417

The Genetics of Dementia

Janice L. Farlow, BS, BA1 Tatiana Foroud, PhD1

1 Department of Medical and Molecular Genetics, Indiana University Address for correspondence Tatiana Foroud, PhD, Department of
School of Medicine, Indianapolis, Indiana Medical and Molecular Genetics, Indiana University School of
Medicine, 410 West 10th Street (HS 4021), Indianapolis, IN 46202
Semin Neurol 2013;33:417–422. (e-mail: [email protected]).

Abstract Over the past decade, there has been a dramatic evolution of genetic methodologies
that can be used to identify genes contributing to disease. Initially, the focus was
primarily on classical linkage analysis; more recently, genomewide association studies,

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and high-throughput whole genome and whole exome sequencing have provided
efficient approaches to detect common and rare variation contributing to disease risk.
Application of these methodologies to dementias has led to the nomination of dozens of
Keywords causative and susceptibility genes, solidifying the recognition that genetic factors are
► genetic risk factors important contributors to the disease processes. In this review, the authors focus on
► dementia current knowledge of the genetics of Alzheimer’s disease and frontotemporal lobar
► Alzheimer’s disease degeneration. A working understanding of the genes relevant to common dementias
► frontotemporal lobar will become increasingly critical, as options for genetic testing and eventually gene-
degeneration specific therapeutics are developed.

Overview of Modern Genetic Technologies disease to controls who do not have the disease. Because
many genetic risk factors have modest individual effect on
The past few decades have seen exponential advances in the disease risk, large samples of cases and controls are needed to
ability to identify genes contributing to disease. Beginning obtain robust, reproducible associations. More recently,
with the identification of microsatellite markers and then meta-analysis has been widely used to combine results
single nucleotide polymorphisms (SNPs) in the early 1990s, from multiple studies. This has resulted in studies using
researchers were able to interrogate the genome to detect data from thousands of cases and controls to identify SNPs
genes causing Mendelian disorders. Linkage analysis was the that are associated with disease risk. A GWAS is based on the
most common use of these markers and sought to identify premise of linkage disequilibrium, meaning that many SNPs
chromosomal regions shared by affected members within a are tested and used as proxies for the entire genome. Thus,
family. It was hypothesized that a gene that caused the analyses can determine that a SNP is associated with disease
disease lay within these shared chromosomal regions. The risk, but cannot confirm that this particular SNP functionally
result of linkage analysis was a rapid identification of the contributes to disease risk.
genetic cause for many Mendelian disorders. This in turn has In the past few years, technology has further advanced to
provided key insights into disease pathogenesis and in some allow sequencing of DNA to be cost effective on a large scale.
cases has led to novel therapeutics. Rather than limiting sequencing to a gene or a small region of
Over the past decade, advancing genetic technologies have a chromosome, it is now possible to sequence the entire
allowed millions of SNPs to be efficiently interrogated using genome (whole genome sequencing) or only the gene-coding
genotyping arrays. These arrays include primarily common regions, the gene exons (whole exome sequencing). The
variation and have allowed scientists to explore new hypoth- ability to perform such extensive DNA sequencing has al-
eses about the role of genetics in human disease. For example, lowed researchers to examine the role of rare variation in
studies can now be designed to identify genetic factors that disease. For example, whole exome sequencing within a
increase or decrease the risk of disease. The most common family or across many families can be used to identify genes
approach that has been used is a genomewide association in which rare variants are found at greater frequency among
study (GWAS), which compares a sample of cases with the affected individuals as compared with control subjects

Issue Theme Neurodegenerative Copyright © 2013 by Thieme Medical DOI http://dx.doi.org/

