Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative

Dec 27, 2021Journal of Alzheimer's disease : JAD

Total Cholesterol and APOE Gene Risk Linked to Alzheimer's Disease

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Abstract

Total cholesterol was higher in APOE4+ carriers compared to APOE3 and APOE2+ carriers (ps < 0.04).

Participants with Alzheimer's disease (AD) and late mild cognitive impairment (MCI) had significantly higher total cholesterol levels than cognitively normal controls (ps < 0.001).
Predicted odds ratios indicate that for each mg/dL increase in total cholesterol, the risk for MCI was 1.11 (95% confidence interval, 1.04-7.32) and for AD was 1.21 (1.09-54.05).
Higher total cholesterol could be linked to increased risk of AD, especially in individuals carrying the APOE4 allele.
These findings suggest that cholesterol metabolism may play a role in the mechanisms underlying the genetic risk associated with APOE.

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BACKGROUND: APOEɛ4 allele confers greatest genetic risk for Alzheimer's disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk.

OBJECTIVE: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer's Disease Neuroimaging Initiative.

METHODS: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument.

RESULTS: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04-7.32), 1.05 for early MCI (1.01-3.22), 1.13 for late MCI (1.05-11.70), 1.21 for AD (1.09-54.05), and 1.13 for composite dementia (MCI or AD; 1.06-11.59) (ps < 0.05, F-statistics > 10).

CONCLUSION: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.

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