A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders

Alzheimer’s disease (AD), already one of the most serious health problems in the U.S., will carry an ever burgeoning impact as the proportion of elderly continues to increase. Clinically, AD is a progressive neurodegenerative disorder characterized by global cognitive decline. Neuropathologically, the brains of AD patients contain abundant amounts of neurofibrillary tangles (NFT) and β-amyloid in the form of senile plaques (SP) and blood vessel deposits. While the etiological events that lead to AD have not been clearly resolved, genetic factors clearly play a major role; there is an emerging consensus that AD is a complex and genetically heterogeneous disorder that is best explained by an age-dependent dichotomous model. On one hand, early-onset (<60) AD is caused by defects in any of three different genes: presenilin 1 (PSEN1) on chromosome 14 (1), presenilin 2 (PSEN2) on chromosome 1 (2), and the amyloid β protein precursor (APP) on chromosome 21 (3). On the other hand, late-onset AD is associated with genetic polymorphisms that appear to operate as risk factors and/or genetic modifiers.