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.
Bibliographical noteFunding Information:
The authors thank the School Sisters of Notre Dame and the men of the HAAS for participation and the late Dr. William Markesbery for his contributions to both studies and to the field of neuropathologic evaluation. Supported by NIH grants U01 AG046871 and R03 AG046614; the Intramural Research Program of the NIH, National Institute on Aging, ALZ Assn ZEN-12-239028; the Chia-Ling Chang Fund of the Hawaii Community Foundation; the Office of Research and Development, Department of Veterans Affairs Pacific Islands Health Care System; and the Nancy and Buster Alvord Endowment.