Dementias; Guest Editor, Brandy R. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0033-1359313.
Matthews, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
418 The Genetics of Dementia Farlow, Foroud

who do not have the disease. Whole exome sequencing is deletions. All APP mutations reported to be pathogenic are
often focused on the identification of rare, functional variants, located at secretase sites or inside the sequence for the
which may alter the structure or function of the resulting resulting Aβ peptide, in or near exons 16 and 17 (►Fig. 1).4
protein. The types of variants that can be identified with this The majority of EOAD mutations are found in the prese-
method are not limited to single nucleotide variants, but can nilin 1 (PSEN1) gene, located on chromosome 14 and discov-
also include small insertions and deletions. ered a few years after APP.5 There have been 185 different
Whole exome and whole genome sequencing presents a mutations found in this gene alone, most clustering in the
challenge to researchers due to the large number of sequence transmembrane portion of the protein. Sequence homology
variants that are identified ( 40,000 per exome and 3 million with PSEN1 prompted the relatively rapid identification of the
per genome). Large numbers of subjects are required to presenilin 2 (PSEN2) gene on chromosome 1.6,7 Mutations in
identify candidate genes in complex diseases like Alzheimer’s this gene are quite rare and were initially due to a founder
disease (AD), and the cost is often prohibitive. New bioinfor- mutation among individuals of Volga-German ancestry. Mu-
mation technologies are constantly in development for anal- tations in PSEN2 have now been found in individuals of other
ysis of sequencing experiments, but further effort will be ancestry as well.8–10 Of those that have been reported as

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required to validate, compare, and combine these tools. pathogenic mutations, the distribution within resultant pro-
Almost all of these genetic tools and technologies have tein domains is similar to that of PSEN1. Together, presenilin 1
been used to study dementia. This review will describe (PSEN1) and presenilin 2 (PSEN2) serve as critical catalytic
what has been learned about the genetics of specific types components of the γ-secretase.11
of dementia, Alzheimer’s disease, and frontotemporal lobar Over 200 different mutations have been identified in these
degeneration (FTLD). three EOAD genes, and most are fully penetrant (►Table 1;
consult the Alzheimer Disease and Frontotemporal Dementia
Mutation database, http://www.molegen.ua.ac.be/ADMuta-
The Genetics of Alzheimer’s Disease
tions, for updated information).12 Disease-causing mutations
Alzheimer’s disease is the most common neurodegenerative in these three genes all lead to an increase in extracellular Aβ
disorder among the elderly, as well as the most common cause or a relative overabundance of the Aβ42 species, which is
of dementia overall. The key neuropathologic findings in AD thought to increase Aβ aggregation and amyloid fibril forma-
are amyloid plaques composed of β-amyloid (Aβ) and neurofi- tion.13 The discovery of APP, PSEN1, and PSEN2 contributed to
brillary tangles consisting of the tau protein. Alzheimer’s the amyloid hypothesis, which posits that amyloid plays a
disease is likely caused by a combination of genetic and critical role in AD pathology.
environmental factors. Alzheimer’s disease is typically catego-
rized into early onset (EOAD; onset < 60 years) and late-onset Late-Onset Alzheimer Disease
(onset  60 years). Early-onset Alzheimer’s disease makes up Although most LOAD cases do not have a clear heritable
less than 5% of cases, but because a subset of families has a clear etiology, genetic factors still play an important role in disease
pattern of Mendelian inheritance, mutations have been iden- risk. The lifetime risk of developing AD is  10%, and is twice
tified in several causative genes. The identification of these that for individuals having an affected first-degree relative
genes has significantly advanced the understanding of the with AD.14 Studies have estimated that the genetic
biological underpinnings of all AD cases.

Early-Onset Alzheimer’s Disease

Researchers observed that among families with EOAD, a
significant number displayed autosomal dominant inheri-
tance. This allowed linkage analysis to be successfully em-
ployed to identify three causative genes (APP, PSEN1, and
PSEN2).
APP was the first EOAD gene to be identified.1,2 It is located
on chromosome 21 and encodes the β-amyloid precursor
protein. The β-amyloid precursor protein is a neuronal pro-
tein that is sequentially cleaved by two specific proteases
(β-secretase and γ-secretase) to release Aβ. Even before APP
was identified, biochemical analysis had identified cerebral
Aβ deposits in the brains of patients with AD. In addition, it
had been found that patients with Down’s syndrome were
more likely to develop AD; therefore, it was predicted that a
gene on chromosome 21 would function to produce Aβ and Fig. 1 Location of mutations within the APP protein product as
generated from the Alzheimer Disease and Frontotemporal Dementia
would cause AD when mutated.3
Mutation database. 12 Depicted is the chain of amino acids produced
Mutations in APP are found in less than a quarter of EOAD from the APP gene. Green indicates sites of reported nonpathogenic
patients. A variety of different mutations have been found in mutations, and red indicates sites of reported pathogenic mutations.
APP including point mutations, gene duplications, and gene Sites of cleavage by secretases are shown in blue.

