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. Author manuscript; available in PMC: 2017 Sep 6.
Published in final edited form as: Neurobiol Aging. 2016 Feb 16;41:200.e7–200.e12. doi: 10.1016/j.neurobiolaging.2016.02.006

CETP Genotype Modifies the Effect of Apolipoprotein ε4 on Memory Decline in Older Adults

EE Sundermann a, C Wang a,b, M Katz a, ME Zimmerman a,c, CA Derby a,b, CB Hall a,b, LJ Ozelius d, RB Lipton a,b
PMCID: PMC5586214  NIHMSID: NIHMS760656  PMID: 27033407

Abstract

Apolipoprotein ε4 (ApoE4) is a strong genetic risk factor for sporadic Alzheimer’s disease (AD) and memory decline in older adults. A single-nucleotide polymorphism in the cholesteryl ester transfer protein (CETP) gene (isoleucine to valine; V405) is associated with slower memory decline and a lower risk of AD. As both genes regulate cholesterol, we hypothesized that the favorable CETPV405 allele may buffer the effect of ApoE4 on memory decline in older adults. Using linear regression, we examined the interactive effect of ApoE4 by CETPV405 on memory decline among 909 community-dwelling, nondemented, older adults (≥70 years) from the Einstein Aging Study. Episodic memory was measured using the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+ir). There was a significant ApoE × CETP interaction on decline in pFCSRT+ir scores (p=0.01). ApoE4 carriers experienced faster decline than non-carriers among CETPI405I homozygotes (p=0.007) and in CETPI405V heterozygotes (p=0.015), but not in CETPV405V homozygotes (p=0.614). Results suggest that the CETPV405 allele buffers ApoE4-associated memory decline in a gene dose-dependent manner.

Keywords: ApoE ε4, CETP, I405V, gene-gene interaction, memory decline

1. Introduction

The apolipoprotein ε4 allele (ApoE4) is the most common genetic risk factor for sporadic Alzheimer’s disease (AD) (Strittmatter et al., 1993), and has also been associated with accelerated memory decline in older adults (Bretsky et al., 2003; Hall et al., 2014). ApoE4 carriers have aberrant cholesterol homeostasis and greater β-amyloid plaque deposition (Kik et al, 2009), a pathological hallmark of AD (Pugielli et al., 2003). Many ApoE4 carriers do not develop AD, suggesting that gene-gene or gene-environment interactions may modify the risk of memory decline and dementia.

One candidate gene-gene interaction is the ApoE and the cholesteryl ester transfer protein (CETP) genes given that they are both expressed in the brain, linked to cerebral cholesterol metabolism and associated with cognitive function. There is a functional genetic variant at codon 405 of CETP in which the ancestral isoleucine allele is replaced by valine (NCBI dbSNP rs5882; CETPV405). Compared to CETP isoleucine allele homozygotes (CETPI405I), The CETPV405 allele is associated with reduced CETP protein levels and higher high density lipoprotein cholesterol (HDL-C) levels (Thompson et al., 2008). Whereas ApoE4 promotes the production of Aβ, the higher HDL-C levels associated with the CETPV405 allele hinder the aggregation of Aβ into amyloid plaques (Olesen & Dago, 2000).

