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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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“including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratify-”
BackgroundMethodInfluentialSelf-citationLimbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging
Kapasi, A., Yu, L., Boyle, P. A., Barnes, L. L., Bennett, D. A., & Schneider, J. A. (2020) · Neurology · doi:10.1212/wnl.0000000000010454 · Cited by 100
Self-citationNew fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease
Park, S. A., Han, S. M., & Kim, C. E. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0418-9 · Cited by 96
Immunotherapies for Aging-Related Neurodegenerative Diseases—Emerging Perspectives and New Targets
Kwon, S., Iba, M., Kim, C., & Masliah, E. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00853-2 · Cited by 97
“effective at treating these disorders than monotherapy [36, 37].”
BackgroundZhou, M., Haque, R. U., Dammer, E. B., Duong, D. M., Ping, L., Johnson, E. C. B., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2020) · Clinical Proteomics · doi:10.1186/s12014-020-09285-8 · Cited by 92
“For example, most cases of dementia are due to a complex mixture of pathologies that are also seen in aging and other neurodegenerative diseases [5].”
Minoshima, S., Mosci, K., Cross, D. J., & Thientunyakit, T. (2021) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2021.01.002 · Cited by 93
Is tau in the absence of amyloid on the Alzheimer’s continuum?: A study of discordant PET positivity
Weigand, A. J., Bangen, K. J., Thomas, K. R., Delano‐Wood, L., Gilbert, P. E., Brickman, A. M., Bondi, M. W., & Initiative, A. D. N. (2019) · Brain Communications · doi:10.1093/braincomms/fcz046 · Cited by 93
Tosun, D., Hausle, Z., Iwaki, H., Thropp, P., Lamoureux, J., Lee, E. B., MacLeod, K., McEvoy, S., Nalls, M. A., Perrin, R. J., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13858 · Cited by 86
Alzheimer’s Disease Neuropathological Comorbidities are Common in the Younger-Old
Beach, T. G., & Malek‐Ahmadi, M. H. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-201213 · Cited by 88
Neuropathological assessment of the Alzheimer spectrum
Jellinger, K. A. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02232-9 · Cited by 85
Mehta, R. I., & Schneider, J. A. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000912 · Cited by 87
“Moreover, the relative contribution of specific neuropathologies to cognitive loss was found to vary widely [34].”
BackgroundSelf-citationA computational model of neurodegeneration in Alzheimer’s disease
Jones, D., Lowe, V., Graff-Radford, J., Botha, H., Barnard, L., Wiepert, D., Murphy, M. C., Murray, M., Senjem, M., Gunter, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29047-4 · Cited by 78
“Consistent with clinical experience, and the fact that pathologies are the most common pathologic fi ndings in autopsy studies 45 , clinical phenotypes did not separate into distinct clusters in the fi rst three dimensions of the model.”
BackgroundWennberg, A. M., Whitwell, J. L., Tosakulwong, N., Weigand, S. D., Murray, M. E., Machulda, M. M., Petrucelli, L., Mielke, M. M., Jack, C. R., Knopman, D. S., et al. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.01.008 · Cited by 79
“Another study found that the presence of AD pathology (tau and Aβ) was the biggest contributor to cognitive decline, followed by vascular pathology, but again in a cohort that included both cognitively impaired and unimpaired subjects (Boyle et al., 2018).”
BackgroundNeuropathologic burden and the degree of frailty in relation to global cognition and dementia
Wallace, L. M. K., Theou, O., Darvesh, S., Bennett, D. A., Buchman, A. S., Andrew, M. K., Kirkland, S. A., Fisk, J. D., & Rockwood, K. (2020) · Neurology · doi:10.1212/wnl.0000000000010944 · Cited by 79
“This is likely not specific to the frailty index measurement.(1,2) It also is a way to respond to the critique of AD being studied as though all that mattered about age was exposure duration, whereas “the problems of old age come as a package.”
BackgroundResultInfluentialSelf-citationStricker, N. H., Christianson, T. J. H., Lundt, E. S., Alden, E., Machulda, M. M., Fields, J. A., Kremers, W. K., Jack, C. R., Knopman, D. S., Mielke, M. M., et al. (2020) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617720000752 · Cited by 91
“Some of these processes can now be measured in vivo (Jack et al., 2016), whereas amajority can only bemeasured at autopsy or remain unknown (Boyle et al., 2017; 2018).”
