Does early-onset Alzheimer disease constitute a distinct subtype? The contribution of molecular genetics

Alzheimer disease (AD) is a clinical and pathologic diagnosis and refers to the findings of neurofibrillary tangles and amyloid plaques in the brain of a patient with dementia. Clinically it is recognized that there are familial and sporadic forms, with further division into those with presenile and senile onset. Clinical, neuroimaging, neuropathological, and neurochemical studies have attempted to identify differences between cases with an earlier and later onset, but have not identified a categorical biologic difference between the two groups. Recent advances in the molecular genetics of familial Alzheimer disease (FAD) and the discovery of defined genetic abnormalities have provided a robust approach to distinguishing between early- and late-onset cases within the group of autosomal dominant FAD. The precise biologic classification made possible by molecular genetic analysis of FAD provides a benchmark against which phenotypic differences can be assessed. This article argues that future studies will be able to contrast early-onset familial versus late-onset familial disease, and early-onset familial versus early-onset sporadic disease. Previous reports of phenotypic differences within AD may have been the result of including FAD within early-onset groups, though this remains to be established.