Clinical Review & Education

JAMA Internal Medicine | Review

Dementia Prevention and Treatment

A Narrative Review
David B. Reuben, MD; Sarah Kremen, MD; Donovan T. Maust, MD, MS

Viewpoint
IMPORTANCE Dementia affects 10% of those 65 years or older and 35% of those 90 years or JAMA Internal Medicine
older, often with profound cognitive, behavioral, and functional consequences. As the baby Patient Page
boomers and subsequent generations age, effective preventive and treatment strategies will
CME at jamacmelookup.com
assume increasing importance.
OBSERVATIONS Preventive measures are aimed at modifiable risk factors, many of which have
been identified. To date, no randomized clinical trial data conclusively confirm that
interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may
have other health benefits and should be considered. Alzheimer disease can be treated with
cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last Author Affiliations: Multicampus
modestly slowing cognitive and functional decline in people with mild cognitive impairment Program in Geriatric Medicine and
or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may Gerontology, David Geffen School of
Medicine, University of California, Los
benefit persons with other types of dementia, including dementia with Lewy bodies,
Angeles (Reuben); Department of
Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Neurology, Cedars-Sinai Medical
Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic Center, Los Angeles, California
management, including identifying and mitigating the underlying causes and individually (Kremen); Jona Goldrich Center for
Alzheimer’s and Memory Disorders,
tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy Cedars-Sinai Medical Center,
for treating these symptoms and are associated with increased mortality and clinically Los Angeles, California (Kremen);
meaningful risks of falls and cognitive decline. Several emerging prevention and treatment Department of Psychiatry, University
of Michigan, Ann Arbor (Maust);
strategies hold promise to improve dementia care in the future.
Center for Clinical Management
CONCLUSIONS AND RELEVANCE Although current prevention and treatment approaches to Research, VA Ann Arbor Healthcare
System, Ann Arbor, Michigan (Maust).
dementia have been less than optimally successful, substantial investments in dementia
Corresponding Author: David B.
research will undoubtedly provide new answers to reducing the burden of dementia Reuben, MD, Multicampus Program
worldwide. in Geriatric Medicine and
Gerontology, David Geffen School of
Medicine, University of California,
Los Angeles, 10945 Le Conte Ave,
JAMA Intern Med. doi:10.1001/jamainternmed.2023.8522 Ste 2339, Los Angeles, CA
Published online March 4, 2024. 90095-1687 (dreuben@
mednet.ucla.edu).

D
ementia, which has both cognitive deficits and func- Beyond its effects on patients, dementia affects caregivers,
tional consequences,1 is a disorder of aging with preva- with at least 11 million providing care in the US in 2022.3 The toll
lence ranging from 3% among those 65 to 70 years old of dementia caregiving can be enormous—up to 40% report
to 35% among those 90 years and older.2 As the baby boomers depressive symptoms, 5 and 30% regularly feel completely
(born between 1946 and 1964) age over the next 3 decades, the overwhelmed6; their role and needs must also be considered in
effect of dementia will be monumental, with the number of indi- the care of the patient.
viduals in the US with Alzheimer disease (AD) expected to double Despite the promise of amyloid immunomodulators for AD, it
above the current estimate of 6.7 million.3 From a global perspec- is likely that most persons with dementia will not be eligible for these
tive, more than 55 million people have dementia worldwide— at the time of diagnosis; moreover, the clinical effectiveness and du-
more than 60% of whom live in low- and middle-income ration of effect of these drugs remain uncertain. In this review, we
countries—with nearly 10 million new cases each year.4 summarize the current evidence and explore emerging science on
The most common cause of dementia is AD, which accounts for the prevention and treatment of dementia to inform clinical decision-
an estimated 60% to 80% of cases. Other causes of dementia in- making (Figure).
clude vascular (approximately 5%-10%), frontotemporal degenera-
tion (3% of those with onset 65 years or older and 10% of those with
onset younger than 65 years), and Lewy body disease (approxi-
Methods
mately 5%), although Lewy body disease may be underdiagnosed
in clinical practice. Moreover, more than 50% of those diagnosed Th i s N a r ra t i ve Rev i e w d raw s f r o m s eve ra l sy st e m a t i c
with AD have mixed dementia with more than 1 identifiable cause.3 reviews published between 2018 and 2023, including the 2020

