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Original Investigation
May 28, 2019

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

Author Affiliations
  • 1Division of Neurology, Atlanta Veterans Affairs Medical Center, Decatur, Georgia
  • 2Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
  • 3Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
  • 4Division of Mental Health, Atlanta Veterans Affairs Medical Center, Decatur, Georgia
  • 5Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia
  • 6Biomarker Core Laboratory, Atlanta Veterans Affairs Medical Center, Decatur, Georgia
  • 7Department of Neurology, University of California, San Francisco
JAMA Neurol. 2019;76(7):809-817. doi:10.1001/jamaneurol.2019.0648
Key Points

Question  Is circulating cholesterol level associated with early-onset Alzheimer disease, and if so, what is the underlying genetic mechanism?

Findings  This case series of plasma samples from 2125 cases and controls found an association between early-onset Alzheimer disease and higher levels of low-density lipoprotein cholesterol independent of the effects of APOE, as well as demonstrated enrichment of rare coding variants of APOB, a gene known to influence plasma cholesterol levels, in samples from patients with early-onset Alzheimer disease.

Meaning  Two parallel lines of evidence suggest that circulating low-density lipoprotein cholesterol levels may play a role in the pathogenesis of early-onset Alzheimer disease, and future work should elucidate whether APOB influences the risk for early-onset Alzheimer disease by acting through plasma low-density lipoprotein cholesterol levels or through other mechanisms.


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.