Cited by 323Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Much of late life cognitive decline is not due to common neurodegenerative pathologies

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Boyle, Patricia A., Wilson, Robert S., Yu, Lei, Barr, Alasdair M., Honer, William G., Schneider, Julie A., Bennett, David A.·2013·Annals of Neurology

Abstract

Objective: The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline. Methods: A total of 856 deceased participants from 2 longitudinal clinical–pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7.5 annual evaluations, including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of global Alzheimer pathology, amyloid load, tangle density, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. Random coefficient models were used to examine the linear relation of pathologic indices with global cognitive decline. In subsequent analyses, random change point models were used to examine the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline (ie, nonlinear decline). Results: Cognition declined a mean of about 0.11U per year (estimate = −0.109, standard error [SE] = 0.004, p < 0.001), with significant individual differences in rates of decline; the variance estimate for the individual slopes was 0.013 (SE = 0.112, p < 0.001). In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline. Interpretation: The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline. Ann Neurol 2013;74:478–489

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  • Pathologies such as β-amyloid plaques, neurofibrillary tangles, microinfarct, macroinfarct, and Lewy bodies together capture only about 41% of the variance in cognitive trajectory, leaving 59% unexplained.

    “However, pathologies such as β-amyloid plaques, neurofibrillary tangles, microinfarct, macroinfarct, and Lewy bodies together capture only about 41% of the variance in cognitive trajectory, leaving 59% unexplained5,7.”

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  1. [29]Schneider JA Arvanitakis Z Bang W Bennett DA Mixed brain pathologic indices account for most dementia cases in community-dwelling older persons. Neurology 2007 69 24 2197 204 17568013

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Authors
Boyle, P. A., Wilson, R. S., Yu, L., Barr, A. M., Honer, W. G., Schneider, J. A., & Bennett, D. A.
Affiliations
  • Rush University Medical Center (US)
  • University of British Columbia (CA)
Corresponding author
Boyle, Patricia A.
Venue
Annals of Neurology
Publisher
Wiley
Published
2013-07-10
Volume
74
Issue
3
Pages
478-489
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
OpenAlex
W1581476053
Cited by
323
References
39
Citations by year
2026: 17 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 25 · 2021: 20 · 2020: 26 · 2019: 30 · 2018: 36 · 2017: 31 · 2016: 33 · 2015: 24 · 2014: 17 · 2013: 11
FWCI
20.08
Type
journal article
Language
en
Open access
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Canadian Institutes of Health Research (CBG101827)
  • National Institute on Aging (R01 AG33678, R01AG017917, P30-AG 10161, R01-AG34374, R01‐AG17917, R01 AG15819, R01AG015819, P30AG010161, R01AG033678, R01AG034374)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
late-life cognitive decline, Alzheimer's disease, cerebrovascular disease, Lewy body disease, neurodegeneration, neuropathology, amyloid, neurofibrillary tangles, microinfarcts, dementia, cognitive trajectories, older adults, Religious Orders Study
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Cognition Disorders, Female, Humans, Longitudinal Studies, Male, Nerve Degeneration, Neuropsychological Tests

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