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Cited by 119Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchLipoproteins and Cardiovascular Health

Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB

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Wingo, Thomas S., Cutler, David J., Wingo, Aliza P., Le, Ngoc-Anh, Rabinovici, Gil D., Miller, Bruce L., Lah, James J., Levey, Allan I.·2019·JAMA Neurology
DOI 10.1001/jamaneurol.2019.0648PMC PMC6547122
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Abstract

Importance: Early-onset Alzheimer disease (EOAD) is a rare form of Alzheimer disease (AD) with a large genetic basis that is only partially understood. In late-onset AD, elevated circulating cholesterol levels increase AD risk even after adjusting for the apolipoprotein E ε4 (APOE E4) allele, a major genetic factor for AD and elevated cholesterol levels; however, the role of circulating cholesterol levels in EOAD is unclear. Objectives: To investigate the association between circulating cholesterol levels and EOAD and to identify genetic variants underlying this possible association. Design, Setting, and Participants: In this case series, plasma cholesterol levels were directly measured in 267 samples from the AD research centers (ADRCs) of Emory University and University of California, San Francisco, collected from January 21, 2009, through August 21, 2014. The association between cholesterol and EOAD was examined using multiple linear regression. To determine the underlying genetic variants, APOB, APP, PSEN1, and PSEN2 were sequenced in samples from 2125 EOAD cases and controls recruited from 29 ADRCs from January 1, 1984, through December 31, 2015. Data were analyzed from November 23, 2016, through April 10, 2018. Exposures: Clinical diagnosis, age at clinical diagnosis, plasma cholesterol measures (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B), and genetic variants in APOE, APP, PSEN1, PSEN2, and APOB. Main Outcomes and Measures: The primary outcome was the association between EOAD and plasma cholesterol measures. The secondary outcome was the association between EOAD and the burden of genetic variants in APOB. Results: Of the 2125 samples that underwent genetic sequencing, 1276 were from women (60.0%) and 654 (30.8%) were from patients with EOAD (mean [SD] ages, 55.6 [4.3] years for cases and 72.0 [9.6] years for controls). APOE E4 explained 10.1% of the variance of EOAD. After controlling for APOE E4, EOAD cases had higher levels of total cholesterol (mean difference [SE], 21.9 [5.2] mg/dL; P = 2.9 × 10-5), LDL-C (mean difference [SE], 22.0 [4.5] mg/dL; P = 1.8 × 10-6), and ApoB (mean difference [SE], 12.0 [2.4] mg/dL; P = 2.0 × 10-6) than controls in 267 frozen samples. Approximately 3% of EOAD cases carried known AD-causing mutations. Gene-based rare variant burden testing in 2066 samples showed that rare APOB coding variants were significantly more abundant in EOAD cases after adjusting for sex, APOE E4, genetic principal components, ADRC center, and batch (effect size, 0.20; P = 4.20 × 10-4). Conclusions and Relevance: Elevated LDL-C levels were associated with higher probability of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which codes for the major protein of LDL-C. Collectively, these novel findings highlight the important role of LDL-C in EOAD pathogenesis and suggest a direct link of APOB variants to AD risk.

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  • Elevated apoB was significantly associated with increased risk of early onset AD (EOAD) and EOAD cases were enriched for apoB rare functional variants.

    “which observed that elevated apoB was significantly associated with increased risk of early onset AD (EOAD) and EOAD cases were enriched for apoB rare functional variants”

    From Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants (2023) · cites this paper as [12]

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Cited by

Sorted by citations

Authors
Wingo, T. S., Cutler, D. J., Wingo, A. P., Le, N.-A., Rabinovici, G. D., Miller, B. L., Lah, J. J., & Levey, A. I.
Affiliations
  • Emory University (US)
  • Atlanta VA Medical Center (US)
  • University of California, San Francisco (US)
Corresponding author
Wingo, Thomas S.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2019-07-01
Volume
76
Issue
7
Pages
809
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2019.0648
PMC
PMC6547122
OpenAlex
W2947761451
Cited by
119
References
7
Citations by year
2026: 8 · 2025: 12 · 2024: 14 · 2023: 17 · 2022: 18 · 2021: 21 · 2020: 24 · 2019: 5
FWCI
11.66
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (IK2 BX001820)
  • National Alzheimer's Coordinating Center (U01AG016976)
  • National Institutes of Health (AG016976, AG019610, AG013846, AG008702)
  • National Institute on Aging (AG 016976, P30AG053760, P30AG010129, P30AG010133, R01AG056533, P30AG049638, P30AG028383, P30AG012300, R01AG045611, P50AG005133, U01AG016976, P50AG005131, P50AG005138, AG019610, P30AG010124, P50AG016573, P50AG047366, P30AG008017, P30AG010161, U24 AG21886, P30AG008051, P50AG008702, P50AG033514, P30AG035982, AG013846, P50AG005681, P50AG005142, P50AG047270, P30AG019610, P50AG005146, P30AG013846, P50AG005136, P50AG005134, P30AG013854, R56AG062633, P50AG025688, P50AG047266, U24AG021886, P50AG023501, P50AG016574)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
early-onset Alzheimer's disease, LDL cholesterol, serum cholesterol, rare coding variants, APOE ε4, apolipoprotein B, APP, presenilin 1, presenilin 2, genetic risk factors, triglycerides, HDL cholesterol, total cholesterol, lipid metabolism, familial Alzheimer's disease, sporadic Alzheimer's disease
MeSH terms
Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Case-Control Studies, Amyloid beta-Protein Precursor, Age of Onset, Codon, Nonsense, Genetic Predisposition to Disease, Mutation, Missense, Apolipoprotein B-100, Apolipoprotein E4, Presenilin-1, Presenilin-2

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