pivotal to Supporting Role for the Growth-Associated Protein (GAP-43) in the Coordination of
Axonal Structural and Functional Plasticity. Front. Cell. Neurosci. 2017, 11, 266. [CrossRef]
71. Sandelius, Å.; Portelius, E.; Källén, Å.; Zetterberg, H.; Rot, U.; Olsson, B.; Toledo, J.B.; Shaw, L.M.; Lee, V.M.Y.; Irwin, D.J.; et al.
Elevated CSF GAP-43 is Alzheimer’s disease specific and associated with tau and amyloid pathology. Alzheimer’s Dement. 2018,
72. Remnestål, J.; Just, D.; Mitsios, N.; Fredolini, C.; Mulder, J.; Schwenk, J.M.; Uhlén, M.; Kultima, K.; Ingelsson, M.; Kilander, L.;
et al. CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer’s
disease. Proteom.–Clin. Appl. 2016, 10, 1242–1253. [CrossRef]
73. Qiang, Q.; Skudder-Hill, L.; Toyota, T.; Wei, W.; Adachi, H. CSF GAP-43 as a biomarker of synaptic dysfunction is associated with
tau pathology in Alzheimer’s disease. Sci. Rep. 2022, 12, 17392. [CrossRef]
74. Franzmeier, N.; Dehsarvi, A.; Steward, A.; Biel, D.; Dewenter, A.; Roemer, S.N.; Wagner, F.; Groß, M.; Brendel, M.; Moscoso, A.;
et al. Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease. Nat. Commun.
2024, 15, 202. [CrossRef] [PubMed]
75. Rehli, M.; Niller, H.-H.; Ammon, C.; Langmann, S.; Schwarzfischer, L.; Andreesen, R.; Krause, S.W. Transcriptional Regulation of
CHI3L1, a Marker Gene for Late Stages of Macrophage Differentiation. J. Biol. Chem. 2003, 278, 44058–44067. [CrossRef]
76. Baldacci, F.; Lista, S.; Cavedo, E.; Bonuccelli, U.; Hampel, H. Diagnostic function of the neuroinflammatory biomarker YKL-40 in
Alzheimer’s disease and other neurodegenerative diseases. Expert Rev. Proteom. 2017, 14, 285–299. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2024, 25, 6951 26 of 28
77. Muszyński, P.; Groblewska, M.; Kulczyńska-Przybik, A.; Kułakowska, A.; Mroczko, B. YKL-40 as a Potential Biomarker and a
Possible Target in Therapeutic Strategies of Alzheimer’s Disease. Curr. Neuropharmacol. 2017, 15, 906–917. [CrossRef]
78. Wang, L.; Gao, T.; Cai, T.; Li, K.; Zheng, P.; Liu, J. Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer’s disease. Neurosci.
Lett. 2019, 715, 134658. [CrossRef] [PubMed]
79. Dore, K.; Malinow, R. Elevated PSD-95 Blocks Ion-flux Independent LTD: A Potential New Role for PSD-95 in Synaptic Plasticity.
Neuroscience 2020, 456, 43–49. [CrossRef]
80. Shao, C.Y.; Mirra, S.S.; Sait, H.B.R.; Sacktor, T.C.; Sigurdsson, E.M. Postsynaptic degeneration as revealed by PSD-95 reduction
occurs after advanced Aβ and tau pathology in transgenic mouse models of Alzheimer’s disease. Acta Neuropathol. 2011, 122,
81. Kivisäkk, P.; Carlyle, B.C.; Sweeney, T.; Quinn, J.P.; Ramirez, C.E.; Trombetta, B.A.; Mendes, M.; Brock, M.; Rubel, C.; Czerkowicz,
J.; et al. Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with
Alzheimer’s disease. Alzheimer’s Res. Ther. 2022, 14, 58. [CrossRef] [PubMed]
82. Kádková, A.; Radecke, J.; Sørensen, J.B. The SNAP-25 Protein Family. Neuroscience 2019, 420, 50–71. [CrossRef] [PubMed]
