Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels.
Methods:The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined.Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy.Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life. A 1997 Nun Study (NS) report demonstrated a powerful effect on cognitive function of comorbid brain infarcts and Alzheimer disease (AD) neuropathologic changes, reporting an odds ratio (OR) of 20.7 for dementia in participants with both high levels of AD neuropathologic changes and cerebral infarcts.1 A 2002 report of 285 autopsied participants in the Honolulu-Asia Aging Study (HAAS) provided a comprehensive description of 4 major neuropathologic abnormalities, each robustly associated with late-life cognitive impairment: AD neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis (HS), and microinfarcts.2 Subsequent HAAS analyses demonstrated that generalized brain atrophy may occur independently, as a fifth common abnormality associated with cognitive impairment.3,4 Extensive analyses using autopsy and clinical data have further documented both the multiplicity of neuropathologic abnormalities associated with late-life dementia and the complex relationships between them. [5][6][7][8][9][10][11][12] Indeed, the high frequency of neuropathologic comorbidity in older persons with dementia has become widely appreciated around the globe. [13][14][15][16][17][18][19][20][21] In 2013, the first 22 brain autopsies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were reported. 22 All had been diagnosed during life with AD dementia or AD-type mild cogniti...