Cholesterol-Alzheimer's Link Backed by New Data

The e4 variant of the APOE gene has been strongly linked with susceptibility to Alzheimer's disease. Indeed, one-fourth of the population is estimated to carry this variant. What fewer people are aware of, however, is that the APOE gene is also known to be the major transporter of cholesterol in the blood and central nervous system and a risk factor for coronary disease.

Now a number of other genes involved in cholesterol metabolism appear to be involved in Alzheimer's susceptibility as well, a new study suggests. However, the APOE gene still seems to be the biggest culprit.

The study was led by Andreas Papassotiropoulos, M.D., a psychiatrist and research professor at the University of Zurich in Switzerland. Results appeared in the July Journal of Clinical Psychiatry.

Papassotiropoulos and his colleagues enrolled more than 500 older persons from Switzerland and Greece. Half had been diagnosed with Alzheimer's disease; the other half did not have the illness. The researchers then analyzed DNA samples from these subjects to assess 12 single nucleotide polymorphisms—that is, variants in genetic material—from 11 genes related to cholesterol metabolism and previously linked to Alzheimer's disease. One of the single nucleotide polymorphisms was the APOE e4 variant.

The scientists also examined the DNA samples to see whether they contained 48 single nucleotide polymorphisms that had never been linked with either cholesterol or Alzheimer's.

Finally, they looked for links between any of the single nucleotide polymorphisms and the presence of Alzheimer's.

They found that nine of the 12 single nucleotide polymorphisms previously implicated in cholesterol metabolism and Alzheimer's were also significantly associated with Alzheimer's in their study.

In contrast, they were not able to find any association between Alzheimer's and the 48 single nucleotide polymorphisms not previously tied to cholesterol and Alzheimer's.

Moreover, they found that some of the nine single nucleotide polymorphisms were more strongly associated with Alzheimer's than the others were. The APOE e4 gene variant headed the list. Then came material from a gene called SOAT1. Then came material from the APOE promoter.

“This study is potentially important for several reasons,” Eric Reiman, M.D., a professor of psychiatry at the University of Arizona and deputy editor of the Journal of Clinical Psychiatry, asserted in an editorial accompanying the report. For example, “It implicates a cluster of genes, including, but not limited to, the APOE e4 allele, in the susceptibility to late-onset Alzheimer's disease.”

Also, he added, “It provides further support for the role of higher cholesterol levels in the pathogenesis of Alzheimer's disease and the potential role of cholesterol-lowering strategies in the treatment and prevention of this disorder.”

However, as Reiman cautioned in an interview with Psychiatric News, the findings will not be used clinically any time soon to predict Alzheimer's for several reasons—they have not yet been replicated,“ they do not predict with sufficient certainty whether or when a person might develop symptoms,” and “they don't yet tell the person what he or she might be able to do to prevent the disorder.”

In fact, he said, testing for the APOE e4 variant alone to predict Alzheimer's risk is not recommended for clinical use at this point because of the danger of triggering false alarms or creating false reassurances, and because no preventive measures are available.

Josepha Cheong, M.D., an associate professor of psychiatry at the University of Florida and chair of the APA Council on Aging, told Psychiatric News that the study impressed her for several reasons. For one, the researchers attempted to identify the interplay of a cluster of genes that may be involved in the etiology and clinical presentation of Alzheimer's disease instead of looking for the effect of a single gene at a time, which is more common. For another, she believes that the study“ represents a continuation in the discovery of genes involved in the pathogenesis of Alzheimer's disease.” And finally, whereas the“ research results may not be acutely clinically relevant, they portend significant possibilities for diagnosis and treatment.”

Meanwhile, Papassotiropoulos said, “I anticipate that several genetics groups will attempt to replicate the findings, among others Dr. Jonathan Prince from the Karolinska Institute in Sweden. There are [also] several [other] lipid-related genes to be looked at. In addition, it will be important to combine this genetic information with data on brain activation patterns by means of PET or fMRI.”

The study was funded by the Swiss National Science Foundation, the Early Diagnosis of Alzheimer's Disease and Related Dementia Program in Switzerland, and the National Center for Competence in Research in Switzerland.

“A Cluster of Cholesterol-Related Genes Confers Susceptibility for Alzheimer's Disease” can be accessed online at<www.psychiatrist.com/toc.htm> by searching on the article title in the July issue. ▪