Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people
Open accessAbstract
BACKGROUND: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. OBJECTIVE: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. METHODS: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. RESULTS: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. CONCLUSION: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.
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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 [46]
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Experimental — accuracy not yet measuredThe well-established association between APOE genotype and cognition - whereby APOEε4 accelerates age-related cognitive decline and APOEε2 delays it - is largely mediated by genotype-specific effects on Alzheimer disease neuropathological changes and, to a lesser extent, on comorbid pathologies.
“The well-established association between APOE genotype and cognition — whereby APOEε4 accelerates age-related cognitive decline76 and APOEε2 delays it77 — is largely mediated by genotype-specific effects on AD neuropathological changes and, to a lesser extent, on comorbid pathologies46–48,78,79.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [46]
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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 [46]
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Self-citation
- Authors
- Bennett, D. A.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Bennett, D A
- ORCID
- Bennett, D A
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2005-09-01
- Volume
- 76
- Issue
- 9
- Pages
- 1194-1199
- ISSN
- 0022-3050 (ISSN-L)
- PMC
- PMC1739810
- OpenAlex
- W2168884540
- Cited by
- 99
- References
- 7
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 7 · 2017: 5 · 2016: 1 · 2015: 6 · 2014: 4 · 2013: 7 · 2012: 5
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Rush University
- Iran Nanotechnology Initiative Council
- National Institute on Aging (P30-AG 10161, R01 AG15819, R01AG015819, P30AG010161)
- 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
- amyloid-beta, neurofibrillary tangles, tau protein, cognitive function, Alzheimer's disease, mediation, older adults, Religious Orders Study
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Amyloid, Apolipoproteins E, Autopsy, Cognition Disorders, Female, Humans, Male, Regression Analysis, Case-Control Studies, Apolipoprotein E4
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