The CETPV405 variant was initially identified as a “longevity genotype” based on the observation that allele frequency increased with age (Barzilai et al., 2003). Subsequently, longitudinal studies in older adults found an association between the CETPV405 allele and lower rate of memory decline and a reduced risk of incident dementia (Sanders et al., 2010; Yu et al., 2012; Chen et al., 2014; Lythgoe et al., 2014), although not consistently (Johnson et al., 2007; Qureischie et al., 2008). Although not consistently (Jun et al., 2015), previous studies have reported evidence of the interactive effects of the ApoE and CETP genes on risk of AD (Arias-Vasquez et al., 2007; Murphy et al., 2012; Rodriguez et al., 2006). Furthermore, a structural neuroimaging study reported a CETPV405 by ApoE4 interaction on volume loss in the medial temporal lobe volume (MTL) over a 12-month period (Murphy et al., 2012). In a recent study of 4486 adults aged 65 and older, Lythgoe et al. (2015) found an ApoE4-moderated effect of CETPV405 on cognitive decline across twelve years of follow-up. Specifically, they found a stronger protective effect of the CETP Valine allele on cognitive decline as measured by a global measure of cognitive function (Modified Mini-Mental State Exam scores) among ApoE4 carriers versus non-carriers. We sought to further these findings by being the first to examine the interactive effect of CETPV405 and ApoE4 on decline in the cognitive domain that is most relevant to AD and regulated by the MTL, episodic memory, among older adults. Previous studies examined the moderating role of ApoE on the cognitive effects of CETP genetic variants; however, because the effect of ApoE4 on cognitive decline is robust and well-established, unlike CETPV405, we focused on the moderating role of CETPV405 on the cognitive effects of ApoE4. We hypothesized that the effect of ApoE4 on memory decline would be greatest in CETP isoleucine homozygotes (CETPI405I), whereas, among CETPV405 carriers, the effect of ApoE4 on memory decline would be attenuated in a dose-dependent manner.

2. Methods

2.1. Participants

Participants were recruited from the Einstein Aging Study (EAS), a prospective study that aims to identify risk factors for cognitive decline and incident dementia in a community-dwelling sample of ethnically/racially-diverse, older adults. Systematic sampling procedures are used to recruit participants who are at least 70 years of age, ambulatory and proficient in English. Sampling frames have been generated from Medicare enrollee lists (1993–2004) and Bronx County Voter Registration lists (since 2004). A total of 2238 participants were enrolled in the EAS between October 1993 and November 2014. Among the 2238 participants enrolled, 950 consented to genotyping and had valid genotyping data. Participants who were clinically diagnoses with dementia at the time of study enrollment were excluded from analyses (n=38). Diagnosis of dementia was assigned by consensus at clinical case-conferences using standardized clinical criteria provided by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (American Psychiatric Association, 1994). Three participants were also excluded because they had no memory performance data (Free and Cued Selective Reminding Test scores). Consequently, 909 participants were included in analyses. The use of human subjects and the study protocol were approved by the local institutional review board (IRB), and IRB-approved informed consent forms were obtained at clinic visits.

2.2 Procedure

2.2.1 Overall EAS Protocol

EAS procedures have been previously described (Katz et al., 2012). Annual clinic visits at the EAS Clinic involve assessments of sociodemographic characteristics (age, sex, race/ethnicity, etc.), medical history and current medical status. Trained neuropsychological assistants administered a standard neuropsychological and clinical test battery at each annual clinic visit.

2.2.2 Outcome Measure of Memory Decline

The Free and Cued Selective Reminding test (FCSRT) is an episodic memory test that controls attention and the strategy used during the encoding phase of a memory task. We used the picture version of the FCSRT with immediate recall (pFCSRT+ir), previously described in detail (Grober et al., 2000). Briefly, the test involves the learning of 16 unrelated pictures by identifying and naming each picture. After all 16 are correctly identified, the participant recalls as many of the pictures as possible in a “free recall” trial. There are three free recall trials, and this analysis uses the sum of correctly-recalled pictures across trials (pFCSRT+ir; score range 0–48). pFCSRT+ir scores have been found to be predictive of incipient dementia (Buschke, 1984; Grober et al., 2000).

2.2.3 Independent Measures

DNA was genotyped for the CETPV405 and ApoE4 single nucleotide polymorphisms (SNP). A phlebotomist drew 20cc whole blood samples from participants who had provided genotyping consent at the EAS clinic. DNA was extracted from whole blood or was isolated from buffy coat that had been stored at −70°C using the Puregene DNA Purification System (G entra System, Minnesota) at the Albert Einstein General Clinical Research Center. DNA was genotyped for the CETPV405 SNP (NCBI dbSNP rs5882) and for the two ApoE SNPs, rs429358 (position 112) and rs7412 (position 158). The primers used for amplification and sequencing were designed using the PSQ version 1.0.6 software (Biotage) and the reverse primer was biotinylated for all variants. Genotyping was performed using a Pyrosequencing PSQ HS 96A system 1.2 (http://www.pyrosequencing.com) according to manufacturer’s instructions.

