Genetic Factors Point to Cholesterol Metabolism in Alzheimer's Disease Risk

Abstract & Commentary

By Michael Lin, MD, Dr. Lin is Assistant Professor of Neurology at Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study.

Synopsis: Cholesterol ester transfer protein gene alleles may confer longevity as well as a reduced risk for Alzheimer's disease.

Source: Sanders AE, et. al. Association of a functional polymorphism in the cholesteryl ester transfer protein (CETP) gene with memory decline and incidence of dementia. JAMA 2010 ;303(2):150-158.

The apolipoprotein e (apoe) gene is associated with risk of late-onset Alzheimer's disease (AD). The E4 allele is associated with increased AD risk, and the E2 allele with decreased AD risk. In a recent study, Sanders and colleagues examined the V405 allele (valine at codon 405 instead of isoleucine) of another gene involved in cholesterol homeostasis, the cholesteryl ester transfer protein (CETP). This allele of CETP had previously been associated with increased longevity, and the authors now show in a prospective cohort study that it is associated with decreased risk for memory decline and dementia.

CETP mediates the exchange of cholesteryl esters from high density lipoprotein (HDL) to apoB-containing lipoproteins, promoting uptake of cholesterol by the liver. The common V405 allele is associated with reduced serum CETP levels and activity, increased HDL levels, and increased HDL and LDL particle sizes. These changes are associated with reduced risks for hypertension, cardiovascular disease, and the metabolic syndrome, and with exceptional longevity — V405 homozygosity is present in 25% of centenarians compared to 9% of those in their 70s.1 Moreover, in a previous cross-sectional study, V405 homozygosity appeared to protect cognitive function.2 Centenarians with good cognitive function had a higher frequency of V405 homozygosity than those with poor cognition (29% vs 14%). In an independent cohort of subjects age 75–85, those without dementia were five times more likely to be V405 homozygous than those with dementia (21% vs 4%).

The authors now report on a 15-year, prospective, community-based study drawn from the Einstein Aging Study in the Bronx. Subjects were adults age 70 years or older, identified from lists of Medicare recipients or registered voters, who were ambulatory and non-institutionalized. From 1994 to 2009, participants had annual cognitive examinations, including tests of episodic memory (Free and Cued Selective Reminding Test, FCSRT), attention (digit span), and psychomotor speed (digit-symbol substitution). The associations of V405 genotype with longitudinal cognitive performance and with incident dementia were then examined, with adjustments for sex, race, education, apoE4 status, and medical comorbidities.

Out of 523 subjects non-demented at baseline, with available CETP genotype and adequate follow-up, 178 were I405 homozygotes, 110 were V405 homozygotes, and 235 were heterozygotes. On the FCSRT memory test, V405 homozygotes lost only 0.21 [95% CI, 0.04–0.39]) points/year compared to 0.43 [95% CI, 0.29–0.58] points/year for I405 homozygotes. Although the absolute magnitude of the difference was small (0.22 [95% CI, 0.02–0.41] points/year on a 48 point scale), it was statistically significant (p = 0.03). Heterozygotes were indistinguishable from I405 homozygotes. There was no difference among CETP genotypes in tests of attention (digit span) or psychomotor processing speed (digit-symbol substitution).

There were 40 cases of incident dementia during follow-up. Compared to I405 homozygotes, the hazard ratios for V405 homozygotes were 0.28 [95% CI, 0.10–0.85] (p = 0.02) for dementia and 0.31 [95% CI, 0.10–0.95] (p = 0.03) for AD. The hazard ratios for heterozygotes were also less than 1, but did not reach statistical significance.

Commentary

This is the first longitudinal study suggesting that the longevity-associated V405 allele of CETP is associated with slower memory decline and decreased risk of dementia and AD. This observation is promising for several reasons. It accords with a previous cross-sectional study from the same group showing that this allele is associated with better cognitive status.2 Additionally, heterozygotes have an intermediate dementia risk, suggesting a gene dose effect, adding to biologic plausibility. The association of apoE with AD risk also lends plausibility to involvement of another gene related to cholesterol homeostasis.

On the other hand, apoE is still the only genetic risk factor for AD that has held up robustly in multiple studies. One previous case-control study of V405 CETP in AD showed an elevated odds ratio (1.67) for AD in non apoE4 carriers,3 and two recent genome-wide association studies identifying apoJ as an AD risk did not identify CETP. Thus, replication is still needed. In vitro studies establishing mechanism would also be helpful in proving a role for CETP in AD pathogenesis. If valid, then reduction in CETP levels or activity, mimicking the effect of the V405 allele, could be a potential pharmacologic target for AD prevention.

References

1. Barzilai N, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 2003;290:2030-2040.

2. Barzilai N, et al. A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology 2006;67:2170-2175.

3. Arias-Vásquez A, et al. The cholesteryl ester transfer protein (CETP) gene and the risk of Alzheimer's disease. Neurogenetics 2007;8:189-193.