Cerebral amyloid deposition and diffuse plaques in ``normal'' aging

Histopathologic Alzheimer's disease (AD) is marked by the presence in the cerebral cortex of two major features, the neurofibrillary tangle (NFT) and the senile plaque (SP). Although the comparative relevance of these lesions for the etiopathogenesis of AD is controversial, ^[1] quantitation or semiquantitation of SPs, rather than of NFTs, forms the basis of current neuropathologic diagnostic criteria for AD. ^[2,3] This approach acknowledges that SPs are abundantly present in virtually all AD patients; also, cases have been recognized with typical clinical features of AD and many SPs but with very few or no neocortical NFTs (so-called ``plaque-only'' AD), ^[4] whereas cases of NFT-predominant AD are rare. ^[5] Further support for SPs as primary markers of AD comes from genetic and neurobiological evidence that beta-amyloid protein (A beta), the hallmark constituent of SP, may be critical for the processes leading to neuronal death in AD. ^[6] A beta is derived from the chromosome 21-encoded amyloid precursor protein (APP). Evidence for its potentially causative role in AD includes observations that overexpression of APP by an apparent gene dose effect in trisomy 21 (Down syndrome) is associated with premature development of AD and that some forms of familial AD are linked to mutations clustered around the A beta sequence of the APP gene. ^[7] Even for most AD cases that are not linked to chromosome 21 abnormalities, an amyloid cascade hypothesis proposes multiple other factors that can trigger the abnormal production and deposition of A beta with neurotoxic effects. ^[8]

Arguments have been raised, however, against A beta deposition as the critical event in AD pathogenesis. ^[9] One argument is that many apparently nondemented individuals have appreciable numbers of A beta-containing SPs in cerebral cortex. ^[10,11] In particular, the presence in cerebral cortex of diffuse SPs (amorphous or fibrillar deposits of A …