Gene variant might guard against Alzheimer’s, other dementia

Carrying a variant form of the CETP gene is looking more and more like holding a winning genetic lottery ticket.

This version of the gene might protect against Alzheimer’s disease and other forms of dementia, researchers report in the Jan. 13 Journal of the American Medical Association. Earlier research linked the variant to impressive longevity and high levels of HDL, the “good” cholesterol.

But before running out to get your genes tested, be aware that the scientists reporting the most recent discovery don’t know for certain how the genetic variant might achieve any of these salutary effects, particularly dementia prevention.

They do know that people harboring the variant form of CETP make less of the CETP protein, and apparently less is better. “What CETP does in the brain is less clear,” says study coauthor Richard Lipton, a neurologist at the Albert Einstein College of Medicine of Yeshiva University in New York City.

In the new study, Lipton and his colleagues identified 523 people, average age 78. Blood samples showed that roughly one-fifth carried two copies of the variant form of CETP (one copy comes from each parent). About 45 percent harbored a single variant copy (from one parent) and one-third had two copies of the standard version of CETP (no variant).

Over the next four years, those endowed with two copies of the variant were only one-third as likely to develop dementia or Alzheimer’s disease as were those who carried the standard CETP gene. Those harboring one copy of the variant CETP didn’t seem to glean protection from it.

Even so, the findings may be a cause for optimism, says John Ringman, a neurologist at the University of California, Los Angeles. “I believe this is a real, but small, effect,” he says. “Whether or not it will generalize to the population is an open question.”

“Smaller samples in published studies tend to have larger effects,” cautions Wendy Johnson a psychologist at the University of Edinburgh, whose group had earlier failed to detect any link between the CETP variant and cognitive function in elderly people.

Only 40 of the 523 people in the new study developed Alzheimer’s disease or dementia during the study years. Replication of these findings is critical, Johnson says, “as with all such modest-sized studies of potential genetic markers of disease, longevity or [cognitive] decline.”

Earlier work by Lipton’s group linked the CETP variant to increased longevity, finding that very old people — roughly half the people tested were at least 100 years old — were more likely to harbor the variant than were people in the general population. Other work showed that CETP carriers tend to have higher HDL cholesterol levels, which might explain the longevity, Lipton says.

The CETP protein regulates the metabolism of fats, which Lipton says may lend a biological rationale to these findings. Another protein showing protection against Alzheimer’s disease is encoded by two helpful forms of the APOE gene, which also regulates fat metabolism.

Meanwhile, the strong HDL effect of the CETP variant suggests that it might protect against dementia by preventing small strokes in the brain, Lipton says. His group continues to study the CETP gene, which encodes the cholesteryl ester transfer protein, in hopes of discerning its biological mechanism.