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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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“A large UK brain bank study with prospective clinical review reported that additional neurodegenerative copathologies were associated with a 20-fold increase in conversion to dementia,(1) and another report from a large prospective autopsy series found additionally that LB disease was a potent contributor at the perso…”
BackgroundColloby, S. J., McAleese, K. E., Walker, L., Erskine, D., Toledo, J. B., Donaghy, P. C., McKeith, I. G., Thomas, A. J., Attems, J., & Taylor, J. (2024) · Brain · doi:10.1093/brain/awae372 · Cited by 33
Chaudhry, A., Houlden, H., & Rizig, M. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116886 · Cited by 33
Schoemaker, D., Charidimou, A., Zotin, M. C. Z., Raposo, N., Johnson, K. A., Sanchez, J. S., Greenberg, S. M., & Viswanathan, A. (2021) · Neurology · doi:10.1212/wnl.0000000000011745 · Cited by 30
Development of a Multicomponent Intervention to Prevent Alzheimer's Disease
Saitô, S., Yamamoto, Y., & Ihara, M. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00490 · Cited by 30
“Mixed AD/CVD pathology is commonly seen in patients with clinically diagnosed AD (7, 8).”
BackgroundHachinski, V., Einhäupl, K. M., Ganten, D., Alladi, S., Brayne, C., Stephan, B. C. M., Sweeney, M. D., Zloković, B. V., Iturria‐Medina, Y., Iadecola, C., et al. (2019) · International Journal of Stroke · doi:10.1177/1747493019871915 · Cited by 28
“Recent studies using circulating biomarkers and longitudinal MRI have emphasized a role of secondary neurodegeneration after stroke as a source of ongoing neuroaxonal injury, which may extend many months and possibly years after stroke.(119,120) Whether secondary neurodegeneration contributes to cognitive decline afte…”
BackgroundElahi, F. M., Ashimatey, B. S., Bennett, D. J., Walters, S. M., Joie, R. L., Jiang, X., Wolf, A. A., Cobigo, Y., Staffaroni, A. M., Rosen, H. J., et al. (2021) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12181 · Cited by 29
Self-citationKim, Y., Kim, J., Son, M., Lee, J., Yeo, I., Choi, K. Y., Kim, B. C., Kim, B. C., Lee, K. H., & Kim, Y. (2022) · Scientific Reports · doi:10.1038/s41598-022-05384-8 · Cited by 29
Huseby, C. J., Delvaux, E., Brokaw, D. L., & Coleman, P. D. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12880 · Cited by 26
Brain microRNAs are associated with variation in cognitive trajectory in advanced age
Wingo, A. P., Wang, M., Liu, J., Breen, M. S., Yang, H.-S., Tang, B., Schneider, J. A., Seyfried, N. T., Lah, J. J., Levey, A. I., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01806-3 · Cited by 31
“Second, it likely captures cooccurring disease processes and co-occurring age-related pathologies which are known to be prevalent in the brains of aged individuals [1, 2].”
BackgroundSelf-citationPagnotti, R. M. B., Pudumjee, S. B., Cross, C. L., & Miller, J. B. (2023) · Neurology · doi:10.1212/wnl.0000000000207159 · Cited by 37
“Our findings are similar to those from Boyle et al.(23) on the predicted trajectory of cognitive decline, who found that individuals with TDP-43 pathology had a shorter time between symptom onset and death compared with AD, LBD, and cerebrovascular disease.”
