Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques
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IMPORTANCE: β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis. OBJECTIVES: To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD. DESIGN, SETTING, AND PARTICIPANTS: Data on participants included in this study were obtained from the National Alzheimer Coordinating Center's Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015. MAIN OUTCOMES AND MEASURES: Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes. RESULTS: Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4 carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features. CONCLUSIONS AND RELEVANCE: In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition.
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Case-control studies without neuropathological or biomarker assessments of AD may have underestimated the impact of APOE genotypes on Alzheimer's dementia odds ratios due to the confounding effects of APOE genotypes on the percentages of neuropathologically misclassified cases and controls.
“This possibility has remained unaddressed, because case–control studies without neuropathological or biomarker assessments of AD may have underestimated the impact of APOE genotypes on Alzheimer’s dementia ORs due to the confounding effects of APOE genotypes on the percentages of neuropathologically misclassified cases and controls8–10.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [8]
The Results and Discussion (page unavailable) report minimal AD plaques in 37% of clinically diagnosed APOE4 noncarriers versus 13% of carriers, supporting genotype-related differences in potentially misclassified cases. The paper does not assess misclassified controls or estimate how such misclassification affects case–control odds ratios, so the proposed underestimation is not established by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDue to prioritized ascertainment, the number of misclassified cases and controls available through the AD Genetics Consortium is much smaller than the estimated number of neuropathologically misclassified cases and controls, limiting the ability to clarify the impact of brain donation on APOE ORs in post hoc analyses.
“Due to the prioritized ascertainment of those cases who met the clinical and neuropathological criteria for Alzheimer’s dementia and those unimpaired controls without AD, the number of misclassified cases and controls available through the AD Genetics Consortium12 is much smaller than our estimated number of neuropathologically misclassified cases and controls8–11, limiting our ability to clarify”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [8]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAPOE4 non-carriers tend to be misclassified more frequently, such that 13% of APOE4 carriers versus 37% of non-carriers with the clinical diagnosis of mild-to-moderate Alzheimer's dementia do not meet neuropathological criteria for AD.
“In fact, APOE4 non-carriers tend to be misclassified more frequently, such that 13% of APOE4 carriers versus 37% of non-carriers with the clinical diagnosis of mild-to-moderate Alzheimer’s dementia do not meet neuropathological criteria for AD8.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [8]
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- Authors
- Monsell, S. E., Kukull, W. A., Roher, A. E., Maarouf, C. L., Serrano, G., Beach, T. G., Caselli, R. J., Montine, T. J., & Reiman, E. M.
- Affiliations
- University of Washington (US)
- Banner Sun Health Research Institute (US)
- Mayo Clinic (US)
- Translational Genomics Research Institute (US)
- Corresponding author
- Reiman, Eric M.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-10-01
- Volume
- 72
- Issue
- 10
- Pages
- 1124
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4833059
- OpenAlex
- W1855414735
- Cited by
- 82
- References
- 22
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 9 · 2018: 12 · 2017: 11 · 2016: 17 · 2015: 2
- FWCI
- 11.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30AG010129, P30AG010133, P30AG028383, P30AG012300, P50AG005133, U01AG016976, P50AG005131, P50AG005138, P50AG016570, P30AG010124, P50AG016573, P30AG008017, P30AG010161, R01AG031581, P30AG008051, P50AG008702, P50AG033514, P30AG035982, P50AG005681, P50AG005142, P30AG019610, P50AG005146, P30AG013846, P50AG005136, P50AG005134, P30AG013854, P50AG025688, P50AG023501, P50AG016574)
- 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
- APOE ε4, Alzheimer's disease, amyloid plaques, cerebral amyloidosis, neurofibrillary degeneration, Braak stages, neuropathologic diagnosis, diffuse plaques, autopsy neuropathology
- MeSH terms
- Aged, Alzheimer Disease, Female, Genotype, Humans, Male, Middle Aged, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Neurofibrillary Tangles, Apolipoprotein E4, 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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