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Person-specific contribution of neuropathologies to cognitive loss in old age
Open accessAbstract
Objective: Mixed neuropathologies are the most common cause of dementia at the population level, but how different neuropathologies contribute to cognitive decline at the individual level remains unknown. We quantified the contribution of 9 neuropathologies to cognitive loss at an individual level. Methods: Participants (n = 1,079) came from 2 longitudinal clinical–pathologic studies of aging. All completed 2 + cognitive evaluations (maximum = 22), died, and underwent neuropathologic examinations to identify Alzheimer disease (AD), other neurodegenerative diseases, and vascular pathologies. Linear mixed models examined associations of neuropathologies with cognitive decline and estimated the proportion of cognitive loss accounted for by each neuropathology at a person‐specific level. Results: Neuropathology was ubiquitous, with 94% of participants having 1+, 78% having 2+, 58% having 3+, and 35% having 4+. AD was most frequent (65%) but rarely occurred in isolation (9%). Remarkably, >230 different neuropathologic combinations were observed, each of which occurred in <6% of the cohort. The relative contributions of specific neuropathologies to cognitive loss varied widely across individuals. Although AD accounted for an average of about 50% of the observed cognitive loss, the proportion accounted for at the individual level ranged widely from 22% to 100%. Lewy bodies and hippocampal sclerosis also had potent effects, but again their impacts varied at the person‐specific level. Interpretation: There is much greater heterogeneity in the comorbidity and cognitive impact of age‐related neuropathologies than currently appreciated, suggesting an urgent need for novel therapeutic approaches that embrace the complexity of disease to combat cognitive decline in old age. Ann Neurol 2018;83:74–83
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“Studies suggest that mixed dementia is the norm, not just for those diagnosed with Alzheimer's dementia but also for those diagnosed with other types of dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [37]
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“As inquiries move in this direction—through the use of PET imaging, cerebrospinal fluid, blood, or autopsy—it is important to note that mixed dementia is the most common type of dementia and that a diverse set of neuropathologies may contribute to the clinical syndrome that we diagnose as dementia (Boyle et al. 2018; Brenowitz et al. 2017; Power et al. 2018b).”
From Exposure to Air Pollution in Relation to Risk of Dementia and Related Outcomes: An Updated Systematic Review of the Epidemiological Literature (2021) · cites this paper as Boyle et al. 2018
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“A further RCT of cognitively stimulating activities for people with delirium in dementia did not improve the delirium.293”
From Dementia prevention, intervention, and care: 2020 report of the Lancet Commission (2020) · cites this paper as [293]
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“First, it captures all the factors affecting cognition, including diverse pathologies as well as biological mechanisms independent of pathologies4–6.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [5]
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“Second, it likely captures co-occurring disease processes and co-occurring age-related pathologies, which are known to be prevalent in the brains of aged individuals4,5.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [5]
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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 [5]
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The Heart Brain Team and Patient-Centered Management of Ischemic Stroke
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Right fronto-parietal networks mediate the neurocognitive benefits of enriched environments
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“Although neuropathological markers of Alzheimer’s Disease are associated with cognitive deficits, over 50% of the variability in symptomatology still remains unexplained (Boyle et al., 2018; Boyle et al. 2021).”
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“Thus, the synergistic effect of combined AD or worse vascular injury due to severe CAA may contribute to cognitive decline [50, 51].”
BackgroundCorrelated decline of cognitive and motor phenotypes and ADRD pathologies in old age
Buchman, A. S., Wang, T., Oveisgharan, S., Zammit, A. R., Agrawal, S., Yu, L., & Bennett, D. A. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13347 · Cited by 10
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“In prior work using data from Rush Memory and Aging Project (MAP), we examined a variety of approaches linking pathology to change in cognition over multiple years before death [19,20].”
MethodSelf-citationCanevelli, M., Bacigalupo, I., Gervasi, G., Lacorte, E., Massari, M., Mayer, F., Vanacore, N., & Cesari, M. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00282 · Cited by 10
“Finally, most of dementia cases (including AD dementia) are underlined by a mixed neuropathology (Boyle et al., 2018).”
