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Prior work estimated that the three most studied of these, Alzheimer\u2019s disease, infarcts, and Lewy bodies, account for \u223c40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline [e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions]. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n\u2009=\u20091164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer\u2019s disease, non- Alzheimer\u2019s disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = \u22120.101, SE = 0.003, P\u2009&amp;lt;\u20090.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P\u2009&amp;lt;\u20090.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer\u2019s disease-related indices accounted for 30\u201336% of the variation, non-Alzheimer\u2019s disease neurodegenerative indices 4\u201310%, and cerebrovascular indices 3\u20138%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.<\/jats:p>","DOI":"10.1093\/brain\/awab092","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T08:12:42Z","timestamp":1615968762000},"page":"2166-2175","source":"Crossref","is-referenced-by-count":223,"title":["To what degree is late life cognitive decline driven by age-related neuropathologies?"],"prefix":"10.1093","volume":"144","author":[{"given":"Patricia A","family":"Boyle","sequence":"first","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Wang","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S","family":"Wilson","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Dawe","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Diagnostic Radiology and Nuclear Medicine, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Arfanakis","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Diagnostic Radiology and Nuclear Medicine, Chicago, IL 60612, USA"},{"name":"Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A","family":"Schneider","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Department of Pathology, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Rush Alzheimer\u2019s Disease Center, Chicago, IL 60612, USA"},{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,20]]},"reference":[{"key":"2021081715523355900_awab092-B1","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1212\/WNL.0000000000002480","article-title":"Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia aging 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