We examined the three possible CETPV405 genotypes: CETP Isoleucine homozygotes (CETPI405I), CETPV405I heterozygotes (CETPI405V) and Valine homozygotes (CETPV405V). ApoE genotype was categorized into ApoE4 carriers and non-carriers because of the low prevalence of ApoE4 homozygotes (1.7%) in our study. The more common genotype of ApoE4 non-carriers served as the reference group.

2.2.4 Clinical Covariates

To assess functional ability, participants completed the Lawton Brody Activities of Daily Living questionnaire which includes the subscale of Instrumental Activities of Daily Living (IADL; Lawton & Brodie, 1969). Scores ranged from 0 (low function, dependent) to 8 (high function, independent). A medical comorbidity index was calculated using data from self-report questionnaires administered annually and defined as the combined presence of the following health conditions: hypertension, diabetes, angina, myocardial infarction, congestive heart failure, stroke, Parkinson’s disease, rheumatoid arthritis, chronic obstructive pulmonary disease, and depression (score range: 1–10).

2.3 Statistical Analysis

Demographic and baseline characteristics within each ApoE and CETP genotype group were assessed using summary statistics. Comparisons between ApoE and CETP genotype groups were performed using Kruskal-Wallis tests or ANOVA for continuous variables and chi-square tests for categorical variables. We used a Chi-square test to determine if ApoE and CETP genotype distributions met Hardy-Weinberg equilibrium.

Linear mixed effects models with random intercepts and random slopes were used to examine the separate and joint effects of ApoE and CETP genotypes on the rate of decline in pFCSRT+ir scores, and test the hypothesis that the CETP Valine allele demonstrates a gene-dose effect in its buffering of ApoE4-associated memory decline. Models stratified by genotype as well as models including interaction terms were used for these analyses. All analyses were adjusted for age, sex, education, ethnicity/race (non-Hispanic White, non-Hispanic Black and Asian/other), IADL and the medical comorbidity index. All covariates were pre-determined based on biological plausibility and/or potential for confounding of the relationship between ApoE/CETP genotype and pFCSRT+ir performance. In order to examine a more homogeneous population, sensitivity analyses including only non-Hispanic white study participants was performed; it was not possible to repeat such analyses in other ethnic/racial groups because of limited sample size. Lastly, because the ApoE2 allele of the ApoE ε polymorphism may have a protective effect on cognitive decline and AD risk that counters the deleterious ApoE4 effect (Suri et al., 2013), we also examined the interactive effect of CETP and ApoE2 carrier status on rate of pFCSRT+ir decline among ApoE4 non-carriers in a secondary analysis. All statistics were performed using SAS version 9.3 (SAS Institute Inc., Cary, N.C).

3. Results

Table 1 summarizes participant demographic, clinical, and cognitive characteristics at baseline based on CETP and ApoE genotype. The sample included 909 older adults (60.1% female) with an average age of 78.5 years and a mean of 13.2 years of education. The sample was predominantly White (66.9%). Subjects were followed for an average of 4.7 years with a median of 4 annual administrations of the pFCSRT+ir per person (range 1 to 16). Seventy-eight percent of participants had at least one follow-up pFCSRT+ir. The distribution of number of repeated pFCSRT+ir administrations did not differ by CETP genotype (p=0.36) or ApoE genotype (p=0.55). ApoE4 carriers were significantly younger (p=0.004) and consisted of a significantly higher proportion of Whites (p<0.0001) compared to ApoE4 non-carriers. Among CETP genotype groups, there were significant differences in race (p<0.0001), IADL scores (p=0.04) and pFCSRT+ir scores (p=0.01). The genotype distributions met Hardy-Weinberg equilibrium for both the CETP (p=0.10) and ApoE (p=0.21) SNPs.

Table 1.

