The neuropathology of probable Alzheimer disease and mild cognitive impairment
Open accessAbstract
Objective: Mixed pathologies are common in older persons with dementia. Little is known about mixed pathologies in probable Alzheimer disease (AD) and about the spectrum of neuropathology in mild cognitive impairment (MCI). The objective of this study was to investigate single and mixed common age‐related neuropathologies in persons with probable AD and MCI. Methods: The study included 483 autopsied participants from the Religious Orders Study and the Rush Memory and Aging Project with probable AD (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria), MCI (amnestic and nonamnestic), or no cognitive impairment. We excluded 41 persons with clinically possible AD and 14 with other dementias. We documented the neuropathology of AD (National Institute on Aging–Reagan criteria), macroscopic cerebral infarcts, and neocortical Lewy body (LB) disease. Results: Of 179 persons (average age, 86.9 years) with probable AD, 87.7% had pathologically confirmed AD, and 45.8% had mixed pathologies, most commonly AD with macroscopic infarcts (n = 54), followed by AD with neocortical LB disease (n = 19) and both (n = 8). Of the 134 persons with MCI, 54.4% had pathologically diagnosed AD (58.7% amnestic; 49.2% nonamnestic); 19.4% had mixed pathologies (22.7% amnestic; 15.3% nonamnestic). Macroscopic infarcts without pathologically diagnosed AD accounted for 4.5% of probable AD, 13.3% of amnestic MCI, and 18.6% of nonamnestic MCI. Pure neocortical LB disease was uncommon in all persons with cognitive impairment (<6%). Microscopic infarcts (without macroscopic infarcts) were common as a mixed pathology, but rarely accounted for a clinical diagnosis of probable AD (n = 4) or MCI (n = 3). Interpretation: Clinically diagnosed probable AD and MCI, even amnestic MCI, are pathologically heterogeneous disorders, with many persons exhibiting mixed pathologies. Ann Neurol 2009;66:200–208
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Although the specific importance of subcortical infarcts and interaction has not been confirmed, subsequent studies have established that infarcts are additive with Alzheimer disease pathology in lowering cognitive function and increasing the odds of dementia or clinical Alzheimer disease.
“Although the specific importance of subcortical infarcts and interaction has not been confirmed, subsequent studies have established that infarcts are additive with Alzheimer disease pathology in lowering cognitive function17,57 and increasing the odds of dementia17,18,62,63 or clinical Alzheimer disease.61”
From Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association (2011) · cites this paper as [61]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThose with amnestic mild cognitive impairment do not always have AD at autopsy even though they have a reported risk for developing dementia of 10-15%, and sometimes they do not have any discernable pathology at autopsy.
“Those with amnestic mild cognitive impairment do not always have AD at autopsy even though they have a reported risk for developing dementia of 10–15%, and sometimes they do not have any discernable pathology at autopsy [145, 146].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [146]
The Results (Mild Cognitive Impairment; page unavailable) report pathologically diagnosed AD in 59% of people with amnestic MCI, supporting that they do not always have AD at autopsy. Our copy does not report a 10–15% risk of developing dementia or establish that people with amnestic MCI sometimes have no discernible pathology at autopsy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAD neuropathologic change is documented in approximately 80% of cases with a traditional clinical diagnosis of "AD dementia".
“AD neuropathologic change is documented in approximately 80% of cases with a traditional clinical diagnosis of “AD dementia” (see Fig. 5 for an example of clinical misdiagnosis of “AD dementia”) [50–52,162,185,209–211].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [185]
The Results section (Probable Alzheimer's disease) reports pathologically confirmed AD in 157 of 179 people clinically diagnosed with probable AD—87.7%, described as almost 90%. This supports the general point that most such diagnoses had AD pathology, but not the cited estimate of approximately 80%. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn mild cognitive impairment, Alzheimer disease is the most frequently found pathology.
“Alzheimer disease has been found to be the most common pathology,61,65,66,69”
In one study, pure infarct and mixed Alzheimer disease and infarct pathology occurred as often as pure Alzheimer disease pathology in both amnestic and nonamnestic mild cognitive impairment.
“In 1 study the frequency of pure infarct and mixed Alzheimer disease and infarct pathology was comparable to the frequency of pure Alzheimer disease pathology in both amnestic and nonamnestic MCI.61”
Most people with dementia and almost half of those with clinically probable Alzheimer disease have mixed pathology, most commonly Alzheimer disease and infarcts.
“In addition, most people with dementia12 and almost half of those with clinically probable Alzheimer disease61 have mixed pathology, most commonly Alzheimer disease and infarcts.”
Mixed pathologies are also common in mild cognitive impairment.
“but mixed pathologies are also common.61,65–69”
MCI is a highly heterogeneous clinical syndrome that can be caused by several different neurodegenerative and nonneurodegenerative conditions.
“MCI is a highly heterogeneous clinical syndrome that can be caused by several different neurodegenerative and nonneurodegenerative conditions24.”
From Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability (2024) · cites this paper as [24]
Most dementia cases show mixed pathology, combining Alzheimer's features and ischemic lesions.
“community based clinical-pathological studies revealed that the largest proportion of dementia cases have mixed pathology, comprising features of AD (amyloid plaques and neurofibrillary tangles) as well as ischemic lesions (Launer et al., 2008; Schneider et al., 2009).”
From The Pathobiology of Vascular Dementia (2013) · cites this paper as Schneider et al., 2009
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NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
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“Those with amnestic mild cognitive impairment do not always have AD at autopsy even though they have a reported risk for developing dementia of 10–15%, and sometimes they do not have any discernable pathology at autopsy [145, 146].”
BackgroundNeuropathological alterations in Alzheimer disease
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“MCI is a highly heterogeneous clinical syndrome that can be caused by several different neurodegenerative and nonneurodegenera-tive conditions 24 .”
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Disentangling the effects of age and APOE on neuropathology and late life cognitive decline
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Self-citationDissecting the human leptomeninges at single-cell resolution
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Selected Findings from the Religious Orders Study and Rush Memory and Aging Project
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- Authors
- Schneider, J. A., Arvanitakis, Z., Leurgans, S. E., & Bennett, D. A.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Schneider, Julie A.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-08
- Volume
- 66
- Issue
- 2
- Pages
- 200-208
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2812870
- OpenAlex
- W2134836371
- Cited by
- 935
- References
- 165
- Citations by year
- 2026: 46 · 2025: 58 · 2024: 67 · 2023: 42 · 2022: 60 · 2021: 44 · 2020: 71 · 2019: 71 · 2018: 58 · 2017: 48 · 2016: 50 · 2015: 57 · 2014: 54 · 2013: 64 · 2012: 54
- FWCI
- 29.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG017917, K08 AG00849, P30-AG 10161, K23 AG 23675, R01‐AG17917, R01 AG15819, R01AG015819, P30AG010161, K08AG000849, U19AG010483, K23AG023675)
- 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, mild cognitive impairment, amnestic MCI, non-amnestic MCI, Religious Orders Study, Rush Memory and Aging Project
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Brain, Cognition Disorders, Female, Humans, Longitudinal Studies, Male, Odds Ratio, Lewy Bodies, Neocortex, Brain Infarction
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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