Morphological substrates of cognitive decline in nonagenarians and centenarians: A new paradigm?
Open accessAbstract
Brain aging is characterized by the formation of neurofibrillary tangles (NFT) and senile plaques (SP) in both cognitively intact individuals and patients with Alzheimer's disease (AD). The ubiquitous presence of these lesions and the steady increase of the prevalence of dementia up to 85 years have strongly supported a continuum between normal brain aging and AD. In this context, the study of nonagenarians and centenarians could provide key informations about the characteristics of extreme aging. We provide here a detailed review of currently available neuropathological data in very old individuals and critically discuss the patterns of NFT, SP and neuronal loss distribution as a function of age. In younger cohorts, NFTs are usually restricted to hippocampal formation, whereas clinical signs of dementia appear when temporal neocortex is involved. SPs would not be a specific marker of cognitive impairment as no correlation was found between their quantitative distribution and AD severity. The low rate of AD lesions even in severe AD as well as the weakness of clinicopathological correlations reported in the oldest-old indicate that AD pathology is not a mandatory phenomenon of increasing chronological age. Our recent stereological observations of hippocampal microvasculature in oldest-old cases challenge the traditional lesional model by revealing that mean capillary diameters is an important structural determinant of cognition in this age group.
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In brains from cognitively intact subjects, hippocampal CA1 neuron counts do not correlate with age.
“In brains from cognitively intact subjects, hippocampal CA1 neuron counts do not correlate with age [47–49].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [49]
Not all studies are in agreement that the prevalence of high NP and high NFT pathologic diagnosis levels off in the oldest old.
“However, not all studies are in agreement on this point (185, 186); these “survivors” represent a small fraction of the human population with underrepresentation of APOE ε4 allele (187).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [185]
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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
“However, not all studies are in agreement on this point (185, 186); these ‘‘survivors’’ represent a small fraction of the human population with underrepresentation of APOE ?”
BackgroundSelf-citationLimbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report
Nelson, P. T., Dickson, D. W., Trojanowski, J. Q., Jack, C. R., Boyle, P. A., Arfanakis, K., Rademakers, R., Alafuzoff, I., Attems, J., Brayne, C., et al. (2019) · Brain · doi:10.1093/brain/awz099 · Cited by 1,547 · see citing works
Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship
Nelson, P. T., Braak, H., & Markesbery, W. R. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181919a48 · Cited by 643 · see citing works
Nelson, P. T., Head, E., Schmitt, F. A., Davis, P. R., Neltner, J. H., Jicha, G. A., Abner, E. L., Smith, C. D., Van Eldik, L. J., Kryscio, R. J., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0826-y · Cited by 365 · see citing works
Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study
Kawas, C. H., Kim, R. C., Sonnen, J. A., Bullain, S. S., Trieu, T., & Corrada, M. M. (2015) · Neurology · doi:10.1212/wnl.0000000000001831 · Cited by 303 · see citing works
Brain aging, Alzheimer's disease, and mitochondria
Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306 · see citing works
“In brains from cognitively intact subjects, hippocampal CA1 neuron counts do not correlate with age [47–49].”
BackgroundNelson, P. T., Jicha, G. A., Schmitt, F. A., Liu, H., Davis, D. G., Mendiondo, M. S., Abner, E. L., & Markesbery, W. R. (2007) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/nen.0b013e31815c5efb · Cited by 292 · see citing works
Nelson, P. T., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Jicha, G. A., Smith, C. D., Davis, D. G., Poduska, J. W., Patel, E., Mendiondo, M. S., et al. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00244.x · Cited by 239 · see citing works
Drachman, D. A. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.11.003 · Cited by 224 · see citing works
Dementia From Alzheimer Disease and Mixed Pathologies in the Oldest Old
James, B. D. (2012) · JAMA · doi:10.1001/jama.2012.3556 · Cited by 199 · see citing works
Brayne, C., the Cambridge City over-75s Cohort (CC75C) study neuropathology collaboration, Richardson, K., Matthews, F. E., Fleming, J., Hunter, S., Xuereb, J. H., Paykel, E., Mukaetova-Ladinska, E. B., Huppert, F. A., et al. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1182 · Cited by 191 · see citing works
“New Old Pathologies”: AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS)
Nelson, P. T., Trojanowski, J. Q., Abner, E. L., Al-Janabi, O. M., Jicha, G. A., Schmitt, F. A., Smith, C. D., Fardo, D. W., Wang, W.-X., Kryscio, R. J., et al. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw033 · Cited by 158 · see citing works
Role of the neuropathology of Alzheimer disease in dementia in the oldest-old
Haroutunian, V., Schnaider-Beeri, M., Schmeidler, J., Wysocki, M., Purohit, D. P., Perl, D. P., Libow, L. S., Lesser, G. T., Maroukian, M., & Grossman, H. T. (2008) · Archives of Neurology · doi:10.1001/archneur.65.9.1211 · Cited by 154 · see citing works
Is synaptic loss a unique hallmark of Alzheimer’s disease?
Scheff, S. W., Neltner, J. H., & Nelson, P. T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.12.028 · Cited by 118 · see citing works
Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old
Robinson, J. L., Geser, F., Corrada, M. M., Berlau, D. J., Arnold, S. E., Lee, V. M.-Y., Kawas, C. H., & Trojanowski, J. Q. (2011) · Brain · doi:10.1093/brain/awr308 · Cited by 88 · see citing works
Huang, C.-Q., Dong, B.-R., Zhang, Y.-L., Wu, H.-M., & Liu, Q.-X. (2009) · Cognitive and Behavioral Neurology · doi:10.1097/wnn.0b013e3181b2790b · Cited by 62 · see citing works
Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp?
Jellinger, K. A. (2009) · Acta Neuropathologica · doi:10.1007/s00401-008-0466-z · Cited by 60 · see citing works
Diagnosing dementia in the oldest-old
Brumback-Peltz, C., Balasubramanian, A. B., Corrada, M. M., & Kawas, C. H. (2011) · Maturitas · doi:10.1016/j.maturitas.2011.07.008 · Cited by 49 · see citing works
- Authors
- Imhof, A., Kövari, E., von Gunten, A., Gold, G., Rivara, C.-B., Herrmann, F. R., Hof, P. R., Bouras, C., & Giannakopoulos, P.
- Affiliations
- University of Geneva (CH)
- Icahn School of Medicine at Mount Sinai (US)
- Venue
- Journal of the Neurological Sciences
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 257
- Issue
- 1-2
- Pages
- 72-79
- ISSN
- 0022-510X (ISSN-L)
- OpenAlex
- W2019428673
- Cited by
- 106
- References
- 97
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 8 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 3 · 2012: 8
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Journal of the Neurological Sciences (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion)
- Funders
- National Institute on Aging (AG-02219, AG 05138, P50AG005138, P01AG002219)
- 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 › Neurological Disease Mechanisms and Treatments
- Keywords
- cognitive decline, nonagenarians, centenarians, brain aging, Alzheimer's disease, neurofibrillary tangles, amyloid plaques, neuronal loss, capillary diameter, oldest old, clinicopathological correlation, dementia
- MeSH terms
- Aged, 80 and over, Aging, Alzheimer Disease, Brain, Cerebral Arteries, Cognition Disorders, Hippocampus, Humans, Neurofibrillary Tangles, Disease Progression, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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