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 The Genetics of Dementia Farlow, Foroud 419

Table 1 Mendelian genes causing familial early-onset Alzheimer’s disease (EOAD)

Gene Protein Chromosome Mutation frequency Types of mutations reported

location in EOAD patientsa
APP B-amyloid precursor protein 21q21.2 6–26% Missense, duplications, deletions
PSEN1 Presenilin 1 14q24.3 28–61% Missense, deletions, insertions
PSEN2 Presenilin 2 1q31–42 Rare Missense
a
Mutation frequencies reported by Cohn-Hokke et al.31

contribution to LOAD susceptibility (i.e., heritability) is as Other than APOE, almost 50 additional genetic risk factors
high as 80%.15 Of note, no single gene has been identified that have now been linked to AD. Varying levels of support exist for
has a causative effect on disease risk in LOAD, which would be each gene. Nine genes have been labeled as established risk
analogous to the role of APP, PSEN1, or PSEN2 in EOAD. factors for AD, based on genome-wide significance (p value

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The apolipoprotein E gene (APOE) was the first gene  5  10 8) in meta-analyses and replication in multiple
discovered as a risk factor for LOAD, and it remains the studies.22 Much work remains to characterize exact variants
identified locus that confers the greatest susceptibility to in or near these susceptibility genes; however, the genes have
the disease. APOE is a well-known gene involved in lipid been linked to the metabolism of Aβ and synaptic function
metabolism, and it is thought to be important in Aβ clearance, (APOE, BIN1, CD33, CLU, CR1, PICALM), the immune system and
as well. There are three isoforms of APOE (ε2, ε3, ε4) that differ inflammation (ABCA7, CD33, CLU, CR1, MS4A), and lipid me-
by a single amino acid substitution. It has been shown that tabolism (ABCA7, APOE, BIN1, CLU, PICALM). These susceptibili-
this minor difference leads to different levels of clearance of ty genes, with the exception of APOE, all confer a relatively
Aβ, with the ε4 allele of APOE (APOE4) significantly decreasing small risk for AD, with odds ratios of 0.85 to 1.2 (►Table 2).23,24
the speed of clearance at the blood–brain barrier.16 The proportion of LOAD cases that could be prevented if these
The ε4 allele of APOE (APOE4) increases the risk of AD with nine (GWAS-identified) genetic risk factors were eliminated,
reported odds ratios ranging from 4 to 15.17 The effect of referred to as the cumulative population attributable risk, is
APOE4 is consistently present across populations and ethnic- estimated to be as high as 35%.25 Studies are actively underway
ities.18–20 The APOE4 effect is additive, with those having two to identify additional disease-related associations in LOAD.
APOE4 alleles having a 15-fold greater risk of AD as compared
with the 4-times increased risk for those carrying a single
Genetics of Frontotemporal Lobar
copy of the risk allele.21 Meanwhile, the ε2 allele (APOE2)
Degeneration
decreases the risk of AD by approximately a quarter, and is
considered a protective allele.21 The ε3 allele of APOE Frontotemporal lobar degeneration (FTLD) is a term that
(APOE3), the most common of the 3 APOE isoforms, has not describes the neuropathology underlying several different
been shown to have a detrimental or protective effect. clinical syndromes, all characterized by progressive damage
Importantly, the APOE2 and APOE4 alleles modify the risk to the frontal and/or temporal lobes of the brain. As a result,
of AD, but neither is causative (i.e., sufficient to cause or behavior and language are progressively impaired in individ-
protect against AD alone). uals affected with FTLD. Frontotemporal lobar degeneration