Participant characteristics at baseline by ApoE/CETP genotype group.

Genotype Group
CETPI405I
homozygotes
(N=312)		 CETPV405I
heterozygotes
(N=420)		 CETPV405V
homozygotes
(N=177)
Characteristics ApoE4+ ApoE4− ApoE4+ ApoE4− ApoE4+ ApoE4−
N 70 242 91 329 43 134
Age at baseline, yr, mean (SD) 77.0 (4.5) 78.6 (5.3) 78.0 (5.5) 78.8 (5.2) 77.3 (4.3) 78.9 (5.8)
Education, yr, mean (SD) 13.5 (3.4) 13.3 (3.7) 13.9 (3.4) 13.1 (3.6) 12.1 (3.4) 12.9 (3.6)
Female (%) 62.9 58.3 59.3 57.8 60.5 67.9
Race
  White (%) 68.6 83.5 54.9 69.0 37.2 48.5
  Black (%) 25.7 12.4 39.6 24.0 62.8 42.5
  Asian/other race (%) 5.7 4.1 5.5 7.0 0.0 9.0
Follow-up time, yr, mean (SD) 4.0 (3.3) 4.2 (3.7) 4.0 (4.0) 4.4 (3.9) 4.7 (4.1) 4.7 (4.1)
Medical Comorbidity Index, mean (SD) 1.7 (1.3) 1.7 (1.1) 1.8 (1.4) 1.8 (1.1) 1.9 (1.1) 1.9 (1.2)
IADL, mean (SD) 6.6 (1.5) 6.4 (1.6) 6.6 (1.5) 6.4 (1.7) 6.6 (1.5) 6.8 (1.6)
pFCSRT+ir score, mean (SD) 31.3 (6.6) 31.1 (5.9) 29.5 (5.8) 30.1 (5.9) 30.2 (6.6) 30.5 (5.3)
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*

Non-Hispanic.

CETP = cholesterol ester transfer protein.

CETPI405I = cholesterol ester transfer protein isoleucine homozygotes.

CETPV405I = cholesterol ester transfer protein valine heterozygotes.

CETPV405V = cholesterol ester transfer protein valine homozygotes.

ApoE4 = apolipoprotein ε4 allele.

IADL = Instrumental Activities of Daily Living.

pFCSRT+ir = picture version of the Free and Cued Selective Reminding Test with immediate recall.

As expected, there was a significant interaction between CETP and ApoE genotypes on the rate of decline in pFCSRT+ir performance (p=0.01). Table 2 displays the rates of decline in pFCSRT+ir scores by ApoE genotype groups in analyses adjusted for age, education, sex, race, IADL and medical comorbidities and stratified by CETP genotype. Among CETPI405I homozygotes, ApoE4 carriers showed a faster decline in pFCSRT+ir scores than non-carriers by 0.70 points per year (−1.02 vs. −0.32, p=0.007). The difference in the rates of decline between ApoE4 carriers and non-carriers was reduced but remained significant among CETPI405V heterozygotes (difference=−0.49 points/year, p=0.01). Among CETPV405V homozygotes, there was no difference in the rates of decline between ApoE4 carriers and non-carriers (difference=0.11 points/year, p=0.61). When analyses were stratified on ApoE4 status, the rate of decline in CETP Valine homozygotes was significantly slower than that in CETPI405I homozygotes among ApoE4 carriers (difference=0.72 points/year, p=0.02), but not among ApoE4 non-carriers (difference=−0.09 points/year, p=0.768). The expected longitudinal trajectories of pFCSRT+ir scores over time by ApoE and CETP genotype are depicted in Figure 1; ApoE4 carriers who are CETPV405V homozygotes resemble ApoE4 non-carriers more than ApoE4 carriers who are CETPI405I homozygotes. Among ApoE4 carriers, as the number of Valine alleles increased, protection from ApoE4-associated memory decline also increased (estimate=0.37 points/year, p=0.01). Results were similar when analyses were restricted to the non-Hispanic White subgroup (Web Table A), albeit they were not significant, possibly due to reduced sample size. When examining ApoE2 carriers versus non-carriers (excluding ApoE4 carriers), the ApoE2 allele did not show a significant protective effect on decline in pFCSRT+ir performance (p=0.44). Additionally, there was no interactive effect of CETP and ApoE2 carrier status on rate of decline in pFCSRT+ir performance (p=0.88) indicating that the interactive effect of CETP and ApoE genotype on pFCSRT+ir decline is contingent upon ApoE4, but not ApoE2, carrier status.

