Alzheimer disease (AD), Lewy body variant of Alzheimer disease (LBV), and the frontotemporal dementias (FTD) are a class of adult-onset neurodegenerative dementias characterized by the intracellular and/or extracellular accumulation of proteins which assemble into β-pleated sheet fibrils.
Missense mutations in the β-amyloid precursor protein (βAPP) gene on chromosome 21, in the presenilin 1 (PS1) gene on chromosome 14, and the presenilin 2 (PS2) on chromosome 1, are associated with early-onset forms of familial Alzheimer disease. Mutations in these genes result in altered processing of βAPP and the relative overproduction of either all forms of the β-amyloid peptide or specific overproduction of isoforms ending at residue 42.
The ∊4 (Cys112Arg) variant of apolipoprotein E (APOE) is associated in a dose-dependent fashion with increased risk for late-onset Alzheimer disease (after age 55) and with Lewy body variant of Alzheimer disease. The inheritance of one or more APOE ∊4 alleles is not deterministic for AD, and the mechanism by which inheritance of one or more ∊4 alleles causes AD is unclear.
Allelic association studies have identified several putative candidate genes in which nucleotide sequence variants have been associated with AD. These studies have received only partial replication, and the true role of these candidate genes in AD remains unclear.
Hyperphosphorylated forms of the microtubule-associated protein Tau are consistent neuropathologic features of AD, LDV, and FTD. Coding region and splice-site mutations in the Tau gene on chromosome 17 are associated with a subtype of frontotemporal dementia (FTDP-17). These mutations probably affect filament assembly by several different mechanisms including alterations in the sequence of microtubule binding sites and alterations in the relative abundance of longer (4 repeat) isoforms of Tau relative to shorter (3 repeat) isoforms.
The currently identified genes associated with inherited risk for these diseases represent approximately half of the probable genetic factors causing these diseases. As the remaining susceptibility genes are identified, they will likely contribute to a more complete understanding of the pathogenesis of these disorders.