83. Nilsson, J.; Ashton, N.J.; Benedet, A.L.; Montoliu-Gaya, L.; Gobom, J.; Pascoal, T.A.; Chamoun, M.; Portelius, E.; Jeromin, A.;
Mendes, M.; et al. Quantification of SNAP-25 with mass spectrometry and Simoa: A method comparison in Alzheimer’s disease.
Alzheimer’s Res. Ther. 2022, 14, 78. [CrossRef] [PubMed]
84. Halbgebauer, S.; Steinacker, P.; Hengge, S.; Oeckl, P.; Abu Rumeileh, S.; Anderl-Straub, S.; Lombardi, J.; Arnim, C.A.F.V.; Giese, A.;
Ludolph, A.C.; et al. CSF levels of SNAP-25 are increased early in Creutzfeldt-Jakob and Alzheimer’s disease. J. Neurol. Neurosurg.
Psychiatry 2022, 93, 1059–1065. [CrossRef] [PubMed]
85. Wang, S.; Zhang, J.; Pan, T. APOE ε4 is associated with higher levels of CSF SNAP-25 in prodromal Alzheimer’s disease. Neurosci.
Lett. 2018, 685, 109–113. [CrossRef]
86. Butt, O.H.; Long, J.M.; Henson, R.L.; Herries, E.; Sutphen, C.L.; Fagan, A.M.; Cruchaga, C.; Ladenson, J.H.; Holtzman, D.M.;
Morris, J.C.; et al. Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25. Neurobiol. Aging 2021, 102, 64–72.
[CrossRef]
87. Wen, L.; Lu, Y.-S.; Zhu, X.-H.; Li, X.-M.; Woo, R.-S.; Chen, Y.-J.; Yin, D.-M.; Lai, C.; Terry, A.V.; Vazdarjanova, A.; et al. Neuregulin
1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc. Natl. Acad. Sci. USA 2009, 107,
1211–1216. [CrossRef]
88. Mouton-Liger, F.; Dumurgier, J.; Cognat, E.; Hourregue, C.; Zetterberg, H.; Vanderstichele, H.; Vanmechelen, E.; Bouaziz-Amar, E.;
Blennow, K.; Hugon, J.; et al. CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease. Alzheimer’s
Res. Ther. 2020, 12, 88. [CrossRef]
89. Banack, S.A.; Stark, A.C.; Cox, P.A. A possible blood plasma biomarker for early-stage Alzheimer’s disease. PLoS ONE 2021, 17,
e0267407. [CrossRef]
90. Nakamura, A.; Kaneko, N.; Villemagne, V.L.; Kato, T.; Doecke, J.; Doré, V.; Fowler, C.; Li, Q.-X.; Martins, R.; Rowe, C.; et al. High
performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 2018, 554, 249–254. [CrossRef]
91. Cai, H.; Pang, Y.; Fu, X.; Ren, Z.; Jia, L. Plasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts.
Nat. Commun. 2023, 14, 6747. [CrossRef] [PubMed]
92. Moscoso, A.; Grothe, M.J.; Ashton, N.J.; Karikari, T.K.; Rodríguez, J.L.; Snellman, A.; Suárez-Calvet, M.; Blennow, K.; Zetter-
berg, H.; Schöll, M.; et al. Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain with
Neurodegeneration in Alzheimer Disease. JAMA Neurol. 2021, 78, 396–406. [CrossRef]
93. Gonzalez-Ortiz, F.; Turton, M.; Kac, P.R.; Smirnov, D.; Premi, E.; Ghidoni, R.; Benussi, L.; Cantoni, V.; Saraceno, C.; Rivolta, J.; et al.
Brain-derived tau: A novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain 2022, 146, 1152–1165.
[CrossRef]
94. McGrath, E.R.; Beiser, A.S.; O’donnell, A.; Yang, Q.; Ghosh, S.; Gonzales, M.M.; Himali, J.J.; Satizabal, C.L.; Johnson, K.A.; Tracy,
R.P.; et al. Blood Phosphorylated Tau 181 as a Biomarker for Amyloid Burden on Brain PET in Cognitively Healthy Adults. J.
Alzheimer’s Dis. 2022, 87, 1517–1526. [CrossRef] [PubMed]
95. Karikari, T.K.; Pascoal, T.A.; Ashton, N.J.; Janelidze, S.; Benedet, A.L.; Rodriguez, J.L.; Chamoun, M.; Savard, M.; Kang, M.S.;
