Dementia is a syndrome, not a unique disease and rarely occurs in the absence of substantial brain pathology. However, many older individuals can have similar brain pathology without dementia. About 65% of older individuals aged 90+ have evidence of dementia usually due to Alzheimer’s disease (AD) pathology and vascular disease. The AD neurodegenerative process is associated with Aβ amyloid and phosphorylated tau deposition and usually coexists with vascular disease and other proteinopathies. Individuals who survive to age 90+ free of dementia, about 5%–10% of the population, include two populations: (1) little vascular and amyloid pathology and low risk of clinical AD (50%); and (2) others with pathology and cognitive reserve (50%).
We do not know the initial pathological event that leads to neuronal death. Brain microvascular disease and blood–brain barrier dysfunction are probably playing an important role in development of AD pathology in relation to clearance and metabolism of beta amyloid 1–42 (Aβ1-42). Major determinants of successful survival without dementia to older ages 85–90+ include low atherosclerosis and arteriosclerosis burden, less brain microvascular disease and neurodegeneration and fitness.