CETP Variant Linked to Slower Cognitive Decline and Reduced Dementia Risk

Susan Jeffrey

January 13, 2010

January 13, 2010 — A new study shows that a functional variant of the cholesterol ester transfer protein (CETP) gene, which has already been linked with exceptional longevity and a lower risk for cardiovascular disease, is also associated with slower memory decline and a reduced risk for Alzheimer's disease (AD) and dementia.

"People who carried the longevity variant of CETP have their risk of developing Alzheimer's disease reduced by 70%," even after adjustment for a variety of confounding factors, including apolipoprotein (APOE) ε4 status, senior study author Richard B. Lipton, MD, from the Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, told Medscape Neurology.

"I have to say in fairness that this is a single estimate, and in a larger replication sample the effect may not remain that large, but a 70% risk reduction is huge," Dr. Lipton said. Those who carried the favorable variant — CETP V405 valine homozygosity — also had less memory decline than their age-matched counterparts who did not carry this variant.

Their report, with first study author Amy E. Sanders, MD, also at Albert Einstein College of Medicine, is published in the January 13 issue of the Journal of the American Medical Association.

Einstein Aging Study

Of genes that have currently been linked to AD, still the most common and most important in the general population is the APOE ε4 allele, which confers a substantially increased risk, Dr. Lipton said. Another approach is to look instead at genes associated with exceptional longevity, he said, "and ask the question, do these longevity genes also promote successful brain aging and protect against dementia?"

Some studies, for example, have linked the APOE ε2 allele with both increased lifespan and lower dementia risk, the study authors note. Like APOE, the CETP gene is involved in cholesterol homeostasis in the central nervous system and has also been associated with longevity. The association has been strongest among Ashkenazi Jews, although some but not all case-control studies in non-Ashkenazi subjects have also shown a relationship between CETP and dementia prevalence.

Previous work by Nir Barzilai, MD, Dr. Lipton's colleague at Albert Einstein College of Medicine and a coauthor on this article, for example, has linked CETP with exceptional longevity and better cognitive function among centenarians who carried the V405 genotype, a single-nucleotide polymorphism at CETP codon 405 that substitutes valine for isoleucine.

It has also been associated with a lower CETP protein serum concentration activity with corresponding increases in high-density lipoprotein levels and in the size of low-density lipoprotein particles that could potentially have positive effects on cardiovascular risk.

"This made us hopeful that this CETP variant might protect against cognitive aging and dementia," Dr. Lipton noted. To examine the possibility further, they studied this functional polymorphism of CETP in the context of the Einstein Aging Study, a prospective cohort study of community-dwelling adults who were free of dementia at baseline.

A total of 523 subjects who had a CETP genotype available and sufficient follow-up were included in this analysis. They underwent standardized neuropsychological and neurologic testing annually between 1994 and 2009. The valine allele frequency was 43.5%.

During a mean of 4.3 years of follow-up, there were 40 incident cases of dementia. Compared with those who were homozygous for the isoleucine variant, valine homozygotes had significantly slower memory decline as measured by the Free and Cued Selective Reminding Test, with an average decline of 0.43 point per year for the isoleucine homozygotes vs 0.21 point per year for the valine homozygotes (difference in linear slope, 0.22; P = .03). There were no differences on the tests of attention or psychomotor speed between groups, they note.

Valine homozygotes also had significantly lower risks for dementia and AD than isoleucine homozygotes.

Table. Risk for Dementia and Alzheimer's Disease Among Valine Homozygotes vs Isoleucine Homozygotes

Outcome Hazard Ratio (95% CI) P Value
Dementia 0.28 (0.10 – 0.85) .02
Alzheimer's disease 0.31 (0.10 – 0.95) .04

CI = confidence interval

Those heterozygous for valine had a lower risk for dementia and AD than those heterozygous for isoleucine, but the differences did not reach statistical significance.

The study authors caution that their study cannot address whether the associations they describe are causal, but point out that the fact that the risk for valine heterozygotes was between that of isoleucine homozygotes and valine homozygotes argues for a causal role.

Growing evidence also suggests a link between cholesterol metabolism and AD pathology, the study authors conclude. "Future studies investigating intermediate steps in the putative causal pathway — mediation by endophenotypic biomarkers, such as CETP plasma levels and protein activity, for example — might provide useful first steps toward eventual resolution of the causality question," they write.

Largest Population to Date

Asked for perspective on these findings, Ronald Devere, MD, director of the Alzheimer's Disease and Memory Disorders Center in Austin, Texas, pointed out that although the origin of Alzheimer's disease is still unclear, more information is accumulating about genetic factors that increase risk, such as APOE ε4, or decrease risk, such as APOE ε2 and the V405 (valine) genotype of CETP.

In this new report, Sanders and colleagues studied this genotype in the largest population to date with long follow-up and found that those with the V405 genotype had significantly slower memory decline and a lower incidence of AD than those without this genotype.

"The information does not transfer to any immediate clinical application," Dr. Devere told Medscape Neurology. It does, however, strengthen the importance of genes that regulate cholesterol metabolism in determining dementia risk, he said. "It also will lead to more studies verifying and looking at the potential protective cognitive effects of the CETP gene and its mechanism of action, he added, and potentially, a future specific gene therapy for AD.

The Einstein Aging Study is supported by the National Institute on Aging. Dr. Barzilai is supported by the National Institute on Aging. Dr. Sanders is supported by the Einstein Clinical and Translation Science Award, the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Dr. Lipton reported receiving compensation from Advanced Bionics, Allergan, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cierra, Endo, GlaxoSmithKline, Minster, Merck, Neuralieve, Novartis, and Ortho-McNeil.

JAMA. 2010;303:150-158.

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