Therriault, J.; et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: A diagnostic performance and
prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020, 19, 422–433. [CrossRef] [PubMed]
96. Janelidze, S.; Mattsson, N.; Palmqvist, S.; Smith, R.; Beach, T.G.; Serrano, G.E.; Chai, X.; Proctor, N.K.; Eichenlaub, U.; Zetterberg,
H.; et al. Plasma P-tau181 in Alzheimer’s disease: Relationship to other biomarkers, differential diagnosis, neuropathology and
longitudinal progression to Alzheimer’s dementia. Nat. Med. 2020, 26, 379–386. [CrossRef]
97. Milà-Alomà, M.; Ashton, N.J.; Shekari, M.; Salvadó, G.; Ortiz-Romero, P.; Montoliu-Gaya, L.; Benedet, A.L.; Karikari, T.K.;
Lantero-Rodriguez, J.; Vanmechelen, E.; et al. Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical
Alzheimer’s disease. Nat. Med. 2022, 28, 1797–1801. [CrossRef]
98. De Vos, A.; Jacobs, D.; Struyfs, H.; Fransen, E.; Andersson, K.; Portelius, E.; Andreasson, U.; De Surgeloose, D.; Hernalsteen, D.;
Sleegers, K.; et al. C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease.
Alzheimer’s Dement. 2015, 11, 1461–1469. [CrossRef]
99. Jia, L.; Zhu, M.; Kong, C.; Pang, Y.; Zhang, H.; Qiu, Q.; Wei, C.; Tang, Y.; Wang, Q.; Li, Y.; et al. Blood neuro-exosomal synaptic
proteins predict Alzheimer’s disease at the asymptomatic stage. Alzheimer’s Dement. 2020, 17, 49–60. [CrossRef]
Int. J. Mol. Sci. 2024, 25, 6951 27 of 28
100. Chatterjee, P.; Pedrini, S.; Doecke, J.D.; Thota, R.; Villemagne, V.L.; Doré, V.; Singh, A.K.; Wang, P.; Rainey-Smith, S.; Fowler,
C.; et al. Plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer’s disease continuum: A cross-sectional and
longitudinal study in the AIBL cohort. Alzheimer’s Dement. 2022, 19, 1117–1134. [CrossRef]
101. Baiardi, S.; Quadalti, C.; Mammana, A.; Dellavalle, S.; Zenesini, C.; Sambati, L.; Pantieri, R.; Polischi, B.; Romano, L.; Suffritti, M.;
et al. Diagnostic value of plasma p-tau181, NfL, and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias.
Alzheimer’s Res. Ther. 2022, 14, 153. [CrossRef]
102. Steinacker, P.; Mollenhauer, B.; Bibl, M.; Cepek, L.; Esselmann, H.; Brechlin, P.; Lewczuk, P.; Poser, S.; Kretzschmar, H.A.; Wiltfang,
J.; et al. Heart fatty acid binding protein as a potential diagnostic marker for neurodegenerative diseases. Neurosci. Lett. 2004, 370,
103. Westwood, S.; Leoni, E.; Hye, A.; Lynham, S.; Khondoker, M.R.; Ashton, N.J.; Kiddle, S.J.; Baird, A.L.; Sainz-Fuertes, R.; Leung, R.;
et al. Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. J. Alzheimer’s Dis. 2016,
104. Paula-Lima, A.C.; Tricerri, M.A.; Brito-Moreira, J.; Bomfim, T.R.; Oliveira, F.F.; Magdesian, M.H.; Grinberg, L.T.; Panizzutti, R.;
Ferreira, S.T. Human apolipoprotein A–I binds amyloid-β and prevents Aβ-induced neurotoxicity. Int. J. Biochem. Cell Biol. 2008,
105. Choi, J.; Lee, H.-W.; Suk, K. Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer’s disease. J.
Neurol. 2011, 258, 2181–2185. [CrossRef] [PubMed]
