Methodological Approaches to Study the Genetics of Dementia and Cognitive Function

Alzheimer’s disease (AD) is the main cause of dementia and one of the most burdensome conditions of later life. The prevalence of AD grows exponentially with age, starting at less than 1% at the age of 60 years, reaching as high as 33% at the age of 85 years1. Smoking is one of the few non-genetic risk factors known to be involved in AD. Family history of AD has long been known as a strong predictor of the disease and the heritability of the disease was estimated as high as 79%2. Several genetic factors involved in AD have been identifi ed since the end of last century. These include the amyloid precursor protein gene (APP), the Presenilin 1 gene (PSEN1) and the Presenilin 2 gene (PSEN2), which are involved in early onset AD. Mutations in APP cause excessive cleavage by the β- and γ-secretase enzymes, instead of normal cleavage by the α-secretase enzyme. The result is an increased production of toxic β-amyloid fragments, which are converted into insoluble aggregates that form senile plaques in brain tissue. PSEN1 and PSEN2 are involved in the γ-secretase complex, and mutations lead to excessive cleavage by the γ-secretes enzyme, which results in increased production and accumulation of β-amyloid fragments. To date, no monogenic mutation was described for late-onset AD. The genetic factor, which is most predominant in both early and late onset AD, is the apolipoprotein E gene (APOE). The APOE gene has 3 common allelic forms, E2 (which occurs with a frequency about 8% in Europeans), E3 (about 75%), and E4 (about 15%). The E4 allele is associated with an increased risk of AD. Compared to non-carriers, the carriers of a single copy of the E4 allele have a 3-4 fold increased risk to develop AD, and the carriers of two copies of the E4 allele have a 10-12 fold increased risk to develop AD. APOE is involved in cholesterol transport and β-amyloid formation3, but the exact mechanism how it promotes AD remains unclear. Recently, a genetic test for APOE genotype was marketed as a tool for predicting the risk of AD (http://www.labtestsonline.org).

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