Genetics of Alzheimer disease in the pre- and post-GWAS era

Alzheimer disease (AD), the most common dementia, currently affects an estimated 35 million patients world-wide [1] and is characterized by extracellular accumulation of the amyloid β (Aβ) peptide in senile plaques and intracellular accumulation of the abnormally hyperphosphorylated tau forming neurofibrillary tangles in the brain [2,3]. There is evidence from familial aggregation, transmission patterns, and twin studies that AD has a substantial genetic component that has an estimated heritability of 58% to 79% [4], and the lifetime risk of AD in first-degree relatives of patients may be twice that of the general population [5]. Families with autosomal dominant transmission of AD were described in the literature in the 1980s [6]. In the early 1990s, segregation analysis studies suggested the presence of Mendelian, autosomal, dominant risk factors underlying the risk of early-onset AD, whereas a more complex model possibly involving polygenes and environmental factors emerged for late-onset AD (LOAD) [7,8]. The identification of homology in the Aβ peptide isolated from brains of patients with AD and trisomy 21 (Down syndrome) and localization of the amyloid precursor protein (APP) to chromosome 21 [9,10], where linkage to disease risk was mapped in early-onset familial AD (EOFAD) families [11,12], led to the discovery of first autosomal dominant missense mutations in APP segregating with disease risk [13]. This was followed by identifications of autosomal dominant EOFAD mutations in the presenilin 1 (PSEN1) [14] and PSEN2 [15,16] genes, on chromosomes 14 and 1, respectively. The summary of EOFAD mutations is maintained at the Alzheimer Disease and Frontotemporal Dementia Mutation Database [17,18]. Accordingly, there are currently 32 mutations in APP, 177 in PSEN1, and 14 in PSEN2, identified in 86, 392, and 23 families, respectively. Collectively, the EOFAD mutations in these three genes account for less than 1% of all AD.Aβ, the major peptide constituent of senile