Modeling the Association between 43 Different Clinical and Pathological Variables and the Severity of Cognitive Impairment in a Large Autopsy Cohort of Elderly Persons
Open accessAbstract
We evaluated the association between mini‐mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression‐based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimer's disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high‐functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP‐43‐related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.
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Relatively isolated HS in very old individuals is associated with TDP-43-immunoreactive inclusions and with cognitive impairment.
“Relatively isolated HS may occur in very old individuals, and in this context it is associated with TDP-43-immunoreactive inclusions and with cognitive impairment [45,47].”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [45]
The Discussion reports that hippocampal sclerosis (HS) was associated with lower MMSE scores and states that HS is associated with TDP-43 proteinopathy. The Results describe TDP-43-positive inclusions. Neither passage establishes these associations specifically for relatively isolated HS in very old individuals. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRelatively isolated HS may occur in very old individuals.
“Relatively isolated HS may occur in very old individuals, and in this context it is associated with TDP-43-immunoreactive inclusions and with cognitive impairment [45,47].”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [45]
The Results describe an elderly autopsy cohort that included people over 80, and the Discussion reports hippocampal sclerosis (HS) in the cohort. However, our copy does not identify cases of relatively isolated HS or establish that those cases occurred specifically in very old individuals. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn a recent multivariate analysis, approximately two-thirds of the variation in cognitive ability of elderly subjects was accounted for by variation in CERAD neuritic plaque density and Braak stage.
“In a recent multivariate analysis, approximately two-thirds of the variation in cognitive ability of elderly subjects was accounted for by variation in CERAD neuritic plaque density and Braak stage (41).”
From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [41]
The Results section (page not provided) says that more than two-thirds of MMSE-score variability in the elderly autopsy cohort was associated with Alzheimer-type pathology, specifically neurofibrillary tangles and neuritic plaques. It does not attribute that figure to CERAD neuritic plaque density and Braak stage as the two measures in the claim; the Discussion describes its findings as compatible with Braak staging. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn the revision of the 1997 criteria, combinations of plaque and tangle pathologies considered sufficient to cause dementia and qualify for the neuropathological diagnosis of AD are explicitly stated.
“In the revision of the 1997 criteria, combinations of plaque and tangle pathologies considered sufficient to cause dementia and qualify for the neuropathological diagnosis of AD are explicitly stated (40, 41).”
From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [41]
The Neuropathology section describes how the study counted plaques and tangles, but does not state what combinations qualify for an AD diagnosis or are sufficient to cause dementia. Searches for the 1997 criteria, their revision, and diagnostic thresholds found no passage addressing that claim in our copy; the other relevant matches were in the References section. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe density of tau-positive NPs does correlate directly and statistically independently with some degree of cognitive impairment.
“On the other hand, the density of tau-positive NPs does correlate directly and statistically independently with some degree of cognitive impairment (105-107) (Fig. 2).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [105]
Even in extreme old age, the presence of many neocortical NFTs correlates with antemortem cognitive decline.
“Even in extreme old age, the presence of many neocortical NFTs correlates with antemortem cognitive decline (105, 188-191).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [105]
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- [82]Mendiondo MS Ashford JW Kryscio RJ Schmitt FA Modelling mini mental state examination changes inAlzheimer’s disease Stat Med 2000 19 1607 1616 10844722
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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
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“Relatively isolated HS may occur in very old individuals, and in this context it is associated with TDP-43–immunoreactive inclusions and with cognitive impairment [45, 47].”
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“Even in extreme old age, the presence of many neocortical NFTs correlates with antemortem cognitive decline (105, 188 Y 191).”
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“In the revision of the 1997 criteria, combinations of plaque and tangle pathologies considered sufficient to cause dementia and qualify for the neuropathologic diagnosis of AD are explicitly stated (40, 41).”
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Self-citationPini, L., Brusini, L., Griffa, A., Cruciani, F., Allali, G., Frisoni, G. B., Corbetta, M., Menegaz, G., & Boscolo Galazzo, I. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106866 · Cited by 11 · see citing works
- Authors
- 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., & Markesbery, W. R.
- Affiliations
- University of Kentucky (US)
- ORCID
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2009-12-07
- Volume
- 20
- Issue
- 1
- Pages
- 66-79
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC2864342
- OpenAlex
- W1667268002
- Cited by
- 239
- References
- 126
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 14 · 2023: 22 · 2022: 13 · 2021: 14 · 2020: 17 · 2019: 14 · 2018: 12 · 2017: 17 · 2016: 18 · 2015: 13 · 2014: 14 · 2013: 12 · 2012: 16
- FWCI
- 6.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG028383)
- National Institute of Neurological Disorders and Stroke (K08NS050110)
- 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
- Alzheimer's disease pathology, neurofibrillary tangles, neuritic plaques, Lewy bodies, TDP-43 pathology, hippocampal sclerosis, argyrophilic grains, Mini-Mental State Examination, older adults, apolipoprotein E, diabetes mellitus, heart disease, educational attainment
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Autopsy, Brain, Cerebral Cortex, Cognition Disorders, DNA-Binding Proteins, Female, Hippocampus, Humans, Immunohistochemistry, Male, Neuropsychological Tests, Models, Statistical, Cohort Studies, Linear Models, Databases, Factual
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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