HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease

Posted by & filed under Part 12: LIPIDS, Part 28: NEUROGENETICS.

Leduc V et al. HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study. Mol Psychiatry. 2014 Jul 15

Leduc et al report a new genetic modulator of the risk for sporadic Alzheimer’s disease (AD) occurrence, as well as the risk of conversion from mild cognitive impairment to full-blown AD. HMGCR encodes 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol synthesis and the molecular target of statins. The authors find that G negative (AA) status in the HMGCR rs3846662, an intronic polymorphism involved in exon 13 skipping, is protective with respect to the risk of acquiring AD, the age of onset, and the risk of conversion of mild cognitive impairment to AD, specifically in women.

The methodology is interesting (particularly for those of us with a Montreal connection) in that the authors first identified this association in the more homogeneous French Canadian population, and then found that it could be generalised to two different mixed North American populations.
This study joins the body of evidence suggesting that lipid and cholesterol metabolism is crucial to the pathophysiology of Alzheimer’s disease. However, whether the protective effect identified is mediated by alterations in cerebral cholesterol metabolism directly or by better vascular health remains to be determined.

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