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Much of late life cognitive decline is not due to common neurodegenerative pathologies
Open accessAbstract
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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“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.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [7]
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Metadata
- 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.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2013-07-10
- Volume
- 74
- Issue
- 3
- Pages
- 478-489
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3845973
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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