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 Clinical Review & Education Review Dementia Prevention and Treatment

Figure. Prevention and Treatment of Dementia

Disease treatment
• Amyloid immunomodulators (only for
early-stage AD)
• Cholinesterase inhibitors
• NMDA receptor antagonists
Prevention
Dementia AD indicates Alzheimer disease;
Reduce modifiable risk factorsa
NMDA, N-methyl-D-aspartate.
Treatment of behavioral complications a
Many risk factors are potentially
• Behavioral approaches modifiable, but few have clinical
• Pharmacological (only as a last resort)
trial evidence that modification
reduces risk.

Table 1. Estimated Percentages of Dementia Attributable to Modifiable Risk Factorsa

Relative risk for Dementia attributable to
Risk factor dementia (95% CI) Risk factor prevalence, % each risk factor, %
Less education 1.6 (1.3-2.0) 40.0 7.1
Hearing loss 1.9 (1.4-2.7) 31.7 8.2
Traumatic brain injury 1.8 (1.5-2.2) 12.1 3.4
Hypertension 1.6 (1.2-2.2) 8.9 1.9
Alcohol (>21 units/wk) 1.2 (1.1-1.3) 11.8 0.8
Obesity (BMI ≥30) 1.6 (1.3-1.9) 3.4 0.7
Smoking 1.6 (1.2-2.2) 27.4 5.2
Depression 1.9 (1.6-2.3) 13.2 3.9
Social isolation 1.6 (1.3-1.9) 11.0 3.5
Abbreviations: BMI, body mass index
Physical inactivity 1.4 (1.2-1.7) 17.7 1.6 (calculated as weight in kilograms
Diabetes 1.5 (1.3-1.8) 6.4 1.1 divided by height in meters squared);
NA, not applicable.
Air pollution 1.1 (1.1-1.1) 75.0 2.3
a
Data are from the 2020 report of
All modifiable risk factors NA NA 39.7
the Lancet Commission.7

Lancet Commission review7 and the Alzheimer’s Association’s Education/Cognitive Stimulation

Alzheimer’s Disease Facts and Figures,3 which is updated annually. Higher levels of education in childhood and late adolescence appear
We augmented these reviews by searching PubMed for each to be most important for late-life cognition.40 The effects of educa-
topic heading of the Lancet review plus other topics we were tion and cognitive stimulation in later life are more difficult to ascer-
aware of, adding new studies published from January 2020 to tain because of the possibility of reverse causation (ie, people do not
August 2023. We excluded validation studies, opinion pieces, and participate in these activities because they already have cognitive im-
editorials. When drawing conclusions, emphasis was placed on pairment). Systematic reviews of interventions, such as computer-
meta-analyses of clinical trials (eg, Cochrane reviews), individual ized cognitive training, have failed to find convincing evidence of im-
clinical trials, and, when clinical trial data were unavailable, meta- provement of cognition, 41 though some have demonstrated
analyses of observational studies. improvement on the specific tasks trained.9

Hearing Aids
Evidence on treating hearing loss as a means of preventing
Prevention
dementia is mixed. A meta-analysis of mostly observational stud-
Most of the evidence supporting strategies to prevent dementia is ies concluded that hearing aids and cochlear implants led to a
based on observational studies, and the few randomized clinical trials 19% reduction in cognitive decline,10 but a recent clinical trial of a
(RCTs) have important limitations. Preventive measures are aimed at hearing intervention failed to demonstrate a benefit on cognition
reduction of modifiable risk factors, including social determinants of at 3 years.11
health. In 2019, the World Health Organization published guidelines
on risk reduction of cognitive decline and dementia,8 and in 2020, the Treatment of Cardiovascular Risk Factors
Lancet Commission identified 12 modifiable risk factors that account Observational studies13 and a Cochrane review of clinical trials14
for an estimated 40% of dementia risk worldwide (Table 1).7 None of examining the association of blood pressure control with preven-
these risk factors has a relative risk that exceeds 1.9. Moreover, con- tion of dementia had conflicting results. In the SPRINT MIND
clusive RCT evidence is lacking that modification of any risk factor can trial,12 intensive treatment of blood pressure to a target of less
prevent dementia. Nevertheless, several potentially valuable inter- than 120 mm Hg vs 140 mm Hg reduced incident probable
ventions can be initiated in midlife or later life that may have benefi- dementia by 17%, but this was not a statistically significant find-
cial effects for individual patients (Table 2).9-39 ing. However, secondary outcomes of mild cognitive impairment