106. Chang, K.-A.; Shin, K.Y.; Nam, E.; Lee, Y.-B.; Moon, C.; Suh, Y.-H.; Lee, S.H. Plasma soluble neuregulin-1 as a diagnostic biomarker
for Alzheimer’s disease. Neurochem. Int. 2016, 97, 1–7. [CrossRef] [PubMed]
107. Vrillon, A.; Mouton-Liger, F.; Martinet, M.; Cognat, E.; Hourregue, C.; Dumurgier, J.; Bouaziz-Amar, E.; Brinkmalm, A.; Blennow,
K.; Zetterberg, H.; et al. Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease: A discovery cohort study. Alzheimer’s
Res. Ther. 2022, 14, 71. [CrossRef] [PubMed]
108. Du, Z.; Li, Y.; Li, J.; Zhou, C.; Li, F.; Yang, X. Physical activity can improve cognition in patients with Alzheimer’s disease: A
systematic review and meta-analysis of randomized controlled trials. Clin. Interv. Aging 2018, 13, 1593–1603. [CrossRef] [PubMed]
109. Jia, R.-X.; Liang, J.-H.; Xu, Y.; Wang, Y.-Q. Effects of physical activity and exercise on the cognitive function of patients with
Alzheimer disease: A meta-analysis. BMC Geriatr. 2019, 19, 181. [CrossRef]
110. Rao, A.K.; Chou, A.; Bursley, B.; Smulofsky, J.; Jezequel, J. Systematic Review of the Effects of Exercise on Activities of Daily
Living in People with Alzheimer’s Disease. Am. J. Occup. Ther. 2014, 68, 50–56. [CrossRef]
111. López-Ortiz, S.; Pinto-Fraga, J.; Valenzuela, P.L.; Martín-Hernández, J.; Seisdedos, M.M.; García-López, O.; Toschi, N.; Di Giuliano,
F.; Garaci, F.; Mercuri, N.B.; et al. Physical Exercise and Alzheimer’s Disease: Effects on Pathophysiological Molecular Pathways
of the Disease. Int. J. Mol. Sci. 2021, 22, 2897. [CrossRef] [PubMed]
112. Jensen, C.S.; Portelius, E.; Høgh, P.; Wermuth, L.; Blennow, K.; Zetterberg, H.; Hasselbalch, S.G.; Simonsen, A.H. Effect of physical
exercise on markers of neuronal dysfunction in cerebrospinal fluid in patients with Alzheimer’s disease. Alzheimer’s Dement.
Transl. Res. Clin. Interv. 2017, 3, 284–290. [CrossRef] [PubMed]
113. Law, L.L.; Rol, R.N.; Schultz, S.A.; Dougherty, R.J.; Edwards, D.F.; Koscik, R.L.; Gallagher, C.L.; Carlsson, C.M.; Bendlin, B.B.;
Zetterberg, H.; et al. Moderate intensity physical activity associates with CSF biomarkers in a cohort at risk for Alzheimer’s
disease. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2018, 10, 188–195. [CrossRef] [PubMed]
114. Sewell, K.R.; Rainey-Smith, S.R.; Pedrini, S.; Peiffer, J.J.; Sohrabi, H.R.; Taddei, K.; Markovic, S.J.; Martins, R.N.; Brown, B.M. The
impact of exercise on blood-based biomarkers of Alzheimer’s disease in cognitively unimpaired older adults. GeroScience 2024,
115. Hou, X.-H.; Xu, W.; Bi, Y.-L.; Shen, X.-N.; Ma, Y.-H.; Dong, Q.; Tan, L.; Yu, J.-T. Associations of healthy lifestyles with cerebrospinal
fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: The CABLE study. Alzheimer’s Res. Ther.
2021, 13, 81. [CrossRef]
116. Yu, F.; Han, S.Y.; Salisbury, D.; Pruzin, J.J.; Geda, Y.; Caselli, R.J.; Li, D. Feasibility and preliminary effects of exercise interventions
on plasma biomarkers of Alzheimer’s disease in the FIT-AD trial: A randomized pilot study in older adults with Alzheimer’s
dementia. Pilot Feasibility Stud. 2022, 8, 243. [CrossRef] [PubMed]
