08 Jan 2007

Want to survive to a ripe old age and still manage that cryptic crossword puzzle? Boosting your high-density lipoproteins (HDLs) might be a good idea, in spite of the recent failure of a drug that was meant to do exactly that. While there’s overwhelming evidence linking higher HDLs to reduced morbidity and mortality due to cardiovascular disease, they may also protect against age-related cognitive decline—at least that’s one interpretation of a recent paper linking polymorphisms in the cholesterol ester transfer protein (CETP) gene with longevity and cognition.

The study appeared in the December issue of Neurology. Nir Barzilai and colleagues at the Institute for Aging Research at Albert Einstein College of Medicine, New York, report that in 158 Ashkenazi Jews, who live exceptionally long lives (mean age 99.2 years), those with Mini-Mental State Examination (MMSE) scores over 25 (higher scores are better) are twice as likely to be homozygous for valine as opposed to isoleucine at position 405 of CETP. Conversely, those with the VV genotype were also twice as likely to have MMSE scores greater than 25. How the CETP genotype influences cognition is unclear, but CETP mediates the transfer of cholesterol esters from HDLs to apolipoprotein B, a major component of the low-density lipoprotein complex that carries “bad” cholesterol. Because the researchers also report that the VV genotype is associated with significantly lower plasma levels of CETP and statistically higher HDL levels, the better lipid profile may somehow protect cognition, as has been indicated previously (see Merched et al., 2000). The VV variant is also associated with larger size of lipoprotein particles, which may also be beneficial, the authors suggest.

Interestingly, the cognitive benefit may not necessarily relate to overall improvement in cardiovascular fitness. When the researchers omitted participants with cardiovascular disease or hypertension from the analysis, people with the VV variant still scored statistically better on the MMSE. CETP may, therefore, have local effects on the brain, and. indeed. Barzilai and colleagues report that the protein is expressed in brain endothelial cells. “This raises the possibility that just as ApoE has a local effect in AD, CETP may have a direct effect in the vasculature of the brain, and lipoprotein characteristics in plasma may simply be a marker for this protection,” write the authors.

The population in this study is unique, deriving from a small number of founders. But the CETP genotype effects are broader than that would suggest. Barzilai and colleagues confirmed the link between the VV genotype and cognition in another group of Ashkenazi Jews enrolled in the Einstein Aging Study led by co-author Richard Lipton, while a recent independent study reported that the VV genotype is enriched in the oldest old living around Florence, Italy (see Lucchi et al., 2005).—Tom Fagan