ResultInfluentialCarpenter, C. R., McFarland, F., Avidan, M. S., Berger, M., Inouye, S. K., Karlawish, J. H., Lin, F. R., Marcantonio, E. R., Morris, J. C., Reuben, D. B., et al. (2019) · Journal of the American Geriatrics Society · doi:10.1111/jgs.16093 · Cited by 28
“other copathologies are present by the time the first symptoms of AD appear.(2) Thus, AD can be viewed as a continuous process of synaptic and neuronal deterioration that can be divided roughly into an asymptomatic, preclinical stage, and a symptomatic stage, with the preclinical stage constituting the bulk of the ill…”
BackgroundTosun, D., Yardibi, O., Benzinger, T. L. S., Kukull, W. A., Masters, C. L., Perrin, R. J., Weiner, M. W., Simen, A. A., Schwarz, A. J., & Initiative, A. D. N. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13447 · Cited by 27
Alosco, M. L., Culhane, J. E., & Mez, J. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01028-3 · Cited by 32
Nation, D. A., Ho, J. K., Dutt, S., Han, S. D., Lai, M. H. C., & Initiative, A. D. N. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180525 · Cited by 28
“Recent autopsy series have demonstrated that the most common form of dementia is due to multiple pathologies [29], and over 200 different combinations of pathology were observed in a large autopsy series [30].”
BackgroundCommon age‐related neuropathologies and yearly variability in cognition
Yu, L., Wang, T., Wilson, R. S., Leurgans, S. E., Schneider, J. A., Bennett, D. A., & Boyle, P. A. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50857 · Cited by 24
“These results are consistent with our prior report that AD has the most potent effect on cognitive decline but other less frequent pathologies including neocortical Lewy bodies and hippocampal sclerosis also show strong effects.(14) The impact of vascular diseases is less potent compared to degenerative conditions (Ta…”
ResultSelf-citationChronic Traumatic Encephalopathy and Neuropathological Comorbidities
Stein, T. D., & Crary, J. F. (2020) · Seminars in Neurology · doi:10.1055/s-0040-1713628 · Cited by 28
Walker, J. M., & Richardson, T. E. (2023) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlac115 · Cited by 26
Trares, K., Gao, X. Y., Perna, L., Rujescu, D., Stocker, H. R., Möllers, T., Beyreuther, K. T., Brenner, H., & Schöttker, B. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12081 · Cited by 25
Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years
Josephs, K. A., Weigand, S. D., & Whitwell, J. L. (2022) · Neurology · doi:10.1212/wnl.0000000000200287 · Cited by 39
Sokolovič, L., Hofmann, M., Mohammad, N., & Kukolja, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1267434 · Cited by 33
Utility of Plasma Neurofilament Light in the 1Florida Alzheimer’s Disease Research Center (ADRC)
Barker, W., Quinonez, C., Greig, M. T., Behar, R., Chirinos, C. L., Rodriguez, R. A., Rosselli, M., Rodriguez, M. J., Curiel, R. E., Rundek, T., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200901 · Cited by 25
“On neuropathological examination, AD occurs in isolation only 9% of cases [1].”
BackgroundParikh, N. S., Kumar, S. R., Rosenblatt, R. E., Zhao, C., Cohen, D. E., Iadecola, C., & Kamel, H. (2020) · European Journal of Neurology · doi:10.1111/ene.14384 · Cited by 26
“There is growing appreciation of the complexity underlying cognitive impairment, with interest in understanding the contribution of common medical comorbidities such as liver disease [4,5].”
BackgroundHospitalization, Alzheimer's Disease and Related Neuropathologies, and Cognitive Decline
James, B. D., Wilson, R. S., Capuano, A. W., Boyle, P. A., Shah, R. C., Lamar, M., Ely, E. W., Bennett, D. A., & Schneider, J. A. (2019) · Annals of Neurology · doi:10.1002/ana.25621 · Cited by 25
Self-citationNeuropathologic scales of cerebrovascular disease associated with diffusion changes on MRI
Nguyen, A. T., Kouri, N., Labuzan, S. A., Przybelski, S. A., Lesnick, T. G., Raghavan, S., Reid, R. I., Reichard, R. R., Knopman, D. S., Petersen, R. C., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02465-w · Cited by 24
“Cerebrovascular disease (CVD) is an important contributor to cognitive decline and dementia in the elderly [2, 29].”