Rolandi, E., Dodich, A., Galluzzi, S., Ferrari, C., Mandelli, S., Ribaldi, F., Munaretto, G., Ambrosi, C., Gasparotti, R., Violi, D., et al. (2019) · Aging Clinical and Experimental Research · doi:10.1007/s40520-019-01403-3 · Cited by 11
Whole-exome sequencing of Finnish patients with vascular cognitive impairment
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Mechanisms and Impact of Cognitive Reserve in Normal Aging and Alzheimer’s Disease
Simfukwe, C., An, S. S. A., & Youn, Y. C. (2025) · Diagnostics · doi:10.3390/diagnostics15233068 · Cited by 11
“It was increasingly recognized that the degree of cognitive impairment did not always correspond directly to neuropathological burden; individuals with comparable levels of amyloid accumulations or brain atrophy may exhibit markedly different clinical trajectories [17,18].”
A multi-target therapeutic framework for Alzheimer’s disease: an integrative mechanistic review
Bajinka, O., Jallow, L., & Ozdemir, G. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.01.010 · Cited by 10
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Association of liver fibrosis with cognitive decline in Parkinson’s disease
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Advances in retinal imaging biomarkers for the diagnosis of cerebrovascular disease
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Sex Differences in Associations of Lewy Body Disease with Alzheimer's Disease and Cognitive Decline
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“Mixed dementia presentations are relatively common [52].”
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Self-citationFrailty and the brain: A narrative review of functional and pathological correlates
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“With the increase in the aging population worldwide, driven by improvements in socioeconomic status, greater access to healthcare, and advances in technology, this aging trend is predicted to continue (Boyle et al., 2018; Cheng and Hu, 2020; Power et al., 2019).”
Poole, V. N., Oveisgharan, S., Yu, L., Dawe, R. J., Leurgans, S. E., Zhang, S., Arfanakis, K., Buchman, A. S., & Bennett, D. A. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1194986 · Cited by 8
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“Our findings showed that AD and vascular pathologies have independent effects on primacy decline, which remains consistent with more comprehensive neuropathological analyses carried out in the overall ROS/MAP cohorts (Boyle et al., 2018, 2021).”
ResultSelf-citationChen, T., Lee, W., Chen, J., Chang, S.-Y., Lin, C.-F., & Chen, H.-C. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01083-8 · Cited by 8
“AD pathology rarely occurs in isolation and the number of co-pathologies tends to increase with age [10, 11].”
BackgroundCopper, oxidative stress, Alzheimer's disease, and dementia
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“…are developed for a specific pathology (Mintun et al., 2021; van Dyck et al., 2023), the beneficial effect from treating a single pathology might be minor given the large number of combinations of person-specific burden of mixed-brain pathologies observed in aging brains (Boyle et al., 2018, 2021).”
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“%) in old age, but instead withmixed neuropathologies, and accounts on average for about 50% of the observed cognitive loss (Boyle et al., 2018).”
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Ten Things to Remember (and Not Forget) About Vascular Cognitive Impairment
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Metadata
- Authors
- Boyle, P. A., Yu, L., Wilson, R. S., Leurgans, S. E., Schneider, J. A., & Bennett, D. A.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Boyle, Patricia A.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2018-01
- Volume
- 83
- Issue
- 1
- Pages
- 74-83
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC5876116
- OpenAlex
- W2771599582
- Cited by
- 508
- References
- 26
- Citations by year
- 2026: 33 · 2025: 65 · 2024: 66 · 2023: 67 · 2022: 82 · 2021: 49 · 2020: 82 · 2019: 47 · 2018: 16
- FWCI
- 32.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01AG34374, R01AG42210, R01AG17917, P30AG10161, R01AG15819)
- Illinois Department of Public Health
- 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
- neuropathology, cognitive decline, dementia, Alzheimer's disease, Lewy bodies, hippocampal sclerosis, vascular pathology, neurodegenerative diseases, individual heterogeneity, aging
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Autopsy, Brain, Female, Humans, Longitudinal Studies, Male, Nervous System Diseases, Neuropsychological Tests, Dementia, Vascular, Cohort Studies, Comorbidity, Lewy Body Disease, Cognitive Dysfunction
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