117. Di Battista, A.P.; Moes, K.A.; Shiu, M.Y.; Hutchison, M.G.; Churchill, N.; Thomas, S.G.; Rhind, S.G. High-Intensity Interval
Training Is Associated with Alterations in Blood Biomarkers Related to Brain Injury. Front. Physiol. 2018, 9, 1367. [CrossRef]
118. de Farias, J.M.; Tramontin, N.d.S.; Pereira, E.V.; de Moraes, G.L.; Furtado, B.G.; Tietbohl, L.T.W.; Pereira, B.D.C.; Simon, K.U.;
Muller, A.P. Physical Exercise Training Improves Judgment and Problem-Solving and Modulates Serum Biomarkers in Patients
with Alzheimer’s Disease. Mol. Neurobiol. 2021, 58, 4217–4225. [CrossRef] [PubMed]
119. Desai, P.; Dhana, K.; DeCarli, C.; Wilson, R.S.; McAninch, E.A.; Evans, D.A.; Rajan, K.B. Examination of Neurofilament Light
Chain Serum Concentrations, Physical Activity, and Cognitive Decline in Older Adults. JAMA Netw. Open 2022, 5, e223596.
[CrossRef]
120. Casaletto, K.B.; Kornack, J.; Paolillo, E.W.; Rojas, J.C.; VandeBunte, A.; Lee, S.; Forsberg, L.; Miller, B.L.; Kramer, J.H.; Yaffe, K.;
et al. Association of Physical Activity with Neurofilament Light Chain Trajectories in Autosomal Dominant Frontotemporal
Lobar Degeneration Variant Carriers. JAMA Neurol. 2023, 80, 82–90. [CrossRef]
121. Stojanovic, M.; Schindler, S.E.; Morris, J.C.; Head, D. Effect of exercise engagement and cardiovascular risk on neuronal injury.
Alzheimer’s Dement. 2023, 19, 4454–4462. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2024, 25, 6951 28 of 28
122. Yang, S.-Y.; Shan, C.-L.; Qing, H.; Wang, W.; Zhu, Y.; Yin, M.-M.; Machado, S.; Yuan, T.-F.; Wu, T. The Effects of Aerobic Exercise on
Cognitive Function of Alzheimer’s Disease Patients. CNS Neurol. Disord.-Drug Targets 2015, 14, 1292–1297. [CrossRef] [PubMed]
123. Palmieri, M.; Cariati, I.; Scimeca, M.; Pallone, G.; Bonanno, E.; Tancredi, V.; D’Arcangelo, G.; Frank, C. Effects of short-term
aerobic exercise in a mouse model of Niemann-Pick type C disease on synaptic and muscle plasticity. Alcohol Alcohol. 2019, 55,
124. López-Ortiz, S.; Lista, S.; Valenzuela, P.L.; Pinto-Fraga, J.; Carmona, R.; Caraci, F.; Caruso, G.; Toschi, N.; Emanuele, E.; Gabelle, A.;
et al. Effects of physical activity and exercise interventions on Alzheimer’s disease: An umbrella review of existing meta-analyses.
J. Neurol. 2022, 270, 711–725. [CrossRef] [PubMed]
125. Hoffmann, K.; Sobol, N.A.; Frederiksen, K.S.; Beyer, N.; Vogel, A.; Vestergaard, K.; Brændgaard, H.; Gottrup, H.; Lolk, A.;
Wermuth, L.; et al. Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer’s Disease: A Randomized Controlled
Trial. J. Alzheimer’s Dis. 2016, 50, 443–453. [CrossRef] [PubMed]
126. Bonanni, R.; Cariati, I.; Tarantino, U.; D’arcangelo, G.; Tancredi, V. Physical Exercise and Health: A Focus on Its Protective Role in
Neurodegenerative Diseases. J. Funct. Morphol. Kinesiol. 2022, 7, 38. [CrossRef] [PubMed]
127. Cariati, I.; Bonanni, R.; Pallone, G.; Scimeca, M.; Frank, C.; Tancredi, V.; D’arcangelo, G. Hippocampal Adaptations to Continuous
Aerobic Training: A Functional and Ultrastructural Evaluation in a Young Murine Model. J. Funct. Morphol. Kinesiol. 2021, 6, 101.