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 Dementia Prevention and Treatment Review Clinical Review & Education

Table 2. Evidence Behind Preventive Measures for Cognitive Decline, Mild Cognitive Impairment (MCI), or Dementia

Preventive measure Outcome(s) Study design Conclusion(s)

Single factor
Cognitive training Cognition SR9 Improvement on specific tasks trained
10
Hearing treatment Cognition/dementia OM Less decline/reduced risk
Cognition RCT11 No effect
Treatment of hypertension MCI RCT12 Reduced risk
Dementia RCT12 No effect
12
MCI or dementia RCT Reduced risk
Dementia OM13 Reduced risk
Cognitive impairment or dementia SR14 No association
Statins Cognitive decline or dementia SR15 No association
16
Aspirin Dementia RCT No effect
Alcohol Dementia OM17,18 Lower risk for occasional, light to moderate,
and moderate to heavy drinkers
OS,19 SR20 Higher risk for heavy drinkers
Diet
DASH and MIND diets Dementia OM21 Reduced risk
MIND diet Cognition/MRI findings of dementia RCT22 No effect
23
Weight loss Cognition SR and TM Improved memory and attention
Smoking cessation Dementia OS24 Reduced risk
Treatment of depression Cognition SR and TM25 Improved psychomotor speed and delayed recall
Treatment of obstructive sleep apnea Dementia OS26 Reduced incidence of Alzheimer disease
27
Prevention of delirium Dementia Simulation Reduced risk
Increased social activity Dementia OM28 Reduced risk
Cognition SR29 Improvement on some tests
Exercise Alzheimer disease and dementia OM30,31 Reduced risk
32
Cognitive function SR and TM Improved or maintained global cognition
Treatment of diabetes
Metformin Cognitive impairment TM33,34 Mixed; 1 showed protective effect,33 the
other did not34
Intensive control Cognitive decline SR35 No effect
Multifactorial
Exercise and cognitive training Cognition SR and TM36 Modest improvement
37
Aerobic exercise cognitive stimulation Cognition RCT Improved though inconsistent effects
Cardiovascular risk factors, cognitive Cognition RCT38 Improved
training, exercise, and diet
Personalized risk-reduction strategy Cognition RCT39 Improved
Abbreviations: DASH, Dietary Approaches to Stop Hypertension; MIND, RCT, randomized clinical trial; SR, systematic review; TM, treatment
Mediterranean–DASH Intervention for Neurodegenerative Delay; MRI, magnetic meta-analysis.
resonance imaging; OM, observational meta-analysis; OS, observational study;

(MCI) or MCI or dementia demonstrated similar reductions in risk findings of dementia.22 Among mostly middle-aged persons with
and were statistically significant. The use of statins to reduce cog- overweight and obesity, weight loss was associated with
nitive decline or dementia was not supported in a Cochrane improved attention and memory.23
review,15 nor was aspirin protective in a large clinical trial.16
Alcohol Consumption and Smoking
Diet The evidence on alcohol use and subsequent dementia is mixed.
Observational studies support the protective effect of a Mediter- Many studies suggest that light to moderate drinking has a protec-
ranean diet, the DASH (Dietary Approaches to Stop Hyperten- tive effect compared with abstinence.17,18 Some,19,20 but not all,17
sion) diet, and a hybrid of the 2 called the MIND diet.21 However, a studies suggest that heavy drinking or alcohol use disorders in-
recent clinical trial comparing 3 years of a MIND diet with a con- crease dementia risk. In a longitudinal study, tobacco smoking ces-
trol diet with mild caloric restriction did not demonstrate differ- sation was associated with reduced risk of dementia over the sub-
ences in global cognition or magnetic resonance imaging (MRI) sequent 8 years.24

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 Clinical Review & Education Review Dementia Prevention and Treatment