BackgroundInferring protein expression changes from mRNA in Alzheimer’s dementia using deep neural networks
Tasaki, S., Xu, J., Avey, D. R., Johnson, L., Petyuk, V., Dawe, R. J., Bennett, D. A., Wang, Y., & Gaiteri, C. (2022) · Nature Communications · doi:10.1038/s41467-022-28280-1 · Cited by 89
Self-citationWainberg, M., Andrews, S. J., & Tripathy, S. J. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01244-3 · Cited by 83
“While neurodegenerative disorders are often distinguished by their dominant types of protein aggregates—such as amyloid-beta and tau in AD, alpha-synuclein in PD and other synucleinopathies, and TAR DNA-binding protein 43 (TDP-43) in ALS [1]—patients with one neurodegenerative disorder often present with protein aggre…”
BackgroundAlzheimer’s/Vascular Spectrum Dementia: Classification in Addition to Diagnosis
Emrani, S., Lamar, M., Price, C. C., Wasserman, V., Matusz, E. F., Au, R., Swenson, R. A., Nagele, R. G., Heilman, K. M., & Libon, D. J. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190654 · Cited by 84
Rabin, J. S., Nichols, E., Joie, R. L., Casaletto, K. B., Palta, P., Dams-O’Connor, K., Kumar, R. G., George, K. M., Satizábal, C. L., Schneider, J. A., et al. (2022) · Brain · doi:10.1093/brain/awac178 · Cited by 80
Self-citationBejanin, A., Murray, M. E., Martin, P. R., Botha, H., Tosakulwong, N., Schwarz, C. G., Senjem, M. L., Chételat, G., Kantarci, K., Jack, C. R., et al. (2019) · Brain · doi:10.1093/brain/awz277 · Cited by 75
“formances and increased likelihood of dementia (Josephs et al., 2008a; Nag et al., 2015; Boyle et al., 2018).”
Granzotto, A., Vissel, B., & Sensi, S. L. (2024) · eLife · doi:10.7554/elife.90633 · Cited by 71
“Post-mortem examination of >1000 dementia cases identified >230 different neuropathological combinations ( Boyle et al., 2018 ), indicating almost person-specific pathological signatures and disease trajectories.”
InfluentialHerpes Zoster Vaccination and Dementia Occurrence
Pomirchy, M., Bommer, C., Pradella, F., Michalik, F., Peters, R. K., & Geldsetzer, P. (2025) · JAMA · doi:10.1001/jama.2025.5013 · Cited by 74
A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade
Granzotto, A., Canzoniero, L. M. T., & Sensi, S. L. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.600089 · Cited by 67
“This neuropathological mix is the rule and not the exception in AD and PD- and ALS-related neurodegeneration (Boyle et al., 2018; Karanth et al., 2020).”
BackgroundMorris, J. C., Weiner, M., Xiong, C., Beckett, L., Coble, D., Saito, N., Aisen, P. S., Allegri, R., Benzinger, T. L. S., Berman, S. B., et al. (2022) · Brain · doi:10.1093/brain/awac181 · Cited by 68
“14,15 The age at symptomatic onset in ADAD ranges from the third to the eighth decade of life 75,76 and even in the same pedigree can vary by over 30 years.”
