A 2-process model for neuropathology of Alzheimer's disease
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This study examined relations among neuritic and diffuse plaques, neurofibrillary tangles, age, and apolipoprotein E (APOE) in 2 large samples of neuropathology cases, the Religious Orders Study and the Memory and Aging Project. Cognitive status ranged from normal to demented and AD neuropathology ranged from none to severe. Confirmatory factor analysis identified a best-fitting 4-factor solution to describe interrelationships among plaques and tangles: a global neuritic plaque factor; a global diffuse plaque factor; a factor defined by medial temporal neurofibrillary tangles; and a neocortical tangle factor. Results supported a hypothesis that neuritic plaques mediate the association of age and APOE with neocortical tangles, and similarly mediate the effect of APOE on medial temporal tangles. However, medial temporal tangles were related to age independent of neuritic plaques. These results support a primary amyloid-based AD process that accounts for neocortical tangles and makes the largest contribution to medial temporal tangles. A second, age-related but non-amyloid process likely contributes to medial temporal lobe tangles.
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Relative to the APOEε3 homozygote reference group, carrying one or two APOEε4 alleles is independently associated with a higher Aβ plaque burden and more severe cerebral amyloid angiopathy, whereas APOEε2/ε2 and ε2/ε3 individuals have fewer Aβ plaques but are more likely to have cerebral amyloid angiopathy.
“Relative to the APOEε3 homozygote reference group, carrying one or two APOEε4 alleles is independently associated with a higher Aβ plaque burden and more severe cerebral amyloid angiopathy (CAA), whereas APOEε2/ε2 and ε2/ε3 individuals have fewer Aβ plaques46–50 but are more likely to have CAA51.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [47]
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Experimental — accuracy not yet measuredMost studies agree that the APOEε4-linked effect on tau neurofibrillary tangles is primarily indirect, mediated through its increase of Aβ plaque burden.
“In contrast to Aβ pathology, the existence of a direct effect of APOE genotype on the severity of tau neurofibrillary tangle pathology remains controversial, with most studies agreeing that APOEε4-linked effect on tangles is primarily indirect, mediated through its increase of Aβ plaque burden46–48,53.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [47]
The Abstract and Discussion (page numbers not supplied) report evidence that neuritic plaques mediate the association of APOE ε4 with tangles, especially neocortical tangles. The paper does not establish that most studies agree, and its Discussion cautions that its correlational data cannot establish the proposed causal pathway. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAfter controlling for the presence and severity of Alzheimer disease neuropathology and comorbid pathologies, carrying the APOEε4 allele might still accelerate the rate of cognitive decline in the normal ageing-sporadic Alzheimer disease continuum, whereas carrying the APOEε2 allele might slow down cognitive decline.
“However, after controlling for the presence and severity of AD neuropathology and comorbid pathologies, carrying the APOEε4 allele might still accelerate the rate of cognitive decline in the normal ageing-sporadic AD continuum, whereas carrying the APOEε2 allele might slow down cognitive decline47,77,80,81.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [47]
The Results (Structural Model) examine APOE’s relationship with plaques and tangles, not its effect on the rate of cognitive decline after controlling for pathology. The Discussion says comorbid pathologies were not incorporated and calls for future analyses of their relationship with APOE and cognitive decline. Searches for APOE ε2 and cognitive decline yielded no passage establishing either allele-specific claim. (LLM, conf=0.76)
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- Authors
- Mungas, D., Tractenberg, R., Schneider, J. A., Crane, P. K., & Bennett, D. A.
- Affiliations
- University of California, Davis (US)
- Georgetown University (US)
- Rush University Medical Center (US)
- University of Washington (US)
- Corresponding author
- Mungas, Dan
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 35
- Issue
- 2
- Pages
- 301-308
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3977862
- OpenAlex
- W2094158890
- Cited by
- 58
- References
- 14
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 7 · 2013: 1
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (P30 AG10161, R01 AG15819, R13 AG030995)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neuropathology, neuritic plaques, diffuse plaques, neurofibrillary tangles, apolipoprotein E, age, medial temporal lobe, amyloid hypothesis, Religious Orders Study, cognitive status
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Brain, Female, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Models, Statistical, Cohort Studies, Neurofibrillary Tangles, Plaque, Amyloid
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