Table 3. US Food and Drug Administration (FDA)–Approved Dementia-Specific Pharmacological Treatments

for Alzheimer Disease (AD) Dementia

Medication class/medications FDA-approved indication Adverse effects

Acetylcholinesterase
inhibitors
Donepezil Mild, moderate, or severe
dementia due to AD
GI upset, nausea, vomiting, diarrhea, vivid dreams,
Rivastigmine Mild, moderate, or severe weight loss, bradycardia, syncope, increased GI
dementia due to AD bleeding/peptic ulcer risk with donepezil, and
contact dermatitis with patch only
Galantamine Mild or moderate dementia
due to AD Abbreviations: ARIA, amyloid-related
imaging abnormalities; GI,
NMDA inhibitor memantine Moderate or severe dementia Dizziness, confusion, anxiety, hypotension,
gastrointestinal; NMDA,
due to AD hypertension, diarrhea, and agitation
N-methyl-D-aspartate.
Amyloid immunomodulators a
Provisional FDA approval and will
Aducanumaba ARIA not be available after November
Lecanemab Mild cognitive impairment ARIA, infusion reaction, and headache 2024.
and mild dementia due to AD b
Under consideration for FDA
Donanemabb ARIA, infusion reaction, and headache
approval.

Depression risk, but dementia may cause social isolation rather than the
The relationship between depression and dementia is compli- reverse.28 A systematic review of interventions to increase social ac-
cated. Depression can be a predictor of future dementia, a tivity that included 3 RCTs with a total of 586 participants demon-
prodrome or presenting symptom of dementia, or a concurrent ill- strated small improvements on some cognitive tests.29
ness. Moreover, observational studies generally have not distin-
guished between treated and untreated depression. Although treat- Physical Activity/Exercise
ment of major depression with antidepressants can improve Meta-analyses of observational studies of exercise indicated ben-
psychomotor speed and delayed recall,25 to our knowledge, no RCT efit of exercise on prevention of AD and dementia.30,31 The timing
has demonstrated that treatment of depression prevents of physical activity may be important. Midlife physical activity has
dementia. not been shown to be associated with cognitive performance,49,50
whereas later life physical activity has,30 although reverse causa-
Sleep tion is a possible explanation. A multicomponent exercise interven-
In longitudinal studies, sleep disturbances have been associated with tion that included strength training improved cognition in a RCT, es-
increased risk for all-cause dementia, AD, and vascular dementia.42 pecially for those with MCI.32
Specific sleep disorders were associated with different types of de-
mentia, including insomnia (AD) and sleep-disordered breathing (all- Diabetes
cause, AD, and vascular). Retrospective observational data sug- A Cochrane review found no benefit of intensive control compared
gest that treatment of obstructive sleep apnea with positive airway with standard diabetes management on cognitive decline at 5
pressure can reduce the incidence of dementia and AD specifically.26 years.35 Meta-analyses of the association of metformin use with cog-
Although obstructive sleep apnea is associated with increased AD nitive impairment have been mixed.33,34
cerebrospinal fluid biomarkers, clinical trial evidence is lacking that
treatment with continuous positive airway pressure can reverse Multifactorial Interventions
these changes.43 Various multifactorial interventions have demonstrated benefits on
cognition.36,37 The 2-year Finnish Geriatric Intervention Study to
Delirium Prevention Prevent Cognitive Impairment and Disability (FINGER)38 reported
Delirium, an acute confusional state that affects up to 50% of hos- that a combination of diet, exercise, cognitive training, and man-
pitalized adults and up to 80% in the intensive care unit, is a poten- agement of cardiovascular risk factors improved cognition in healthy
tially modifiable independent risk factor for the subsequent devel- older adults who were at increased risk of cognitive decline; partici-
opment of dementia.44 Delirium is independently associated with pants were not followed up long enough to determine the effect on
cognitive decline and dementia in older adults45 and accelerates the dementia prevention. In the Systematic Multi-Domain Alzheimer Risk
trajectory of cognitive decline in those with dementia.46 More- Reduction Trial (SMARRT), a personalized multifactorial interven-
over, delirium may be preventable in about 50% of cases through tion led to modest improvements in cognitive composite score, risk
multicomponent targeted intervention strategies.47,48 A simula- factors, and quality of life compared with a health education con-
tion estimated that 6 new cases of dementia could be prevented per trol group.39
1000 patients receiving a nonpharmacologic delirium prevention
approach.27 What to Watch For
Ongoing RCTs will likely provide more clarity on the role of com-
Social Isolation bined lifestyle interventions (US POINTER), 51 statin therapy
Longitudinal studies have shown that frequent social contact in (PREVENTABLE),52 and the provision of hearing aids (HearCog)53
middle and early old age was associated with decreased dementia on preventing dementia.

