The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia
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BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.
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In one study of six community cohorts, 4,354 people aged >80 years who died in the US or UK, 91% died with two or more types of neuropathology.
“One study of six community cohorts, comprising 4,354 people aged >80 years who had died in the US or UK, analysed six types of neuropathology and found 91% of people died with two or more types of neuropathology.(20)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [20]
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Experimental — accuracy not yet measuredMultiple neuropathologies are common in older populations and more common than Alzheimer pathology alone.
“Multiple neuropathologies are common in older populations and more common than Alzheimer pathology alone (see figure 1). (20)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [20]
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CAPS: a simple clinical tool for β-amyloid positivity prediction in clinical Alzheimer syndrome
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- Authors
- Nichols, E., Merrick, R., Hay, S. I., Himali, D., Himali, J. J., Hunter, S., Keage, H. A. D., Latimer, C. S., Scott, M. R., Steinmetz, J. D., Walker, J. M., Wharton, S. B., Wiedner, C. D., Crane, P. K., Keene, C. D., Launer, L. J., Matthews, F. E., Schneider, J., Seshadri, S., White, L., Brayne, C., & Vos, T.
- Affiliations
- University of Washington (US)
- University of Cambridge (GB)
- Framingham Heart Study (US)
- Boston University (US)
- University of South Australia (AU)
- Icahn School of Medicine at Mount Sinai (US)
- University of Sheffield (GB)
- The University of Texas at San Antonio Health Science Center (US)
- National Institute on Aging (US)
- Newcastle University (GB)
- Rush University Medical Center (US)
- Pacific Health Research and Education Institute (US)
- Corresponding author
- Nichols, Emma
- ORCID
- Nichols, Emma
- Merrick, Richard
- Hay, Simon I
- Himali, Dibya
- Himali, Jayandra J
- Hunter, Sally
- Keage, Hannah A D
- Latimer, Caitlin S
- Scott, Matthew R
- Steinmetz, Jaimie D
- Walker, Jamie M
- Wharton, Stephen B
- Crane, Paul K
- Keene, C Dirk
- Launer, Lenore J
- Matthews, Fiona E
- Schneider, Julie
- Seshadri, Sudha
- White, Lon
- Brayne, Carol
- Vos, Theo
- Venue
- The Lancet Healthy Longevity
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 4
- Issue
- 3
- Pages
- e115-e125
- ISSN
- 2666-7568 (ISSN-L)
- PMC
- PMC9977689
- OpenAlex
- W4322722320
- Cited by
- 108
- References
- 43
- Citations by year
- 2026: 35 · 2025: 37 · 2024: 26 · 2023: 10
- FWCI
- 21.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Lancet Healthy Longevity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository@Hull (Worktribe) (University of Hull) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Institutes of Health (AG054076, AG049607, HHSN268201500001I, AG059421, AG066524, AG033090, 75N92019D00031, N01-HC-25195)
- National Institute for Health and Care Research
- Office of Research and Development
- Nancy and Buster Alvord Endowment
- National Heart, Lung, and Blood Institute (5 R01 NS041265)
- Bill and Melinda Gates Foundation
- Alzheimer’s Research UK (N01-AG-4-2149, 5 R01 AG017155, N01-HC-05102, 1 UO1 AG19349, ARUK-PhD2017-34)
- Alzheimer’s Disease Research Center, University of Washington (P30 AG066509)
- National Institute on Aging (U19AG066567, U01AG006781)
- U.S. Department of Veterans Affairs
- National Institute of Neurological Disorders and Stroke (UF1NS125513, NS017950, AG062531)
- Medical Research Council (G0400077, G9901400, G0900582, U.1052.00.0013)
- 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
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Cross-Sectional Studies, Dementia, Female, Humans, Male, Prevalence, Cerebral Amyloid Angiopathy, Limbic Encephalitis, Atherosclerosis, TDP-43 Proteinopathies
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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