Gil-García, C.-A., Flores-Álvarez, E., Cebrian-Garcia, R., Mendoza-Lopez, A.-C., González-Hermosillo, L.-M., Garcia-Blanco, M.-D.-C., & Roldán-Valadéz, E. (2022) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2022.101328 · Cited by 72
Pathobiological Subtypes of Alzheimer Disease
Jellinger, K. A. (2020) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000508625 · Cited by 69
Sugarman, M. A., Zetterberg, H., Blennow, K., Tripodis, Y., McKee, A. C., Stein, T. D., Martin, B. M., Palmisano, J. N., Steinberg, E. G., Simkin, I., et al. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.05.011 · Cited by 68
“This is notable in the context of the present sample of participants with AD dementia because AD dementia and neurodegeneration in AD can be result of mixed neuropathologies, including those that that affect the white matter, especially cerebrovascular disease (Alosco et al., 2018; Arvanitakis et al., 2016; Boyle et a…”
BackgroundAddressing Blood–Brain Barrier Impairment in Alzheimer’s Disease
Sharma, C., Woo, H., & Kim, S. R. (2022) · Biomedicines · doi:10.3390/biomedicines10040742 · Cited by 72
Stocker, H. R., Perna, L., Weigl, K., Möllers, T., Schöttker, B., Thomsen, H., Holleczek, B., Rujescu, D., & Brenner, H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0764-y · Cited by 75
“In addition, dementia neuropathologies are complex where AD pathology seldom occurs in isolation[19], further complicating diagnoses.”
BackgroundFerreira, D., Shams, S., Cavallin, L., Viitanen, M. H., Martola, J., Granberg, T., Shams, M., Aspelin, P., Wiberg, M. K., Nordberg, A. K., et al. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.05.028 · Cited by 65
Squitti, R., Faller, P., Hureau, C., Granzotto, A., White, A. R., & Kepp, K. P. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201556 · Cited by 67
Bomba, M., Granzotto, A., Castelli, V., ONOFRJ, M. C., Lattanzio, R., Cimini, A., & Sensi, S. L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-190237 · Cited by 65
Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline
Hüls, A., Robins, C., Conneely, K. N., Edgar, R. D., Jager, P. L. D., Bennett, D. A., Wingo, A. P., Epstein, M. P., & Wingo, T. S. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.01.015 · Cited by 63
Self-citationLecanemab for Alzheimer’s disease
Walsh, S., Merrick, R., Richard, E., Nurock, S., & Brayne, C. (2022) · BMJ · doi:10.1136/bmj.o3010 · Cited by 76
Carey, A. M., & Fossati, S. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12871 · Cited by 62
Casaletto, K. B., Elahi, F. M., Staffaroni, A. M., Walters, S. M., Contreras, W. R., Wolf, A. A., Dubal, D. B., Miller, B. L., Yaffe, K. S., & Kramer, J. H. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.01.007 · Cited by 58
“, 2013; Morrison and Baxter, 2012; Rahimi and Kovacs, 2014), that may each drive a specific clinical phenomenology – the unique combination(s) of which are even more diverse (Boyle et al., 2018).”
BackgroundKayed, R., Dettmer, U., & Lesné, S. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-201965 · Cited by 63
“Furthermore, two recent longitudinal clinical-pathologic studies of aging reported that only 9% presented pure AD pathology and 78% included more than two neuropathologies [12].”
BackgroundEngelsma, T., Jaspers, M., & Peute, L. (2021) · International Journal of Medical Informatics · doi:10.1016/j.ijmedinf.2021.104494 · Cited by 61
CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease
van der Ende, E. L., Veld, S. G. J. G. I. ‘., Hanskamp, I., van der Lee, S. J., Dijkstra, J. I. R., Hok‐A‐Hin, Y. S., Blujdea, E. R., Swieten, J. C. V., Irwin, D. J., Chen‐Plotkin, A. S., et al. (2023) · Brain · doi:10.1093/brain/awad213 · Cited by 59
“Second, symptom onset in ADAD is on average 30 years earlier than in sporadic AD, 6,47 and the effects of ageing-related comorbidities as well as the more frequent occurrence of multiple neuropathologies in sporadic AD 7,48,49 must be taken into account.”
BackgroundThe Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia
Tasaki, S., Gaiteri, C., Mostafavi, S., Jager, P. L. D., & Bennett, D. A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00699 · Cited by 61
Self-citationSex differences in mixed neuropathologies in community-dwelling older adults
Barnes, L. L., Lamar, M., & Schneider, J. A. (2019) · Brain Research · doi:10.1016/j.brainres.2019.05.028 · Cited by 62
“Further, persons with dementia often have multiple co-morbid pathologies in the brain as a cause of dementia, and the patterns can be quite varied from person to person (Boyle et al., 2018; James et al., 2016).”
BackgroundSelf-citation
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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