Neuropathologic Changes of Alzheimer's Disease and Related Dementias: Relevance to Future Prevention

Lon R. White, Maria M. Corrada, Claudia H. Kawas, Brenna A. Cholerton, Steve E. Edland, Margaret E. Flanagan, Thomas J. Montine

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. Objective: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. Methods: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). Results: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. Conclusion: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

Original languageEnglish (US)
Pages (from-to)307-316
Number of pages10
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - Aug 29 2023


  • Alzheimer's disease
  • Alzheimer's disease and related dementias
  • autopsy
  • co-morbidity
  • dementia
  • neuropathology
  • polymorbidity
  • prevention

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Clinical Psychology
  • General Neuroscience


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