The genes involved in late-onset AD increase disease risk and are not inherited in a Mendelian fashion. First-degree relatives of patients with late-onset AD have twice the expected lifetime risk of this disease of people who do not have an AD-affected first-degree relative.143
In addition, AD occurs more frequently in monozygotic than in dizygotic co-twins,144
suggesting a substantial genetic contribution to this disorder. In the largest twin study of dementia, involving 11,884 participants in the swedish registry who were aged >65 years, 395 twin pairs were identified in which either one or both twins had AD.144
This study demonstrated a heritability of 58–79% for late-onset AD, depending on the model that was used in the data analysis.
Apolipoprotein E APOE
is the only established susceptibility gene for late-onset AD and maps to chromosome 19 in a cluster with the genes encoding translocase of outer mitochondrial membrane 40 (TOMM40), apolipoprotein C1 and apolipo-protein C2. APOE is a lipid-binding protein that is expressed in humans as one of three common isoforms, which are encoded by three different alleles, namely APOE ε2
, APOE ε3
and APOE ε4
. The presence of a single APOE ε4
allele is associated with a 2–3-fold increase in the risk of AD, while the presence of two copies of this allele is associated with a fivefold increase in the risk of this disease. Each inherited APOE ε4
allele lowers the age of AD onset by 6–7 years.145–147
Furthermore, the presence of this allele is associated with memory impairment, MCI, and progression from MCI to dementia.148
has been suggested to account for as much as 20–30% of AD risk.
Despite the studies linking APOE ε4
with AD, the presence of this allele is neither necessary nor sufficient for disease: among participants in the Framingham study,149
55% of those who were homozygous for APOE ε4
, 27% of those with one copy of this allele and 9% of those without an APOE ε4
allele developed AD by 85 years of age. Segregation analyses conducted in families of patients with AD support the presence of at least four to six additional major AD risk genes.150
Additional genetic risk variants
, the best-validated gene modulating late-onset AD risk is the sortilin-related receptor 1 (SORL1
) gene, which is located on chromosome 11q23. SorL1 belongs to a group of five type I transmembrane receptors (the others being sortilin, SorCS1, SorCS2 and SorCS3) that are highly expressed in the CNS and are characterized by a luminal, extracellular vacuolar protein sorting 10 domain. From family-based and population-based studies that, together, included over 6,000 individuals from four ethnic groups, Rogaeva et al.
identified two haplotypes in the 3' and 5' regions of SORL1
that are associated with late-onset AD risk.151
In addition, these researchers demonstrated that SorL1 promotes the translocation and retention of APP in subcellular compartments that exhibit low secretase activity, thereby reducing the extent of proteolytic breakdown into both amyloidogenic and nonamyloidogenic products.151
As a consequence, under-expression of SORL1
leads to overexpression of Aβ and an increased risk of AD. Several subsequent studies replicated these initial genetic association findings, and the results were further validated by a collaborative, unbiased meta-analysis of all published genetic data sets that included a total of 12,464 AD cases and 17,929 controls.152
In the past year, two studies demonstrated that, in addition, genetic variation in the SORL1
influences AD risk, cognitive performance, APP processing and Aβ1–40
levels through an effect on γ-secretase processing of APP,153,154
further emphazising the role of SorL1-related proteins in late-onset AD etiology.
Genome-wide association studies for AD using large numbers of cases and controls155–158
have revealed modest effect sizes for several genes on AD risk, with odds ratios in the range of 1.1–1.5, although most of these studies have only confirmed the association of APOE
with this disease. One such study showed that variants of TOMM40
—which is proximally located to and in linkage disequilibrium with APOE
—were associated with AD risk, but whether these genetic associations are independent of the APOE
locus remains unclear.159
Together, two genome-wide association studies identified variants in the clusterin gene (CLU)
, the phosphatidylinositol-binding clathrin assembly protein gene (PICALM
) and complement receptor type 1 gene (CR1
) as being associated with AD, but functional data confirming the roles in AD of the proteins encoded by these genes are still lacking.160,161
Clusterin is a lipoprotein that is expressed in mammalian tissues and is incorporated into amyloid plaques. This protein binds to soluble Aβ in CSF, forming complexes that can penetrate the BBB. Clusterin levels are positively correlated with the number of APOE ε4
alleles, suggesting a compensatory induction of CLU
in the brains of AD patients with the APOE
allele, who show low brain levels of APOE.162
encodes a protein that is likely to contribute to Aβ clearance from the brain,163
while PICALM protein is involved in clathrin-mediated endocytosis, allowing intracellular trafficking of proteins and lipids such as nutrients, growth factors and neurotransmitters.164
PICALM protein also has a role in the trafficking of vesicle-associated membrane protein 2, a soluble N
-ethylmaleimide-sensitive factor attachment protein receptor that is involved in the fusion of synaptic vesicles to the presynaptic membrane in neurotransmitter release.
