Wingo TS, et al. - Through a case series of plasma samples from 2,125 cases and controls, the researchers assessed if circulating cholesterol levels correlates with early-onset Alzheimer disease (EOAD) and to recognize genetic variants underlying this potential association. APOE E4 explained 10.1% of the variance of EOAD. In comparison to controls in 267 frozen samples, EOAD cases had greater levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and APOB, after controlling for APOE E4. Around 3% of EOAD cases had known Alzheimer disease (AD)-causing mutations. After adjusting for sex, APOE E4, genetic principal components, AD research center, and batch, gene-based rare variant burden testing in 2,066 samples demonstrated that rare APOB coding variants were significantly plentiful in EOAD cases. Raised LDL-C levels were correlated with a greater possibility of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which coded for the major protein of LDL-C. These novel findings altogether reflected the major role of LDL-C in EOAD pathogenesis and implied a direct connection of APOB variants to AD risk.