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 Dementia Prevention and Treatment Review Clinical Review & Education

Table 4. Approved Alzheimer Disease (AD) Medications Used for Non-AD Dementiasa

Medication class/medications Non-AD dementia Status

Acetylcholinesterase inhibitors
Donepezil DLB, VaD, PDD, First-line therapy in UK and approved in Japan for DLB
and TBI
Rivastigmine DLB and PDD First-line therapy in UK for DLB and approved in US and UK
for PDD
Galantamine Severe AD, DLB, More RCT data needed to determine efficacy for DLB
and PDD
Abbreviations: DLB, dementia with
NMDA inhibitor memantine DLB, VaD, PDD, May provide small benefit for DLB, VaD, and PDD; further Lewy bodies; NMDA,
and TBI studies needed
N-methyl-D-aspartate; PDD,
Amyloid immunomodulators Parkinson disease dementia; RCT,
Aducanumab randomized clinical trial; TBI,
None of these medications have been tested in mixed traumatic brain injury; VaD, vascular
Lecanemab Mixed dementia
dementia (eg, DLB-AD or VaD-AD) dementia.
Donanemab a
Off label except where noted.

factors, including but not limited to signs of cholinergic deficit, stage

Disease Treatment of disease, rate of disease progression, presence of apathy, concomi-
tant diseases, and education level.64 CIs are associated with modest
Appropriate treatment of dementia is guided by the cause of demen- but persistent cognitive benefits over several years and reduced
tia and the stage. In 2011, the National Institute on Aging and mortality,65,66 and both CIs and memantine have demonstrated pro-
Alzheimer’s Association classified AD into 3 stages: (1) preclinical, in longed time to institutionalization and reduced caregiver burden.66,67
which cognition is normal and AD is defined by abnormal biomarkers; New immunomodulators targeting β-amyloid plaques and pro-
(2) MCI, in which cognition is impaired but function is intact and bio- tofibrils, hallmark neuropathological features of AD, are now ap-
markersmayhelpinformprognosis;and(3)ADdementia,inwhichcog- provedbytheUSFoodandDrugAdministration(FDA)forpersonswith
nition and function are impaired and biomarkers may be helpful in ex- MCI or early AD. Aducanumab, lecanemab, and donanemab indisput-
cluding AD as cause.54,55 In 2018, the National Institute on Aging and ably reduce brain amyloid levels below the threshold level consid-
Alzheimer’s Association proposed the AT(N) schema for AD, a clini- ered to be abnormal on amyloid positron emission tomography. How-
cally agnostic, biologically based classification of AD anchored by key ever, evidence of clinical efficacy has been inconsistent and has
biomarkers: amyloid (A), tau (T), and neurodegeneration (N).56 A new prompted reconsideration of the amyloid hypothesis.68 Many ques-
framework for diagnosis and staging of AD is currently under consid- tions about amyloid remain unanswered, including its biological func-
eration and includes incorporation of plasma biomarkers and classifi- tion and the reason behind its accumulation, the evidence of presymp-
cation criteria to accommodate nonequivalence between fluid and tomatic brain amyloid burden without universal cognitive decline, the
imaging biomarkers.57 Similarly, research and clinical definitions of MCI discordance between location of deposition and cognitive deficits on
and dementia stages have been outlined for dementia with Lewy clinicalexamination,andamoreconsistentrelationshipbetweenphos-
bodies,58 Parkinson disease,59 frontotemporal degeneration,60 and phorylated tau accumulation and cognitive decline.69-71 Lecanemab
vascular cognitive impairment.61 The recent approval of new medica- and donanemab are the first amyloid-targeting drugs to show a mean-
tions for AD and the growing expansion of development pipelines with ingfully slower rate of decline (27%-40%) in multiple cognitive and
potentially more effective drug treatments across all dementia- functional measures compared with placebo, as well as beneficial
relatedconditionswillrequirespecialistsandprimarycarecliniciansalike downstream effects on phosphorylated tau.72,73 It is estimated that
to be able to identify and start treatments earlier in the disease course. these medications (Table 3) may slow disease progression by about 5
AD is treated with cholinesterase inhibitors (CIs) donepezil, riv- months, but it is difficult to know whether they will produce a clini-
astigmine, and galantamine and N-methyl-D-aspartate receptor an- callyimportantandsustainedbenefitinanyparticularindividual.74 Adu-
tagonist memantine. CIs increase acetylcholine availability, which is im- canumab’s effect on reduction of cognitive and functional decline is
portant for memory function, and memantine reduces excitotoxic inconclusive, leading to its provisional FDA approval designation in
damage to neurons and resulting agitation and irritability.62 Donepe- 2021. As of November 2024, aducanumab will no longer be available
zil and rivastigmine are approved to treat mild to severe dementia due in the US.
to AD, whereas galantamine is approved for mild to moderate AD The most noteworthy adverse effects of amyloid immunomodu-
dementia. Memantine is approved for moderate to severe AD demen- latory drugs are vasogenic brain edema and brain bleeding in the form
tia (Table 3). When they were first approved, the efficacy of CIs was of microhemorrhages or macrohemorrhages or superficial siderosis
challenged for multiple reasons, including use of cognitive scales dur- (amyloid-relatedimagingabnormalities[ARIA],namelyARIA-E[edema]
ingthetrialsthatwerenotusedinclinicalpractice,thevariabilityofcog- or ARIA-H [hemorrhagic]).75 Risk of ARIA greatly increases with apo-
nitive benefit across patients, and that despite a statistically signifi- lipoprotein E ε4 genotype, particularly homozygotes. Symptoms may
cant difference between drug and placebo groups in their change from include confusion, headache, seizure, or focal neurological signs. ARIA
baseline scores, the effect size was still small and the clinical impor- is asymptomatic in about 70% of people and requires close MRI and
tance not clear.63 It was also not known whether long-term use would clinical monitoring, particularly in the first 5 months of treatment,
accompany desired outcomes, such as delay in institutionalization. It though ARIA can occur at any time throughout the treatment period.
isnowestablishedthatresponsetoCIsiscomplexandaffectedbymany The frequency of surveillance MRIs to check for ARIA during treat-

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 Clinical Review & Education Review Dementia Prevention and Treatment

