Attributable risk of Alzheimer's dementia attributed to age-related neuropathologies

Ann Neurol. 2019 Jan;85(1):114-124. doi: 10.1002/ana.25380. Epub 2018 Dec 19.


Objective: The degree to which Alzheimer's versus other neuropathologies contribute to the risk of Alzheimer's dementia is unknown. We examined the risk of Alzheimer's dementia attributable to pathologic AD and 8 other neuropathologies.

Methods: Participants (n = 1,161) came from 2 clinical-pathological studies of aging. Multivariable logistic regression models examined associations of 8 neuropathological indices with Alzheimer's dementia and quantified the percentage of cases attributable to each. Furthermore, because some dementia cases are not driven by common neuropathologies, we re-estimated the attributable risks after empirically adjusting for such cases.

Results: Of 1,161 persons, 512 (44.1%) had Alzheimer's dementia at time of death. With the exception of microinfarcts, all neuropathological indices were independently associated with greater odds of Alzheimer's dementia. Two hundred ten (41.0%) Alzheimer's dementia cases were attributable to pathological AD. Separately, 8.9% were attributable to macroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis, 11.7% to transactive response DNA-binding protein 43, 8.1% to cerebral amyloid angiopathy, 6.0% to atherosclerosis, and 5.2% to arteriolosclerosis. A total of 83.3% of cases were attributable to all 8 indices combined. However, after further adjustment for cases driven by other factors, a total of 67.5% of cases were attributable to all 8 neuropathologic indices combined.

Interpretation: Pathological AD accounts for a considerable percentage of Alzheimer's dementia cases, but multiple other neuropathologies also contribute. In total, just over two-thirds of Alzheimer's dementia cases are attributable to common age-related neuropathologies, suggesting that other disease and resilience factors are important. ANN NEUROL 2019;85:114-124.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / pathology*
  • Aging / psychology*
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / psychology*
  • Dementia / pathology
  • Dementia / psychology
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Risk Factors