BackgroundPredicting post-stroke cognitive impairment using machine learning: A prospective cohort study
Ji, W., Wang, C., Chen, H., Liang, Y., & Wang, S. (2023) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2023.107354 · Cited by 27
Cordonnier, C., Klijn, C. J. M., Smith, E. E., Salman, R. A., Chwalisz, B. K., van Etten, E. S., Muir, R. T., Piazza, F., Schreiber, S., Schreuder, F. H. B. M., et al. (2025) · International Journal of Stroke · doi:10.1177/17474930251365861 · Cited by 23
“4.”
Ribaldi, F., Rolandi, E., Vaccaro, R., Colombo, M. M., Frisoni, G. B., & Guaita, A. (2022) · Age and Ageing · doi:10.1093/ageing/afac209 · Cited by 24
Han, X., Zhang, J., Chen, S., Yu, W., Zhou, Y. F., & Gu, X. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14026 · Cited by 23
New and emerging drug therapies for Alzheimer disease
Waite, L. M. (2024) · Australian Prescriber · doi:10.18773/austprescr.2024.021 · Cited by 22
“25 With advancing age, the correlation between biomarkers, clinical phenotype and pathology attenuates making both interpretation and monitoring of biomarkers more challenging.”
BackgroundLongobardi, A., Nicsanu, R., Bellini, S., Squitti, R., Catania, M., Tiraboschi, P., Saraceno, C., Ferrari, C., Zanardini, R., Binetti, G. G., et al. (2022) · Cells · doi:10.3390/cells11030462 · Cited by 22
“A variety of triggers encompassing genetic, environmental, vascular, metabolic and inflammatory factors converge to activate common neurodegenerative mechanisms that take place in the brain of individuals affected by major neurodegenerative dementias and can partially explain their overlap [1].”
BackgroundVascular Dysfunction Is Central to Alzheimer’s Disease Pathogenesis in APOE e4 Carriers
McCorkindale, A. N., Mundell, H. D., Guennewig, B., & Sutherland, G. T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137106 · Cited by 23
“This is likely due to more advanced AD and the exclusion of other pathologies [59] in the MSBB cohort compared to moderate AD and a high prevalence of mixed pathology in ROSMAP [60].”
ResultFibrin-targeting immunotherapy for dementia
Kantor, A. B., Akassoglou, K., & Stavenhagen, J. B. (2023) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2023.105 · Cited by 24
“The two pathologies often coexist in the same patients (2), and CAA is a major factor in AD severity (3).”
BackgroundTap, L., Vernooij, M. W., Wolters, F. J., van den Berg, E., & Mattace-Raso, F. U. S. (2023) · Age and Ageing · doi:10.1093/ageing/afad148 · Cited by 22
“At the time of death, nearly 80% of community-dwelling individuals have multiple types of brain pathology, at least one of which is of a vascular nature [56].”
BackgroundUpdate on modifiable risk factors for Alzheimer's disease and related dementias
Jaisa-aad, M., Muñoz‐Castro, C., & Serrano‐Pozo, A. (2024) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001243 · Cited by 21
Olah, M., Menon, V., Habib, N., Taga, M. F., Yung, C. J., Cimpean, M., Khairalla, A., Dionne, D. A., Hopp, S. C., Frosch, M. P., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/343780 · Cited by 19
Self-citationAssociations of hospital-treated infections with subsequent dementia: nationwide 30-year analysis
Richmond‐Rakerd, L. S., Iyer, M. T., D’Souza, S., Khalifeh, L., Caspi, A., Moffitt, T. E., & Milne, B. J. (2024) · Nature Aging · doi:10.1038/s43587-024-00621-3 · Cited by 20
“Moreover, neuropathologies such as amyloid-β plaques may be less specific than assumed to AD versus other dementia types 35,36 .”
BackgroundThe Effectiveness of Unimodal and Multimodal Warnings on Drivers’ Response Time: A Meta-Analysis
Zhu, A., Ma, K.-H., Choi, A. T. H., Hu, D., Chuan-Peng, H., Peng, P., & He, J. (2025) · Applied Sciences · doi:10.3390/app15020527 · Cited by 23
“Older adults are often experiencing cognitive decline [110,111], causing them to have a smaller cognitive capacity.”
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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