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Longevity Genotype Is Associated
With Preservation of Cognitive Function
SAVANNAH, GA—
Persons with a genotype linked to increased levels of HDL cholesterol are more likely to retain good cognitive function later in life than those without the genotype, according to data presented at the 19th Annual Meeting of the American Neuropsychiatric Association. The same genotype has previously been associated with increased longevity. Both associations are consistent with what one might anticipate from a gene with the potential to protect against vascular disease, including adverse changes in the cerebrovascular system. The finding has a number of implications, including what it may reveal for defining an important mechanism of cognitive decline and, ultimately, how it can be reversed.
PRELIMINARY LONGEVITY GENOTYPE STUDIES
In a previous study, homozygosity for the I405V functional variant of the cholesteryl ester transfer protein (CETP) gene was strongly associated with exceptional longevity. In a recent study, the same variant, which is relatively common, correlated with preserved cognitive function. The genotypic association parallels the phenotypic association. Both lipoprotein particle size and HDL cholesterol level, which is associated with the CETP genotype, have been independently associated with protection against Alzheimer’s disease and other forms of dementia.
“What we do not yet know is whether modulation of this gene prevents age-related decline in the risk of Alzheimer’s disease,” said Nir Barzilai, MD, Director of the Institute for Aging Research and Professor of Medicine and Molecular Genetics at Albert Einstein College of Medicine in New York City. Summarizing results of a series of CETP genotype studies, Dr. Barzilai cautioned that associations do not confirm causation, but the potential for activation of the CETP gene variant to prevent dementia by raising HDL cholesterol is a logical inference that deserves further study.
In an initial study published in 2003, Dr. Barzilai and colleagues reported that the frequency of enrichment of the CETP I405V gene was almost three times greater in a population with an average age of nearly 100 than it was in a comparison group of individuals with a median age of 70. A subsequent study by Italian investigators produced similar results. Based on the lipid profiles in patients with this gene variant, which include high levels of HDL cholesterol and large particles of LDL cholesterol, the obvious hypothesis is that the extended survival is a product of a low risk of vascular disease, which is the most common cause of death in industrialized countries.
LONGEVITY GENOTYPE AND COGNITIVE FUNCTION
In the more recent study, the goal was to look at rates of dementia. Multiple studies have suggested that risk for Alzheimer’s disease and other forms of dementia is at least partially mediated by lipid metabolism, making this a logical extension of the initial evaluation of this genotype. “We were able to link this gene with protection from age-related cognitive decline, which has not been demonstrated previously,” Dr. Barzilai reported. “The genotype conforms to the phenotypic features, including a low CETP level, a higher HDL cholesterol level, and a larger lipoprotein particle size.”
Although studies are ongoing, findings from the cognitive study were first published in Neurology in 2006. One hundred fifty-eight Ashkenazi Jews ages 95 to 107 (average age, 99.2) were evaluated for cognitive function and tested for the CETP I405V genotype. Among patients with good cognitive function—defined as a Mini-Mental State Examination (MMSE) score of more than 25 points—the proportion with the CETP I405V genotype was twice as great as it was in those with poorer cognitive function (29% vs 14%). From the opposite perspective, those with the CETP I405V genotype were twice as likely as those without it to have a MMSE score above 25 points (61% vs 30%).
As part of the same study, the presence of the CETP I405V genotype was also evaluated in individuals participating in the Einstein Aging Study. In this population, all of whom were older than 70, the proportion of patients with good cognitive function with the CETP I405V genotype was more than five times greater than those with poor cognitive function (21% vs 4%). In both groups, those with good cognitive function were more likely to have higher HDL cholesterol levels. In addition, the association between the CETP I405V genotype remained strong after controlling for a broad array of risk factors, such as education, nutritional status, hydration, presence of cardiovascular disease, presence of hypertension, and APOE subtypes.
“Good cognitive function was associated with significantly higher HDL levels, larger average size of HDL, and higher apolipoprotein A-I levels than in those with impaired cognitive function,” reported Dr. Barzilai. Perhaps just as relevant for understanding the importance of the lipid profile on the risk of cognitive impairment, “LDL levels and the percentage of large LDL [particles] were not found to have any relationship with MMSE score,” he added.
Although these findings seem to outline a very simple protective effect in which the activated CETP gene variant produces relatively large levels of HDL cholesterol—which, by preventing atherosclerosis, prevents global risk of vascular disease, including disease in the cerebrovascular system—Dr. Barzilai cautioned against oversimplification. He noted that recent studies at his institution isolated CETP expression in endothelial cells in the CNS, suggesting that there may be very specific local protection generated by expression of the CETP I405V genotype. He also reported that there is evidence that patients with low HDL cholesterol have cognitive impairment even after excluding those with cardiovascular or cerebrovascular disease.
“It is reasonable to speculate that elevated HDL protects the vascular integrity of the aging brain, but there is the potential for protection independent of the vasculature. For example, the antioxidative effects of HDL may have specific beneficial effects in the CNS,” Dr. Barzilai said.
NEW TREATMENT STRATEGIES?
Dr. Barzilai is hopeful that these results may lead to rational strategies for prophylaxis or, perhaps, treatment. While simply raising HDL cholesterol level is one potential approach, recreating the effects of the CETP I405V genotype may be more complicated, requiring changes in lipid particle sizes and inhibition of lipid-related antioxidant effects. Gene therapy may prove to be the most effective and efficient approach to providing the protective effects of the CETP I405V genotype, if additional studies can confirm that the relationship with lower rates of dementia is causal. According to Dr. Barzilai, these studies have outlined an important avenue of research to explain relative vulnerability or relative invulnerability to cognitive loss during aging.
—Ted Bosworth
Suggested Reading
Barzilai N, Atzmon G, Derby CA, et al. A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 2006;67(12):2170-2175.
Barzilai N, Atzmon G, Schechter C, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA. 2003;290(15):2030-2040.
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