Table 2 Established risk loci for late-onset Alzheimer’s disease

Gene Protein Chromosome location Effect size / Odds ratio (95% CI)a
ABCA7 ATP-binding cassette, 19p13.3 1.23 (1.18–1.28)
subfamily A, member 7
APOE Apolipoprotein E 19q13.32 ε3ε4 genotype 3.2 (2.8–3.8)
ε4ε4 genotype 14.9 (10.8–20.6)
BIN1 Bridging integrator 1 2q14.3 1.17 (1.13–1.20)
CD2AP CD2-associated protein 6p12.3 1.12 (1.08–1.16)
CD33 CD33 molecule 19q13.41 0.85 (0.86–0.92)
CLU Clusterin 8p21.1 0.89 (0.86–0.91)
CR1 Complement component receptor 1 1q32.2 1.19 (1.09–1.30)
MS4A4E, MS4A6A Membrane-spanning 4-domains, 11q12.2 0.90 (0.88–0.93)
subfamily A, member 4E and 6A
PICALM Phosphatidylinositol binding 11q14.2 0.88 (0.86–0.91)
clathrin assembly protein
a
Effect sizes calculated from AlzGene meta-analysis.22

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420 The Genetics of Dementia Farlow, Foroud

typically presents at an earlier age than AD ( 45–65 years of Recently, expansions of a GGGGCC hexanucleotide repeat
age) and represents the second most common cause of in the noncoding portion (first intron) of C9orf72 on chromo-
dementia in those under 65 years of age. Almost half of some 9 have been associated with both FTLD and amyotrophic
individuals with FTLD have other affected family members, lateral sclerosis (ALS).36–39 The repeat number, typically less
and an autosomal dominant mode of transmission can be than 25 units in normal individuals, is expanded to greater
identified in  10% of patients.26 than 60 units in FTLD. The expanded number of repeats
Six unrelated genes with over 150 reported mutations results in the loss of one alternatively spliced transcript.
have been implicated in FTLD (►Table 3; Alzheimer Disease However, the function of this lost transcript is not yet known.
and Frontotemporal Dementia Mutation database). Muta- Estimations for the percentage of familial ALS and familial
tions in three genes (C9ORF72, GRN, MAPT) are the most FTLD cases in North American populations attributable to the
common, with rarer causative mutations found in the re- C9orf72 mutation range from 23.5 to 36.2% and 6.3 to 19.1%,
maining three genes (CHMP2B, TARDBP, VCP). Individuals respectively.39 The C9orf72 mutation appears to be more
with mutations in C9ORF72, GRN, or MAPT often present common among northern European populations.35
with the most common frontotemporal dementia clinical Mutations in the other three genes, chromatin modifying

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syndrome, the behavioral variant (bvFTD). Together, muta- 2B (CHMP2B), valosin-containing protein 1 (VCP-1) and TAR-
tions in these three genes account for at least 17% of familial DNA-binding protein 43 encoding gene (TARBDP), are rare
FTLD.27 Although there are strong correlations between the causes of FTD, found in only a few families each. The pheno-
mutated gene and the patient’s neuropathology, there is type in each is quite different and may also be associated with
typically not a clear association between the implicated non-FTD phenotypes. For example, some VCP-1 mutations are
gene and clinical phenotype.27 associated with Paget’s disease of the bone.35
Microtubule-associated protein tau (MAPT), located on There has only been one systematic FTLD GWAS, which
chromosome 17, is involved in microtubule assembly and reported TMEM106B on chromosome 7 as a potential suscep-
maintenance, and has been implicated in FTLD, AD, and other tibility gene for FTLD cases with TAR-DNA-binding protein
neurologic diseases.28–30 Over 40 mutations have been re- inclusions.40 The identified SNPs were associated with in-
ported in the gene since its discovery in 1998, mostly in exons creased TMEM106B expression, but the mechanism of upre-
9–13 (►Fig. 2). Mutations result in a change in the ratio of the gulation and the development of FTLD has not been
three amino acid (3R) and four amino acid (4R) isoforms and established.
are believed to increase the tendency of tau to form neuro-
toxic aggregates. Mutations in MAPT are found in  9 to 21% of
Genetic Counseling and Testing
FTD patients.31
Some FTLD families demonstrated genetic linkage to chro- Definitive diagnoses for AD and FTD can only be made at
mosome 17, but surprisingly no mutations in MAPT could be autopsy, but genetics may be used to increase diagnostic and
found. It was later discovered that many of these families had prognostic accuracy. With the current limitations regarding
mutations in progranulin (GRN), located only 6 Mb from disease-modifying therapies for neurodegenerative diseases
MAPT.32,33 Over 60 disease-producing mutations have been and the complex ethical considerations involved in genetic
reported in GRN. Most result in a premature stop codon and testing, clinicians must carefully consider the appropriate-
the resulting mRNA is degraded through nonsense-mediated ness of genetic analyses for patients. Because both positive
decay resulting in haplo insufficiency.34 Of note, there is and negative findings have significant implications for the
substantial clinical variability in patients carrying a GRN patient and family, thorough genetic counseling is advised
mutation. Mutations have been reported among individuals before and after any genetic testing is performed. For genetic
diagnosed clinically with language variants and bvFTD, AD, tests that are not commercially available, the tests may be
corticobasal degeneration, and mild cognitive impairment. available in the academic research setting. As more is learned
The age of onset has varied widely, even within families.35 about the genetics of AD and FTLD, commercial availability of
GRN mutations are found in  4 to 23% of all FTLD patients.31 genetic testing, and even direct to consumer testing, will

