Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age‐continuous perspective
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Introduction: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals—are they resilient, or resistant to AD‐associated neuropathologies? Methods: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini‐Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non‐AD demented, and non‐demented individuals in an age continuum ranging from 16 to 100+ years. Results: With age, brains from non‐demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16). Discussion: Cognitive health can be maintained despite the accumulation of high levels of AD‐related neuropathological substrates. Highlights: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.
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Genetic variants of genes related to autophagy functions are involved in resilience against AD neuropathology.
“However, it has been reported that genetic variants of genes related to autophagy functions are involved in resilience against AD neuropathology [82, 92, 107].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [107]
The Discussion (page unavailable in our copy) links protective variants associated with autophagy to centenarians’ cognitive health despite AD neuropathology. It proposes that genetically defined resilience may explain this observation; it does not establish that autophagy-related variants are involved in that resilience. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGenetic variants linked to autophagy processes may contribute to resistance against amyloid plaques and NFTs in centenarians.
“Furthermore, genetic variants linked to autophagy processes may contribute to resistance against amyloid plaques and NFTs in centenarians [107]”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [107]
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- Braak NFT stage 36, VI (VI-VI) 110, VI (V-VI) 178, V (V-VI) 292, V (V-VI) 137, V (IV-V) 753, V (V-VI) CERAD NP score 5, 3 (3-3) 16, 3 (3-3) 29, 3 (3-3) 28, 3 (2-3) 17, 3 (2-3) 95, 3 (3-3) Brain weight (g) 42, 1017 (950-1103) 132, 985 (890-1065) 204, 995 (913-1088) 323, 1010 (941-1084) 150, 959 (917-1052) 851, 998 (920-1078) Non-dementia (N) 180 90 161 158 65 654 NIA amyloid stage 18, 0 (0-0) 17, 0 (0-1) 65, 1 (1-2) 90, 1 (0-2) 47, 2 (1-2) 237, 1 (0-2) Braak NFT stage 52, 0 (0-0) 45, I (0-I) 113, I (I-II) 129, II (I-II) 55, II (I-III) 394, I (0-II) CERAD NP score 16, 0 (0-0) 11, 0 (0-0) 27, 0 (0-0) 36, 0 (0-0) 23, 0 (0-1) 113, 0 (0-0) Brain weight (g) 180, 1267 (1190-1360) 90, 1225 (1130-1274) 161, 1160 (1077-1232) 158, 1124 (1050-1199) 65, 1060 (1025-1116) 654, 1179 (1080-1265) Non-AD dementia (N) 49 138 187 200 52 626 NIA amyloid stage 14, 0 (0-0) 58, 1 (0-2) 116, 2 (1-2) 117, 2 (1-3) 35, 2 (1-2) 340, 2 (1-2) Braak NFT stage 15, 0 (0-I) 66, I (I-II) 145, II (I-III) 165, II (I-III) 48, III (II-III) 439, II (I-III) CERAD NP score 13, 0 (0-0) 35, 0 (0-0) 56, 0 (0-0) 37, 0 (0-1) 12, 0 (0-1) 153, 0 (0-0) Brain weight (g) 49, 926 (812-1012) 138, 978 (837-1100) 187, 1036 (946-1147) 200, 1059 (983-1121) 52, 1029 (977-1144) 626, 1029 (935-1125) Total (N) 271 360 552 681 267 2131 Abbreviations: AD, Alzheimer's disease; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; IQR, interquartile range; NBB, Netherlands Brain Bank; NFT, neurofibrillary tangle; NIA, National Institute on Aging; NP, neuritic plaque. 15525279, 0, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12899 by Cochrane Netherlands, Wiley Online Library on [03/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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“However, it has been reported that genetic variants of genes related to autophagy functions are involved in resilience against AD neuropathology [82, 92, 107].”
BackgroundSouchet, B., Michaïl, A., Heuillet, M., Dupuy-Gayral, A., Haudebourg, E., Pech, C., Berthemy, A., Autelitano, F., Billoir, B., Domoto-Reilly, K., et al. (2024) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2024.34 · Cited by 15 · see citing works
- Authors
- Zhang, M., Ganz, A. B., Rohde, S., Rozemuller, A. J. M., Bank, N. B., Reinders, M. J. T., Scheltens, P., Hulsman, M., Hoozemans, J. J. M., & Holstege, H.
- Affiliations
- Amsterdam Neuroscience (NL)
- Department of Pathology Amsterdam Neuroscience Amsterdam UMC Amsterdam The Netherlands
- Netherlands Institute for Neuroscience (NL)
- Delft University of Technology (NL)
- Corresponding author
- Holstege, Henne
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2022-12-30
- Volume
- 19
- Issue
- 7
- Pages
- 2831-2841
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W4313299363
- Cited by
- 43
- References
- 9
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 12
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Research Repository (Delft University of Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
- Funders
- Alzheimer Nederland (WE09.2014–03)
- Stichting Dioraphte (VSM 14 04 14 02)
- 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 › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- centenarians, Alzheimer's disease
- MeSH terms
- Centenarians, Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Humans, Middle Aged, Neurofibrillary Tangles, Young Adult, Plaque, Amyloid
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