CETP valine homozygosity was associated with slower age-related memory decline and a decreased risk of incident dementia, including Alzheimer’s disease.
A single-nucleotide polymorphism in the cholesteryl ester transfer protein (CETP) gene is independently associated with slower age-associated memory decline and lower risk of incident dementia and Alzheimer’s disease, according to a study in the January 13 issue of JAMA.
Amy E. Sanders, MD, Assistant Professor in the Saul R. Korey Department of Neurology at Albert Einstein College of Medicine, and colleagues conducted a prospective cohort study of 608 community-dwelling adults (age 70 or older) without dementia, and who had the CETP genotype available. Fifteen subjects showed prevalent dementia and were excluded, 63 were lost to follow-up, and seven were new to the study and had not yet had follow-up evaluations. The final analysis included 523 participants. Annual standardized neuropsychologic and neurologic measures were administered between 1994 and 2009.
Associations Between CETP Genotype and Cognition
Associations of the target CETP genotype (codon 405, isoleucine to valine, V405, SNP rs 5882) with longitudinal performance on cognitive tests of episodic memory, attention, and psychomotor speed were examined with linear mixed-effects models adjusted for sex, education, race/ethnicity, medical comorbidities, and apolipoprotein E (APOE) e4, and with longitudinal performance on cognitive tests of episodic memory, attention, and psychomotor speed.
The V405 genotype was the main predictor of incident dementia in similarly adjusted Cox proportional hazards models; age served as the time scale.
Isoleucine homozygotes were used as the reference group for both analyses, and memory decline and incident dementia were the main outcome measures.
Forty cases of incident dementia occurred in the study sample. APOE e4 frequency (23%) was similar to other racially and ethnically diverse cohorts. Individuals who developed dementia were older, less educated, and had poorer performance in global cognition, psychomotor speed, and episodic memory than those who did not develop dementia. Groups did not differ by sex, race, Ashkenazi heritage, CETP or APOE genotype, or medical comorbidity burden.
“Allele frequency for valine was 43.5% for the study cohort: 235 of 523 participants (45%) were heterozygotes, 110 (21%) were valine homozygotes, and 178 (34%) were isoleucine homozygotes,” Dr. Sanders and coauthors wrote. “Genotype frequencies differed marginally from Hardy-Weinberg equilibrium, possibly consistent with a longevity effect on allele distribution.”
The three genotype groups showed similar demographic characteristics and baseline neuropsychologic test results, except for premorbid intelligence and race/ethnicity.
“Of the 40 individuals with incident dementia, 35 met criteria for probable or possible Alzheimer’s disease,” Dr. Sanders and colleagues reported. “In the fully adjusted models, valine homozygosity was associated with lower risk of developing both dementia and Alzheimer’s disease.” Hazard ratios (HR) for heterozygotes were less than 1 for both, but they were not statistically significant.
“To address the possibility that racial admixture was confounding our observations, we reran the linear mixed-effects and the final Cox proportional hazards models (minus the indicator variable for African American race) in a white-only subgroup (361 individuals, 24 incident dementia cases),” Dr. Sanders and coauthors stated.
“Among whites, valine homozygotes declined more slowly than the reference group on the Free and Cued Selective Reminding Test (FCSRT), with a difference of 0.14 points per year of age slopes, although the difference was not statistically significant.”
In the Cox model of dementia incidence, the magnitude of the association lessened slightly compared with main results, and the model was not statistically significant (HR, 0.45 for homozygotes; HR, 0.56 for heterozygotes); this is possibly related to lower power.
A Lower Risk of Dementia and Alzheimer’s Disease
“Main findings were statistically significant in adjusted models that included APOE status,” Dr. Sanders and coauthors wrote. “As assessed by FCSRT, memory declined in valine homozygotes by 0.22 points per year more slowly (relative 51%) than in the reference group; homozygosity was associated with lower risk of both dementia and Alzheimer’s disease.
“Despite the small number of incident dementia cases and small decline in memory, this preliminary report suggests that CETP valine homozygosity is associated with slower memory decline and lower risk for incident dementia and Alzheimer’s disease,” Richard Lipton, MD, Professor of Neurology at Albert Einstein School of Medicine in New York and the study’s senior author, concluded.
—Laura Sassano