Table 3 Mendelian genes causing frontotemporal lobar degeneration (FTLD)

Gene Protein Location Mutation frequency Types of mutations reported

in FTLD patientsa
MAPT Microtubule-associated protein tau 17q21.1 9–21% Missense, deletions
GRN Progranulin 17q21.31 4–23% Missense, deletions, insertions
C9orf72 Chromosome 9 open reading frame 72 9p21 18–30% Hexanucleotide repeat expansion
TARDBP TAR DNA binding protein 1p36.22 Rare Missense
VCP Valosin-containing protein 9p13.3 Rare Missense
CHMP2B Charged multivesicular body protein 2B 3p11.2 Rare Missense
a 31
Mutation frequencies calculated by Cohn-Hokke PE et al.

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 The Genetics of Dementia Farlow, Foroud 421

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Fig. 2 Location of mutations within the MAPT protein product as generated from the Alzheimer Disease and Frontotemporal Dementia Mutation
database. 12 Depicted is the chain of amino acids produced from the MAPT gene. Green indicates sites of reported nonpathogenic mutations, and
red indicates sites of reported pathogenic mutations. Exon boundaries are marked by Ex , and microtubule-binding domains are shown in blue.

likely increase. As treatments are developed, testing options the disease-producing mutations. As additional genetic loci
will likely expand further. Clinicians will need to be familiar are recognized and characterized, correlations between gen-
with these options in an effort to counsel patients. otypes and phenotypes will become better understood. Phe-
At present, routine DNA testing in AD is advisable only for notypes will not only include presenting symptoms, but also
EOAD, if the presenting affected individual is a young or biomarkers such as structural and functional imaging and
middle-aged adult (onset < 60 years). Testing for mutations composition of the cerebrospinal fluid. Methodologies for
in PSEN 1, PSEN 2, and APP is currently commercially avail- screening, diagnosis, and prognosis will improve as addition-
able. APOE genotyping is also available, and there are ongoing al genes and mutations are identified and correlated with
studies assessing the advantages and disadvantages of APOE increasingly specific phenotypes. Most importantly, advanc-
genotyping. Most groups do not currently recommend the ing knowledge of underlying genetic factors in neurodegen-
test for predictive risk assessment.41 erative dementias will inform the pursuit of preventative and
With the heterogeneity of FTLD, the recommendations for disease-modifying therapies.
genetic testing in symptomatic patients and their families are
more complex. Considerations include the type of FTLD, the
extent of family history, and the availability and findings of Acknowledgments
autopsy tissue from an affected family member. Genetic This publication was made possible by Grant Number TL1
testing is available for MAPT, GRN, VCP, and C9orf72 in the TR000162 (A. Shekhar, PI) from the National Institutes of
United States. A full algorithm for when genetic testing should Health, National Center for Advancing Translational Sci-
be recommended has been previously reported.42 ences, Clinical and Translational Sciences Award, as well as
the National Cell Repository for Alzheimer’s Disease,
which receives government support under the cooperative
Conclusion and Outlook
agreement grant U24 AG21886.
Although much has been discovered about the genetics of
dementia, the genetic contribution to the vast majority of
sporadic and some Mendelian cases of dementia has not yet
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Seminars in Neurology Vol. 33 No. 4/2013

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