A third large genome-wide association study confirmed the associations of PICALM
and reported two additional loci as being associated with AD: rs744373, which is near the bridging integrator 1 gene (BIN1)
on chromosome 2q14.3, and rs597668, which is located on chromosome 19q13.3.
Bin1 is a member of the Bar (Bin–amphiphysin–rvs) adaptor family, which has been implicated in caspase-independent apoptosis and membrane dynamics, including vesicle fusion and trafficking, neuronal membrane organization, and clathrin-mediated synaptic vesicle formation.166
Of note, the latter process is disrupted by Aβ.167
Changes in BIN1
expression have also been shown in aging mice and in transgenic mouse models of AD.168
The locus rs597668 is not in linkage disequilibrium with APOE
, suggesting that the effect of this locus on AD risk is independent. Six genes are found in this region, of which at least two (genes encoding biogenesis of lysosomal organelles complex 1 subunit 3 and microtubule-associated protein–microtubule affinity-regulating kinase 4) are implicated in molecular pathways linked to AD or other brain disorders.169–171
The results of the published genome-wide association studies are informative, but the genetic associations need functional validation. Indeed, such studies alone cannot prove causality or assess the biological significance of an observed genetic association. Furthermore, while genome-wide association studies represent a method of screening the genome, limitations exist in their ability to detect true associations. Also, the results of such studies can be difficult to replicate if the actual effect is smaller than that observed in the initial study. Finally, the detection of associations with multiple rare variants at a single site (which are better detected by linkage studies) or with single rare variants (minor allele frequency <5%) may not be possible. These limitations have led researchers to focus on additional biological characteristics—including endophenotypes (Box 4
) and epigenetic characteristics (Box 5
)—to facilitate the identification of disease-causing mutations.
Box 4 | Endophenotypes and genetic epidemiology
Endophenotypes (measurable intermediate phenotypes that are closer to the action of the gene than affection status) provide clues to the genetic underpinnings of a disease, and diagnoses can be deconstructed to increase the success of genetic analyses. Age at disease onset is a well-established endophenotype for Alzheimer disease (AD), and is a key indicator of genetic heterogeneity. Recognition of various age-at-onset profiles among families was critical in the initial identification of genetically distinct forms of AD. Age information, such as age-at-onset data for individuals affected by AD and censored age data for unaffected individuals, is also an important covariate used to modify the penetrance function, allowing determination of age-dependent penetrance of the disease as a function of disease genotype, while also increasing the power of genetic linkage studies and the accuracy with which disease genes can be localized. In addition to the use of age at onset as a covariate and as a stratifier in genome scans, this endophenotype has a genetic basis, with several contributing loci having been identified. Nevertheless, despite overwhelming evidence that age is an important variable to be considered in genetic risk factor research for AD, most genome scans for this disease have not incorporated age information. Other quantitative phenotypes that have been proven useful are pathological phenotypes, such as neuritic plaque and neurofibrillary tangle densities, structural brain changes on brain imaging such as white matter lesions, and cognitive function.
Box 5 | Epigenetic mechanisms
Several epigenetic studies are underway using normal brain tissue to identify functional cis-acting regulatory polymorphisms that may be associated with brain disorders such as Alzheimer disease. Allele-specific DNA methylation—an epigenetic marker—is often strongly dependent on nearby single-nucleotide polymorphisms (SNPs) and haplotypes. This observation suggests that mapping allele-specific DNA methylation across the whole genome in human brain DNA could be useful for finding regulatory SNPs that act in this target tissue and are involved in specific brain disorders.