ment is before the 5th, 7th, and 12th (aducanumab) or 14th (lec- arise from or be exacerbated by stressors present in patients (eg, acute
anemab) doses. There are no standard protocols as to how often sur- infection, delirium), their caregivers (eg, communication style), or their
veillance of a patient’s clinical examination or routine laboratory tests environment (eg, excessive auditory stimuli).94 Nearly all patients will
should be carried out while receiving this therapy. If ARIA is sus- exhibitthesesymptomsatsomepointduringthecourseofdementia.92
pected based on an abrupt change in neurological status, a brain MRI When new BPSD occurs, a differential diagnosis should be gen-
should be obtained as part of an emergent workup, and a clinical ex- erated (eg, using the DICE [Describe, Investigate, Create, and Evaluate]
amination and MRI may need to be repeated monthly until neurologi- approach95) to help identify a potential underlying cause. There is a
cal symptoms and changes on the MRI resolve. Appropriate use rec- considerable evidence base supporting nonpharmacological interven-
ommendationshavebeenpublishedforthesemedicationsandprovide tions to address BPSD in persons living with dementia and associated
guidance on administration and management of their routine use and caregiverdistress.96-98 Caregiver-focusedinterventionshavethemost
common adverse effects.76,77 The process to determine a patient’s ap- consistent evidence base—including common elements such as skills
propriateness to receive amyloid immunotherapy is substantial and in- training, psychoeducation, and activity tailoring—and reduce both fre-
cludescognitivetestingtoruleoutmoderateorseveredementia,proof quency and severity of BPSD as well as the caregiver distress in re-
of elevated brain amyloid, apolipoprotein E ε4 testing, and baseline sponse to such symptoms.99 If distressing or dangerous symptoms re-
brain MRI to evaluate for the presence of hemorrhages (1 macrohem- main, time-limited trials of pharmacotherapy targeting BPSD can be
orrhageor>4microhemorrhagesareexclusionarycriteriatostarttreat- considered with clear, objective treatment goals in mind.100 If a pa-
ment). Therapy requires monthly (aducanumab, donanemab) or twice tient is already prescribed psychoactive medications yet the level of
monthly (lecanemab) infusions for up to 12 (donanemab) to 18 months BPSD is severe enough to merit a new medication trial, this suggests
(lecanemab) and possibly beyond (aducanumab), as well as serial sur- that the current regimen is ineffective. Therefore, prior to prescribing
veillance MRIs for the first 4 to 5 months. In light of the high costs of new medications, consider a medication “cleanup” focused on depre-
these drugs and their administration, debate remains regarding the ef- scribing psychoactive medications. Following the approach outlined
fectiveness and value of these amyloid immunomodulators.78,79 by Davies et al,101 cognitive medications (ie, cholinesterase inhibitors
There are no FDA-approved medications for non-AD demen- and memantine) should be continued while medications specifically
tias (Table 4), with the exception of rivastigmine for mild to mod- started for BPSD (as opposed to an underlying, preexisting psychiat-
erate dementia in patients with Parkinson disease and dementia with ric disorder) would be considered for discontinuation prior to starting
Lewy bodies.80,81 Off-label use of CIs and memantine for dementia a new medication. Clinicians might prioritize medications for discon-
with Lewy bodies, vascular dementia, and dementia due to trau- tinuation based on the evidence of harms, such as where a benzodi-
