Compared to a reference group homozygous for the ancestral allele in the full sample, valine homozygosity was independently associated with slower age-associated memory decline and lower risk for incident dementia and Alzheimer’s disease. Main findings were statistically significant in adjusted models, including APOE. In valine homozygotes, memory declined 51% slower than in the reference group; homozygosity was associated with lower risk for both dementia (72%) and Alzheimer’s disease (69%). Risk for dementia and Alzheimer’s disease was nonsignificantly lower in valine heterozygotes compared to individuals homozygous for isoleucine, although the magnitude of the association was less than that observed in homozygotes, suggesting a gene-dose relationship.
In the cognitive decline analysis, our primary hypothesis was that the valine allele would be associated with slower episodic memory decline. To our knowledge, only one study has evaluated the CETP
V405 polymorphism in the context of cognitive change. Johnson et al examined V405 associations with childhood IQ and life-long change in global cognition in a group of Scottish older adults.32
Specific cognitive domains, including memory, were examined cross-sectionally at age 79. They reported that CETP
was associated with cardiovascular disease rate, but detected no significant global longitudinal or domain-specific cross-sectional cognitive associations. In the present report, valine homozygosity was not associated with cross-sectional cognitive function, but protected against memory decline. Thus, the longitudinal design of our study may account for the different results we found. Population differences may also contribute, as valine was at considerably higher frequency (69%) than in our sample.
To our knowledge, this is the first study to examine associations between CETP
genotype and dementia risk in an incidence study. Of 10 case-control studies published since 2004, three investigated the V405 polymorphism. The single population-based case-control study reported that the V405 polymorphism was associated with an elevated odds ratio (OR) of 1.67 for AD in non-APOE
A 2005 Spanish study reported that ε4 carriers homozygous for the minor allele of the C-629 A CETP
polymorphism had a lower OR (2.33) for AD than ε4 non-carriers (OR 7.12) but found no association between V405 and AD.34
In 2009, Qureischie and colleagues reported lack of association between V405 and AD, although a CETP
haplotype including valine was associated with cholesterol profiles in plasma and CSF.35
Studies investigating other CETP
polymorphisms reveal similar heterogeneous results.
Methodological differences among studies may contribute to the disparate results presented here. We suggest that selection bias in case-control studies may be particularly problematic for polymorphisms associated with longevity. Case-control studies may be biased by factors associated with duration of disease in prevalent cases with longevity-favoring genotypes, as they preferentially include dementia cases with longer survival. Based on enhanced survival, such individuals might be over-represented among cases, spuriously attenuating any protective associations. For this reason, case-control studies likely underestimate associations between longevity genes and prevalent dementia. Because we focused on incident cases, our cohort study may have circumvented this potential bias. Our results suggest that prospective studies may offer methodological advantages in assessing associations between longevity genes and risk for incident dementia.
Two recent genome-wide association studies comparing AD cases to non-AD controls failed to identify the CETP
V405 polymorphism.36, 37
This is less surprising than it might appear: in general, GWAS look for polymorphisms with elevated odds ratios, indicating a strong associated with increased risk of disease. Any effect associated with V405 would be protective, with an odds ratio significantly below one and therefore likely to be dismissed as insignificant by current GWAS practices and making it difficult to compare our results with those from traditional dementia GWAS studies.
We detected no bivariate association between Ashkenazi heritage and genotype but race was associated with genotype: though comparable to previously published reports, prevalence of valine was higher in African Americans than Caucasians. African-American and non-African-American participants were similar in median age and crude dementia incidence rates, but African Americans had disadvantaged profiles for several known indices of dementia risk, including education, baseline global cognition, and APOE ε4 frequency. These results might be interpreted as relative protection insofar as there appeared to be higher risk without higher incidence. Conversely, they could be paradoxical, given increased valine allele frequency in African Americans without lower incidence, possibly indicating a genotype-race interaction we were not powered to detect. Alternatively, African Americans may possess a third factor that increases dementia susceptibility despite higher population frequencies of the putatively protective allele. We attempted to account for the potential effects of race by including it as a confounder in our models. After excluding African Americans in the Cox models for dementia, the magnitude of the resulting association changed only slightly, although the upper boundary of the confidence interval included one. The low number of incident dementia cases prevented exploration of interactions in race-stratified analyses. These observations merit further investigation.
Our study cannot directly address the nature of causal relationships underlying the associations reported here, limiting us to informed speculation. Nonetheless, several of the criteria for causation are satisfied. While it remains unknown whether CETP
polymorphisms cause specific differential rates of memory decline or dementia incidence, the basic temporal sequence of the genetic factor preceding downstream effects is indisputable. The gene-dose character of the association between V405 genotype and memory decline and dementia in our sample also would seem to favor causality. CETP is synthesized38
in brain but sparse knowledge limits speculation about CETP’s role in neurodegenerative pathophysiological mechanisms that might influence dementia risk. Growing evidence posits a mechanistic pathway linking cerebral cholesterol metabolism and AD pathology; hypothetical descriptions include genetic susceptibility conferred by cholesterol-metabolism genes such as CETP
and APOE.5, 41
Future studies investigating intermediate steps in the putative causal pathway – mediation by endophenotypic biomarkers, such as CETP plasma levels and activity, for example – might provide useful first steps toward eventual resolution of the causality question.
There are several caveats to our results. Though APOE frequency in our sample was comparable to other aging cohorts, our participants were nonetheless community-residing relatively healthy older adults living in the Bronx and we acknowledge the need to evaluate CETP in other longitudinal studies with greater numbers of incident dementia cases. We used well-established procedures and standardized criteria to diagnose dementia/AD but some misclassification may have occurred. Like any longitudinal study, ours may have had selective attrition, although the duration of follow-up helps allay this concern. At 40, the number of incident dementia cases was small.
Despite the small number of incident dementia cases, this preliminary report suggests that CETP valine homozygosity is associated with slower memory decline and lower risk for incident dementia or Alzheimer’s disease. This potentially-protective association is supported by several observations. First, prior work has shown that at cross-section valine homozygosity was associated with better mental status.2
Second, valine homozygosity is associated with a slower rate of memory decline in our entire sample, not just those who developed dementia. Third, in this sample the influence of CETP
on risk for dementia and AD is gene-dose dependent. Finally, an association between CETP
and cognition and dementia is biologically plausible because other genes involved in lipid metabolism, including APOE,
are associated with dementia risk.