[CrossRef] [PubMed]
128. Zhao, N.; Zhang, X.; Li, B.; Wang, J.; Zhang, C.; Xu, B. Treadmill Exercise Improves PINK1/Parkin-Mediated Mitophagy Activity
Against Alzheimer’s Disease Pathologies by Upregulated SIRT1-FOXO1/3 Axis in APP/PS1 Mice. Mol. Neurobiol. 2022, 60,
129. Zhao, N.; Zhao, N.; Xia, J.; Xia, J.; Xu, B.; Xu, B. Physical exercise may exert its therapeutic influence on Alzheimer’s disease
through the reversal of mitochondrial dysfunction via SIRT1–FOXO1/3–PINK1–Parkin-mediated mitophagy. J. Sport Health Sci.
2020, 10, 1–3. [CrossRef]
130. De la Rosa, A.; Olaso-Gonzalez, G.; Arc-Chagnaud, C.; Millan, F.; Salvador-Pascual, A.; García-Lucerga, C.; Blasco-Lafarga, C.;
Garcia-Dominguez, E.; Carretero, A.; Correas, Á.G.; et al. Physical exercise in the prevention and treatment of Alzheimer’s
disease. J. Sport Health Sci. 2020, 9, 394–404. [CrossRef]
131. Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.-C.;
et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013, 493, 674–678.
[CrossRef] [PubMed]
132. Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.;
Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015, 14, 388–405. [CrossRef] [PubMed]
133. Wang, M.; Zhang, H.; Liang, J.; Huang, J.; Chen, N. Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease. J.
Neuroinflamm. 2023, 20, 76. [CrossRef] [PubMed]
134. Stigger, F.S.; Marcolino, M.A.Z.; Portela, K.M.; Plentz, R.D.M. Effects of Exercise on Inflammatory, Oxidative, and Neurotrophic
Biomarkers on Cognitively Impaired Individuals Diagnosed with Dementia or Mild Cognitive Impairment: A Systematic Review
and Meta-Analysis. J. Gerontol. Ser. A 2018, 74, 616–624. [CrossRef]
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Exercise To Counteract Alzheimer's Disease What Do Fluid Biomarkers Say?

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International Journal of

Int. J. Mol. Sci. 2024, 25, 6951. https://doi.org/10.3390/ijms25136951 https://www.mdpi.com/journal/ijms

2. AD: A Brief Overview of Pathogenesis

Importantly, AD is characterized by the deregulation of several kinases and phosphatases

3. Fluid Biomarkers as Diagnostic and Prognostic Factors of AD

3.1. Biomarkers of Neurodegeneration in the CSF of AD Patients

Table 1. A schematic representation of the main evidence on AD biomarkers in the CSF.

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

3.2. Plasma Biomarkers in AD

Table 2. A schematic representation of the main evidence on AD biomarkers in plasma.

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

Biomarker Study Population Biomarker Levels Evidence References

4. Exercise in AD to Counteract Neurodegeneration

Biomarker Study Population Exercise Protocol CSF Plasma References

Biomarker Study Population Exercise Protocol CSF Plasma References

Biomarker Study Population Exercise Protocol CSF Plasma References

environment in the hippocampus by inducing the production of anti-inflammatory cy-

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