matic brain injury is common, and though evidence is weak,82,83 azepine or gabapentin is coprescribed with an opioid.102,103 But even
there is some evidence to show a small benefit (Table 4).84 CIs and a medication perceived as relatively safe (eg, a serotonin reuptake in-
memantine are not recommended in frontotemporal dementia due hibitor such as sertraline) could be causing gastrointestinal distress or
to lack of efficacy.85 akathisia that is manifesting as agitation in a patient with dementia.
Although evidence of efficacy is lacking, psychotropic medica-
tions such as antidepressants, benzodiazepines, and antiepileptics are
What to Watch For widely prescribed.92,104 Atypical antipsychotics have modest evi-
There are currently 141 individual treatments in trials for AD across denceofefficacy.105 Risperidoneisapprovedforshort-termuseinboth
12 Common Alzheimer Disease Research Ontology mechanisms86 Canada (aggression or psychosis) and the UK (aggression) and is a po-
as well as treatments for AD at the preclinical, asymptomatic stage. tential first pharmacological treatment step for major, potentially dan-
The AHEAD study87 is currently evaluating the use of lecanemab in gerous symptoms that have not responded to behavioral
asymptomatic individuals with mild to moderately elevated brain approaches.93 While quetiapine is the most widely prescribed anti-
amyloid levels. Tau-directed treatments include passive immuno- psychotic for individuals with dementia,94 it is among those with the
therapies and small molecule tau aggregation inhibitors.88 Ongo- least evidence of efficacy for BPSD.99 Two other antipsychotics are
ing studies are also targeting amyloid and tau simultaneously. Thir- worth noting: (1) brexpiprazole, which was recently FDA approved for
teen treatments are under investigation for dementia with Lewy agitation in persons with AD but has the same classwide safety con-
bodies.89 Current investigational medications for frontotemporal de- cerns related to increased mortality as other antipsychotics, and (2)
generation have been focused on people with identifiable genetic pimavanserin, a serotonin-receptor modulator that acts primarily as
variations (GRN, C9ORF72), as well as on various mechanisms to sup- a selective 5-hydroxytryptamine receptor subtype 2A inverse ago-
press expression and pathological dysregulation of tau and pro- nist and antagonist rather than binding to D2 dopamine or histamine
granulin pathways.90 receptors.106 Pimavanserin is FDA approved for the treatment of Par-
kinson disease psychosis (but not psychosis of AD) and has a poten-
tially lower mortality risk than other atypical antipsychotics used for
Treatment of Behavioral this indication.107
Although BPSD may resemble symptoms of psychiatric disorders
and Psychological Complications
in individuals without cognitive impairment, medications that are ef-
Although cognitive impairment is the clinical hallmark of dementia, fectiveforthesedisordersaregenerallynoteffectiveforthesamesymp-
behavioral and psychological symptoms of dementia (BPSD), such as toms in dementia.94 For example, a Cochrane meta-analysis of antide-
apathy, delusions, and agitation, are common and often are the pre- pressant studies for depression in persons living with dementia con-
senting symptoms.91-93 BPSD is a fundamental aspect of the neuro- cluded that there is insufficient evidence of efficacy,108 though
degeneration that is present in all forms of dementia and may either citalopram can reduce agitation.109 Antidepressants are also ineffec-

