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