New research from the US reveals that a variant of the plasma gene CETP that has already been associated with longevity may also be linked to slower age-related memory decline and a lower risk of dementia and Alzheimer disease. The researchers said drugs that mimic the gene’s effect and could protect against Alzheimer’s are now being developed.
The researchers, from the Department of Neurology, Department of Epidemiology and Population Health and the Institute for Aging Research at the Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, and Departments of Genetics and Genomic Sciences and Neurology at the Mount Sinai School of Medicine, New York, New York, revealed their findings in a paper published in the 13 January issue of JAMA, Journal of the American Medical Association.
The authors explained that CETP helps control the size of cholesterol particles, and the favourable variant increases blood levels of “good” cholesterol (HDL, high-density lipoprotein) while also resulting in larger-than-average sized particles of both HDL and low-density lipoprotein (LDL, or “bad” cholesterol).
They suggest the variant alters the way CETP works so that its associated protein functions less well than usual.
Some of the authors were involved in a study published in 2003, where they identified a variant of CETP, the cholesteryl ester transfer protein, was linked to longevity in a population of Ashkenazi Jews. The gene variant has also been linked to lower cardiovascular disease risk.
But until now, links with memory decline and dementia risk have not been clear, so for this study the researchers specifically evaluated the “longevity” variant of CETP where the amino acid isoleucine is replaced by another amino acid valine, and which is associated with lower CETP protein in the blood and higher activity and levels of HDL.
Senior author Dr Richard B. Lipton, the Lotti and Bernard Benson Faculty Scholar in Alzheimer’s Disease and professor and vice chair in the Saul R. Korey Department of Neurology at Einstein, told the media that:
“Most work on the genetics of Alzheimer’s disease has focused on factors that increase the danger.”
As an example he cited a gene variant of APOE that influences cholesterol metabolism and is known to increase the risk of Alzheimer’s among carriers. Lipton said they decided to take the opposite approach, and focus instead on “a genetic factor that protects against age-related illnesses, including both memory decline and Alzheimer’s disease”.
Lipton and colleagues also wanted to test the idea that the CETP longevity variant might be linked to less cognitive decline as people grow older.
For the study, which was funded by the National Institute on Aging, the researchers searched for links between CETP variants and memory performance and risk for new dementia or Alzheimer’s in a community-based sample of 523 healthy adults aged 70 and over.
None of the participants had dementia when the study began, and from blood samples, the researchers were able to determine which CETP variant they carried (the one with isoleucine or the one with valine, the latter being the “longevity” variant).
The participants were taking part in the Einstein Aging Study, an ongoing US federally funded project that has been following an ethnically and racially diverse group of elderly Bronx residents for 25 years, giving this study data covering from 1994 to 2009.
For an average follow up of just over 4 years, the participants underwent annual assessments to test their rates of cognitive decline, and incidence of Alzheimer’s disease and other changes. The tests used standardized neuropsychological and neurological measures, and included memory, attention and psychomotor speed tests (the latter assesses the time it takes to process and react to a signal).
The results showed that:
- 40 new cases of dementia occurred during an average follow-up of 4.3 years.
- People with 2 copies of the longevity variant of CETP (the “valine homozygotes”) had significantly slower memory decline (relative 51 per cent) and lower risk for developing dementia and Alzheimer disease compared to people who had the non-longevity variant of CETP (the “isoleucine homozygotes”).
- The valine homozygotes also had a 72 per cent lower risk of dementia (hazard ratio [HR] 0.28; 95% confidence interval [CI] ranging from 0.10 to 0.85; P = .02), and a 69 per cent lower risk of Alzheimer disease (HR 0.31; 95%CI 0.10-0.95,P = .04), compared to the isoleucine homozygotes.
The authors concluded that:
“Despite the small number of incident dementia cases and small decline in memory, this preliminary report suggests that CETP valine homozygosity [having two copies of the longevity variant] is associated with slower memory decline and lower risk for incident dementia or AD [Alzheimer Disease].”
They added that this “potentially protective” link is supported by several observations:
“First, some (but not all) prior work has shown that at cross-section valine homozygosity was associated with better mental status. Second, valine homozygosity is associated with a slower rate of memory decline in our entire sample, not just those who developed dementia. Third, the hazard ratios in this analysis suggested a possible gene-dose relationship for the CETP gene.”
They argued that a link between CETP status and cognition and dementia makes sense biologically because other genes like APOE that are involved in lipid metabolism are also linked to risk of dementia. They recommended further studies be done to evaluate the “potential protective association of the CETP gene with dementia risk”.
Lipton said drugs are now being developed that mimic the longevity CETP variant’s effect on its protein, and recommended:
“These agents should be tested for their ability to promote successful aging and prevent Alzheimer’s disease.”
“Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (CETP) Gene With Memory Decline and Incidence of Dementia.”
Amy E. Sanders; Cuiling Wang; Mindy Katz; Carol A. Derby; Nir Barzilai; Laurie Ozelius; Richard B. Lipton.
Source: JAMA and Archives Journals, Albert Einstein College of Medicine of Yeshiva University.
Written by: Catharine Paddock, PhD