Early-onset Alzheimer disease (AD) is likelier among those with higher circulating low-density lipoprotein cholesterol (LDL-C), according to a study recently published in JAMA Neurology. An association has also been identified between rare coding changes in apolipoprotein B (APOB) and early-onset AD.

This study included 2125 individuals with and without AD from 29 research centers, 1276 of whom were women and 654 (30.8%) of whom had early-onset AD. Plasma levels of cholesterol were evaluated in 267 samples, with multiple linear regression used to investigate the association between cholesterol and early-onset AD. Adjustments were made for batch, education, sex, and APOE E4 allele copies. Potential genetic variants underlying the disease were identified by sequencing APOE E4, APOB, amyloid precursor protein (APP), and presenilin 1 and 2. Measures included age at diagnosis, type of diagnosis, cholesterol levels, and genetic variants, with the correlation between plasma cholesterol and early-onset AD constituting the primary outcome. The correlation between genetic variants in APOB and early-onset AD was the secondary outcome.

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Genetic testing revealed APOE E4 to underlie 10.1% of the variance of early-onset AD. Compared with controls, early-onset AD was associated with elevated levels of total cholesterol (mean difference, 21.9±5.2 mg/dL; P =.000029), APOB (mean difference, 12.0±2.4 mg/dL; P =.0000020), and LDL-C (mean difference, 22.0±4.5 mg/dL; P =.0000018), with adjustment for APOE E4. Age was not found to be significantly associated with LDL-C. Mutations responsible for AD were identified among 3.4% (n=23) of cases. After adjusting for APOE E4, research center, batch, and genetic principal components, rare APOB coding variants were found to be present in significantly more cases than controls (effect size, 0.20; P =.000420). The Fisher exact test revealed an allele in 5% of those with early-onset AD and 1.7% of controls (P =.0000372).

Limitations to this study include a lack of inference of causality, potential confounding caused by lack of data, and the lack of whole-exome findings and significance.

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The study researchers conclude that “circulating cholesterol is associated with [early-onset AD] independently of APOE E4. Furthermore, we have identified novel rare genetic coding changes in APOB that are associated with [early-onset AD] independently of APOE. The APOB variants we found do not fully explain the association between elevated LDL-C levels and [early-onset AD], indicating that further studies are needed to identify additional genetic variants underlying the contribution of lipid metabolism to AD pathogenesis.”

Disclosure: Several authors reported financial associations with pharmaceutical companies. See the reference for complete disclosure information.


Wingo TS, Cutler DJ, Wingo AP, et al. Association of early-onset Alzheimer disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB [published online May 28, 2019]. JAMA Neurol. doi:10.1001/jamaneurol.2019.0648