Longevity Gene Also Linked to Preserved Memory and Cognitive Function

Susan Jeffrey

December 29, 2006

December 29, 2006 — A new study in people of Ashkenazi Jewish descent older than 95 years of age shows a variant of the cholesterol ester transfer protein (CETP) gene, previously associated with longer life as well as increased HDL levels and LDL particle size, is associated with less dementia and improved memory.

The researchers, led by Nir Barzilai, MD, director of the Institute for Aging Research at Albert Einstein College of Medicine, in the Bronx, New York, also confirmed this association in a second cohort of subjects about 20 years younger.

"The frequency of the CETP VV genotype is increased monotonically in those surviving into advanced age, and it is overrepresented by nearly 3-fold for 100 years of age compared with subjects in their seventh decade of life," the authors write. "This is the first report to link this gene with specific protection against age-related cognitive decline."

Their report appears in the December 26 issue of Neurology.

Studying Exceptional Longevity

Approximately 1 in 10,000 in the general population lives to be 100 years old, the authors note. In a press release on this report from the American Academy of Neurology (AAN), Dr. Barzilai points out that while many studies have identified risk factors associated with developing age-related diseases, "little effort has been made to identify the reasons for longevity in exceptionally old people and why they don't develop disease."

In previous work, Dr. Barzilai and colleagues showed that homozygosity (VV) for a common functional variant of the CETP gene known as 1405V was enriched almost 3-fold, to 25% in a group of subjects with an average age of 100 vs 8% in those aged 30 years or younger. The CETP VV genotype, they explain, is associated with low plasma levels of CETP, a protein involved in reverse cholesterol transport. It mediates the exchange of cholesterol esters between HDL and apoB-containing lipoproteins, thereby promoting the uptake of cholesterol by the liver. Low CETP is also associated with large LDL and HDL particles, they note, "suggesting a direct functional effect of this variant."

In this report, they studied a group of 158 people of Ashkenazi Jewish descent who had achieved exceptional longevity, with an average age of 99 years. Subjects were assessed for CETP genotype and lipoprotein phenotype and underwent the Mini-Mental State Examination (MMSE) to assess cognitive function.

The researchers report that subjects with preserved cognitive function, an MMSE score of greater than 25 vs those with a score of 25 or less, were twice as likely to have the CETP VV genotype.

Percent of Subjects With CETP VV Genotype By MMSE Score

Group
MMSE > 25
MMSE < 25
P
CETP VV genotype (%)
29
14
.02

Those with the VV genotype were also more likely to have an MMSE score of greater than 25, with 61% of the group homozygous for the gene scoring at this level, vs 30% of the group who were not homozygous for the gene. Those with the CETP VV genotype also had significantly lower levels of CETP, higher HDL levels, and larger lipoprotein particles than those who were not.

To confirm their findings, they similarly studied 124 subjects from the Einstein Aging Study (EAS), also of Ashkenazi Jewish descent but between the ages of 75 and 85, and obtained similar results. There was an approximately 5-fold increase in the VV genotype, higher HDL levels, and larger lipoprotein particle sizes among those with more preserved cognitive function.

"Using 2 independent cohorts, we implicate the longevity CETP gene as a modulator of age-related cognitive function," they conclude.

"It's possible that this gene variant also protects against the development of Alzheimer's disease," Dr. Barzilai said in the AAN statement.

Neurology. 2006; 67:2170-2175

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