Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm?

Brain aging is characterized by the formation of neurofibrillary tangles (NFT) and senile plaques (SP) in both cognitively intact individuals and patients with Alzheimer's disease (AD). The ubiquitous presence of these lesions and the steady increase of the prevalence of dementia up to 85 years have strongly supported a continuum between normal brain aging and AD. In this context, the study of nonagenarians and centenarians could provide key informations about the characteristics of extreme aging. We provide here a detailed review of currently available neuropathological data in very old individuals and critically discuss the patterns of NFT, SP and neuronal loss distribution as a function of age. In younger cohorts, NFTs are usually restricted to hippocampal formation, whereas clinical signs of dementia appear when temporal neocortex is involved. SPs would not be a specific marker of cognitive impairment as no correlation was found between their quantitative distribution and AD severity. The low rate of AD lesions even in severe AD as well as the weakness of clinicopathological correlations reported in the oldest-old indicate that AD pathology is not a mandatory phenomenon of increasing chronological age. Our recent stereological observations of hippocampal microvasculature in oldest-old cases challenge the traditional lesional model by revealing that mean capillary diameters is an important structural determinant of cognition in this age group.