Predisposing genetic variants could, in the future, be used to predict who will develop dementia. Individuals genetically predisposed to dementia may benefit from therapeutic interventions in the early stages of the disease. Early intervention could significantly prevent or delay the onset, which in turn would improve quality of life of the patient and their relatives and would significantly reduce the public health burden.
The majority of familial early onset Alzheimer's disease (EOAD) is caused by mutations in APP, PSEN1 and PSEN2. These genes have almost complete penetrance (>85%) and a clear autosomal dominant pattern of inheritance. Thus, the presence of a mutation is virtually synonymous with disease. Complicating the wide-spread use of genetic testing for familial EOAD is the relative rarity of cases and the fact that there are multiple mutations in these genes producing the same phenotype. Thus, genetic testing requires full sequencing of the gene.
Current knowledge suggests that a variety of mechanisms underlie the various neuropathological and clinical changes, and that these have different genetic and environmental components. Thus, it is likely that late-onset cognitive impairment is a complex genetic disorder characterized by an interaction of multiple genes and the environment leading to genetic variants that have incomplete penetrance and a low-magnitude associated risk. Consistent with this notion is the fact that to date only APOE
has been firmly identified as a genetic risk factor, although segregation analyses conducted in families of patients with LOAD support the presence of additional(Daw, Payami et al. 2000
). With a population attributable risk that is estimated at 20–50%, the APOE
ε4 allele increases risk of cognitive impairment, LOAD, and ageof onset of cognitive impairment in a dose-dependent fashion: one ε4 allele is associated with a 2–3 fold increased risk, having two copies is associated with a 5–10 fold increase. Similar effect sizes have been observed for progression of cognitive impairment to dementia.
was identified as a candidate gene in which two haplotypes in the 3' and 5' regions of the gene (Rogaeva, Meng et al. 2007
)found to be associated with LOAD, with effect sizes ranging from odds ratios of 1.4 to 2.2. Subsequent studies have confirmed the association(Reitz, Cheng et al. 2011
). Variants in APOE
lack sufficient sensitivity and specificity to be used as diagnostics. Variants in both increase risk of cognitive impairment in a non-Mendelian fashion, are not fully penetrant, and that they are neither necessary nor sufficient by themselves to cause impairment. The same is likely to be true for the remaining yet-to-be-identified genetic factors associated with cognitive decline.
There have been approximately 16 genome-wide association studies (GWAS) published to date. Most of these studies have included unrelated patients with LOAD and controls, but there are three studies that used family data(Bertram, Lange et al. 2008
; Poduslo, Huang et al. 2009
; Wijsman, Pankratz et al. 2011
). Most GWAS have confirmed the APOE
association with LOAD. Two large studies have identified variants in Clusterin (CLU
), phosphatidylinositol binding clathrin assembly protein (PICALM
) and complement component (3b/4b) receptor 1 (CR1
) as being associated with LOAD risk(Harold, Abraham et al. 2009
; Lambert, Heath et al. 2009
, or apolipoprotein J (APOJ
), is a lipoprotein found to be part of amyloid plaques. CLU
specifically binds soluble Aβ in cerebrospinal fluid to form complexes able to cross the blood brain barrier. It has also been noted that reduced levels of APOE and increased levels of CLU are correlated with the number of ε4 alleles, suggesting a compensatory induction of CLU in the brain of LOAD individuals with the APOE
ε4 allele and low brain levels of APOE. CR1
encodes the complement C3b protein, which is likely to contribute to Aβ clearance(Wyss-Coray, Yan et al. 2002
is involved in clathrin-mediated endocytosis (CME), an essential step in the intracellular trafficking of proteins and lipids such as nutrients, growth factors and neurotransmitters. Of relevance to LOAD, PICALM
also appears to be involved in directing the trafficking of VAMP2, which is a soluble N
-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein that has a prominent role in the fusion of synaptic vesicles to the presynaptic membrane during neurotransmitter release, a process that is crucial to neuronal function. The gene encoding bridging integrator 1 (BIN1
) was also noted initially at a lower threshold of significance(Harold, Abraham et al. 2009
)with stronger results in a recent replication analysis(Seshadri, Fitzpatrick et al. 2010
, a gene expressed in the central nervous system, and is reported to activate a caspase-independent apoptotic process.
Genome-wide significant results at MS4A4A
on chromosome 11, CD2AP
on chromosome 6, EPHA1
on chromosome 7, and CD33
on chromosome 19 were observed in independent meta-analyses by the Alzheimer's Disease Genetic Consortium and another European-American Consortium (Hollingworth, Harold et al. 2011
; Naj, Jun et al. 2011
). The true genetic effector for these genes has not been identified and their roles in the pathogenesis are unknown.
Can any of these genes be used as biomarkers for diagnosis or as measures of disease risk? At this point, only mutations in genes associated with early onset familial Alzheimer's disease could be considered diagnostic. These mutations are virtually 100% penentrant, and therefore those who carry a mutation will develop disease. Of interest, some patients with these mutations also have elevated plasma levels of Aβ42.
Genetic variants associated with late-onset Alzheimer's disease are not useful as diagnostic measures. For example, APOE-ε4 is strongly associated with disease risk, but it has been shown to provide little help in the diagnosis. While there are many candidate genes in which variants are, or may prove to be, associated with increased risk of subsequent disease, none are currently used as biomarkers of risk.