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Cited by 34Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsLipoproteins and Cardiovascular Health

Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia

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Koch, Manja, DeKosky, Steven T., Goodman, Matthew, Sun, Jiehuan, Furtado, Jeremy D., Fitzpatrick, Annette L., Mackey, Rachel H., Cai, Tianxi +4 more·2020·JAMA Network Open
DOI 10.1001/jamanetworkopen.2020.9250PMC PMC7352155
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Abstract

Importance: The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. Objective: To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. Design, Setting, and Participants: This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Exposures: Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Main Outcomes and Measures: Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Results: Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. Conclusions and Relevance: In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia.

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  • In the GEM subset, lower ApoE level in HDL lacking ApoC3 was associated with incident and Alzheimer's disease dementia (HR = 1.16; 95% CI 1.03 to 1.32).

    “as well as with incident and AD dementia (HR = 1.16; 95% CI: 1.03 to 1.32).”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [21]

    The Results section (ApoE in HDL Containing or Lacking ApoC3 or ApoJ; page unavailable) reports that higher apoE in HDL lacking apoC3 was associated with lower dementia risk, with similar associations for Alzheimer dementia. Its reported HR is 0.86 (95% CI, 0.76–0.99) per 1-SD *higher* apoE; reversing that comparison gives an HR of approximately 1.16 for lower apoE, but not the claimed lower confidence limit of 1.03. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In the GEM subset, lower ApoE level was significantly associated with higher ADAS-cog scores only in HDL (β = 0.20; 95% CI 0.10 to 0.30).

    “lower ApoE level was significantly associated with higher ADAS-cog scores only in HDL (β = 0.20; 95% CI: 0.10 to 0.30) [21]”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [21]

    The Results section (page not supplied) reports that higher ApoE in HDL lacking apoC3 was associated with lower baseline ADAS-cog scores, supporting the claimed direction of association. It does not establish that the association held for HDL as a whole, and the reported estimate for that subspecies is −0.17 per 1-SD higher ApoE (95% CI, −0.27 to −0.07), not the cited β of 0.20 (95% CI, 0.10 to 0.30). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In the GEM subset, lower ApoE level in HDL lacking ApoC3 was associated with significantly lower 3MSE scores (β = −0.25; 95% CI −0.42 to −0.07).

    “but also with significantly lower 3MSE scores (β = −0.25; 95% CI: −0.42 to −0.07)”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [21]

  • In the GEM subset, the association of lower ApoE level with higher ADAS-cog scores was confined to HDL lacking ApoC3 (β = 0.17; 95% CI 0.07 to 0.27).

    “this was confined to HDL lacking ApoC3 not only with ADAS-cog (β = 0.17; 95% CI: 0.07 to 0.27)”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [21]

  • To determine the association of plasma ApoE level with risk of incident dementia, hazard ratios per 1-SD lower ApoE level were obtained in 3031 subjects using Cox regression adjusted for baseline age, sex, ethnicity, education, BMI, and research site.

    “To determine the association of plasma ApoE level with risk of incident dementia, we obtained hazard ratios (HRs) per 1-standard deviation (SD) lower ApoE level in 3031 subjects using the Cox regression model [21] adjusted for baseline age, sex, ethnicity, education, BMI, and the research site.”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [21]

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Authors
Koch, M., DeKosky, S. T., Goodman, M., Sun, J., Furtado, J. D., Fitzpatrick, A. L., Mackey, R. H., Cai, T., Lopez, O. L., Kuller, L. H., Mukamal, K. J., & Jensen, M. K.
Affiliations
  • Harvard University (US)
  • University of Florida Health (US)
  • University of Washington (US)
  • Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
  • University of Pittsburgh (US)
  • Beth Israel Deaconess Medical Center (US)
  • University of Copenhagen (DK)
Corresponding author
Koch, Manja
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2020-07-10
Volume
3
Issue
7
Pages
e209250
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2020.9250
PMC
PMC7352155
OpenAlex
W3041041487
Cited by
34
References
5
Citations by year
2026: 5 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 5 · 2021: 4 · 2020: 5
FWCI
4.01
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Network Open (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (P50AG005133)
  • National Center for Complementary and Alternative Medicine
  • National Institute of Neurological Disorders and Stroke (R01NS089638)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
apolipoprotein E, APOE ε4, Alzheimer's disease, dementia risk, high-density lipoprotein, HDL subfractions, apolipoprotein C-III, lipoprotein subclasses, cognitive function, older adults, incident dementia, ADAS-Cog, Mini-Mental State Examination, cardiovascular risk factors, apolipoprotein A-I
MeSH terms
Correlation of Data, Aged, Apolipoproteins E, Cognition, Dementia, Female, Follow-Up Studies, Humans, Male, Neuropsychological Tests, Prospective Studies, Risk Factors, United States, Cohort Studies, Apolipoprotein C-III, Independent Living, Protective Factors

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