Cell and Molecular Neuropathology of Alzheimer Disease

Although forms of dementia arising late in life had been identified by Kraepelin and his colleagues in the 1800s, it was not until 1907 that Alois Alzheimer identified the presenile form of dementia with unique neuropathologic features that now bears his name. Alzheimer described a 51year-old woman who presented with personality changes and soon developed progressively worsening memory loss, disorientation to time, and language disturbances but who had relatively normal neurologic function. Mental deterioration progressed, and she died 4⁄2 years later. On autopsy, her brain showed clear evidence of cerebral atrophy. Under the microscope, Alzheimer discovered that many cortical neurons contained argyrophilic fibrous structures—neurofibrillary tangles (NFTs)—now known to be mainly composed of abnormal filamentous forms of the microtubuleassociated protein, tau. Coexisting in the same affected brain regions were extracellular plaquelike lesions. These neuritic or ‘‘senile’’ plaques were later discovered to contain -amyloid, a fibrillar form of the A peptide, as their signature constituent. In 1910, Kraepelin proposed that this neuropathologic picture was pathognomic of a new presenile dementing disease and introduced the eponym Alzheimer disease (AD). Nearly a century later, genetic analyses have shown AD to be the common neuropathologic outcome of different primary etiologic factors (1). Roughly one-third of patients with AD have a familial predisposition, with at least one other affected first-degree relative. In families with earlyonset AD arising before the age of 65 years, a type accounting for 2% to 10% of all AD cases, the transmission pattern is consistent with an autosomal dominant disorder with age-dependent penetrance. To date, early-onset familial AD (FAD) has been linked to mutations of three different genes: the amyloid precursor protein (APP) gene and the presenilin 1 (PS1) and presenilin 2 (PS2) genes. Together, these muta-