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 Dementia Prevention and Treatment Review Clinical Review & Education

tive for apathy,110,111 although methylphenidate may be beneficial.112 unable to consider the effect of multiple contributors on risk but are
Antiepileptic “mood stabilizers” (eg, valproic acid, carbamazepine) and able to provide some insight from several studies that address more
trazodone are ineffective for irritability and agitation. Valproic acid than 1 risk factor.36-39 We were also unable to compare the relative
merits particular mention because it is perceived as the leading alter- benefits of these interventions across strata of increasing age, where
native to antipsychotics for BPSD in long-term care settings113 despite the balance of risks vs benefits may become less favorable. Al-
a Cochrane review recommending against its use in persons with though not covered here, key aspects of patient-centered care and
dementia.114 health equity must be considered, including focusing on patient- or
Well-established safety concerns about medications for BPSD in- caregiver-identified goals, caregiver support, use of community-
clude an increased risk of fall-related injury for most psychotropics115-117 based services, housing and social issues, and advance directives and
and mortality for antipsychotics.118 Less appreciated is the adverse ef- hospice.
fect on cognition in persons with dementia.119,120 Clinicians should
monitor for psychotropic changes during inpatient or subacute
care120,121 of persons living with dementia and continually reevaluate
Conclusions
the balance of risks and benefits of these treatments.
Although numerous risk factors for developing dementia have been
What to Watch For identified, convincing evidence that modification of these factors,
A trial of electroconvulsive therapy for agitation in moderate to se- either alone or in combination, can prevent dementia is lacking. AD
vere dementia is underway,122 along with a CitAD follow-up using esci- can be treated with cholinesterase inhibitors, an N-methyl-D-
talopram (S-CitAD)123 and studies of cannabinoids.124 On the nonphar- aspartate antagonist, or β-amyloid immunomodulator medica-
macological front, a trial of an online caregiver-directed platform based tions, with the last modestly slowing cognitive and functional de-
on DICE is underway.125 cline in people with MCI or mild dementia due to AD. Ongoing clinical
trials will help to elucidate the long-term clinical efficacy, safety, and
cost-effectiveness of these emerging treatments. Psychotropic medi-
cations have minimal evidence of efficacy for treating BPSD and are
Limitations
associated with notably increased risks of falls and cognitive de-
When considering prevention, we confined this review to existing cline. Ongoing and future research will undoubtedly provide new in-
published data and did not conduct new analyses. Thus, we were sights into prevention and treatment of dementia.

ARTICLE INFORMATION caregivers of patients with Alzheimer disease. J Am Research Group. Effect of intensive vs standard
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jamda.2015.09.007 a randomized clinical trial. JAMA. 2019;321(6):553-
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reported grants from the National Institute on 10.1007/s11606-021-07054-3 dementia and Alzheimer’s disease: a meta-analysis
Aging and the Patient-Centered Outcomes of individual participant data from prospective
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Dr Kremen reported personal fees from Eli Lilly doi:10.1016/S1474-4422(19)30393-X
outside the submitted work. No other disclosures report of the Lancet Commission. Lancet. 2020;
were reported. 396(10248):413-446. doi:10.1016/S0140-6736(20) 14. Cunningham EL, Todd SA, Passmore P, Bullock
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