Cognitive resistance to and resilience against multiple comorbid neurodegenerative pathologies and the impact of APOE status
Open accessAbstract
Alzheimer disease (AD) is currently the leading cause of cognitive decline and dementia worldwide. Recently, studies have suggested that other neurodegenerative comorbidities such as limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Lewy body disease (LBD), and cerebrovascular disease frequently co-occur with Alzheimer disease neuropathologic change (ADNC) and may have significant cognitive effects both in isolation and synergistically with ADNC. Herein, we study the relative clinical impact of these multiple neurodegenerative pathologies in 704 subjects. Each of these pathologies is relatively common in the cognitively impaired population, while cerebrovascular pathology and ADNC are the most common in cognitively normal individuals. Moreover, while the number of concurrent neuropathologic entities rises with age and has a progressively deleterious effect on cognition, 44.3% of cognitively intact individuals are resistant to having any neurodegenerative proteinopathy (compared to 15.2% of cognitively impaired individuals) and 83.5% are resistant to having multiple concurrent proteinopathies (compared to 64.6% of cognitively impaired individuals). The presence of at least 1 APOE ε4 allele was associated with impaired cognition and the presence of multiple proteinopathies, while APOE ε2 was protective against cumulative proteinopathies. These results indicate that maintenance of normal cognition may depend on resistance to the development of multiple concurrent proteinopathies.
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Carriers of the APOEε4 allele have increased odds of a multi-proteinopathy, whereas carrying the APOEε2 allele reduces these odds, relative to APOEε3 homozygosis.
“Carriers of the APOEε4 allele have increased odds of a multi-proteinopathy, whereas carrying the APOEε2 allele reduces these odds, relative to APOEε3 homozygosis60,61.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [61]
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Ageing as a risk factor for neurodegenerative disease
Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0244-7 · Cited by 3,310 · see citing works
Montine, T. J., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., Mirra, S. S., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0910-3 · Cited by 2,992 · see citing works
Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050 · see citing works
Mixed brain pathologies account for most dementia cases in community-dwelling older persons
Schneider, J. A., Arvanitakis, Z., Bang, W., & Bennett, D. A. (2007) · Neurology · doi:10.1212/01.wnl.0000271090.28148.24 · Cited by 1,992 · see citing works
Person-specific contribution of neuropathologies to cognitive loss in old age
Boyle, P. A., Yu, L., Wilson, R. S., Leurgans, S. E., Schneider, J. A., & Bennett, D. A. (2018) · Annals of Neurology · doi:10.1002/ana.25123 · Cited by 508 · see citing works
The Neuropathology of Older Persons with and Without Dementia from Community versus Clinic Cohorts
Schneider, J. A., Aggarwal, N. T., Barnes, L., Boyle, P., & Bennett, D. A. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1227 · Cited by 372 · see citing works
Comorbid neuropathological diagnoses in early versus late-onset Alzheimer's disease
Spina, S., La Joie, R., Petersen, C., Nolan, A. L., Cuevas, D., Cosme, C., Hepker, M., Hwang, J.-H., Miller, Z. A., Huang, E. J., et al. (2021) · Brain · doi:10.1093/brain/awab099 · Cited by 278 · see citing works
The Vascular Impairment of Cognition Classification Consensus Study
Skrobot, O. A., O'Brien, J., Black, S., Chen, C., DeCarli, C., Erkinjuntti, T., Ford, G. A., Kalaria, R. N., Pantoni, L., Pasquier, F., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.10.007 · Cited by 242 · see citing works
Prevalence and clinical phenotype of quadruple misfolded proteins in older adults
Karanth, S., Nelson, P. T., Katsumata, Y., Kryscio, R. J., Schmitt, F. A., Fardo, D. W., Cykowski, M. D., Jicha, G. A., Van Eldik, L. J., & Abner, E. L. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.1741 · Cited by 206 · see citing works
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Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
- Authors
- Walker, J. M., & Richardson, T. E.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-12-02
- Volume
- 82
- Issue
- 2
- Pages
- 110-119
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC9852945
- OpenAlex
- W4310588951
- Cited by
- 26
- References
- 10
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 8
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R21 AG078505)
- NIH (U24 AG072122)
- NIA (P30 AG062429, P30 AG066468, P30 AG062421, P30 AG066509, P30 AG066514, P30 AG066530, P30 AG066507, P30 AG066444, P30 AG066518, P30 AG066512, P30 AG066462, P30 AG072979, P30 AG072972, P30 AG072976, P30 AG072975, P30 AG072978, P30 AG072977, P30 AG066519, P30 AG062677, P30 AG079280, P30 AG062422, P30 AG066511, P30 AG072946, P30 AG062715, P30 AG072973, P30 AG066506, P30 AG066508, P30 AG066515, P30 AG072947, P30 AG072931, P30 AG066546, P20 AG068024, P20 AG068053, P20 AG068077, P20 AG068082, P30 AG072958, P30 AG072959)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, cognitive resilience, cognitive resistance, APOE ε4, APOE ε2, TDP-43, Lewy body disease, cerebrovascular disease, proteinopathies, cognitive decline, dementia, neuropathology
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Cognition, Dementia, Humans, Proteostasis Deficiencies, TDP-43 Proteinopathies
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