Table 2.

Rate of decline (points per year) in pFCSRT+ir scores stratified by ApoE and CETP genotype (adjusting for age, sex, education, race, IADL and the medical comorbidity index)

ApoE4−
B (SE)		 ApoE4+
B (SE)		 p-value*
CETPI405I homozygotes −0.32 (0.08) −1.02 (0.25) 0.007
CETPI405V heterozygotes −0.27 (0.07) −0.75 (0.19) 0.015
CETPV405V homozygotes −0.41 (0.10) −0.30 (0.20) 0.614
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*

For test of difference in rates between ApoE4+ and ApoE4−.

ApoE4 = apolipoprotein ε4 allele.

CETPI405I = cholesterol ester transfer protein isoleucine homozygotes.

CETPV405I = cholesterol ester transfer protein valine heterozygotes.

CETPV405V = cholesterol ester transfer protein valine homozygotes.

pFCSRT+ir = picture version of the Free and Cued Selective Reminding Test with immediate recall.

Figure 1.

Figure 1

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Rate of decline in pFCSRT+ir performance across a ten-year, follow-up period for all ApoE/CETP genotype groups. pFCSRT+ir = Picture Version of the Free and Cued Selective Reminding Test with Immediate Recall. ApoE = apolipoprotein ε4 gene. CETP = cholesteryl ester transfer protein.

4. Discussion

In support of our hypothesis, we found that the CETP Valine allele carriers had a lower rate of ApoE4-associated memory decline in a dose-dependent manner. The adverse effect of the ApoE4 allele on episodic memory decline is striking among persons with the ancestral CETPI405I genotype. In the CETPI405I group, ApoE4 participants demonstrated a decline in pFCSRT+ir scores that was greater than non-carriers by 0.62 points per year. Among CETPI405V heterozygotes, the adverse effect of the ApoE4 allele on memory decline remained significant but was ameliorated such that decline in pFCSRT+ir scores was greater in carriers vs. non-carriers by 0.50 points per year. In contrast, among CETPV405V homozygotes, the adverse effect of the ApoE4 allele was eliminated as there was no significant effect of ApoE4 on rate of memory decline.

Although not consistently (Jun et al., 2015), previous studies have reported interactive effects of CETP genetic variants and ApoE genotype on risk of AD (Arias-Vasquez et al., 2007; Murphy et al., 2012; Rodriguez et al., 2006) and on global cognitive decline (Lythgoe et al., 2015). Analogous to the present findings, others have reported advantageous effects of the CETP Valine allele among ApoE4 carriers; including greater baseline cortical thickness, less 12-month MTL atrophy (Murphy et al., 2012) and preserved cognition over time (Lythgoe et al., 2015) among ApoE4 carriers. Conversely, findings are inconsistent when examining the effect of the CETP Valine allele among ApoE4 non-carriers. Whereas we did not detect an effect of the Valine allele on memory decline among non-carriers, others have reported the reverse association of the Valine allele with disadvantageous outcomes among non-carriers. Specifically, among ApoE4 non-carriers, the Valine allele was associated with greater MTL atrophy (Murphy et al., 2012) and a higher risk of dementia (Arias-Vasquez et al., 2007). Multiple factors could contribute to the discrepancies in the current and past findings including differences in study design (case-control vs. cohort), cognitive outcome (cognitive decline vs. AD incidence), sample size and sample characteristics (age, sex, race). Similar to the current study, the only other study to examine the interactive effects of ApoE and CETP on rates of cognitive decline did not show a reversal of the Valine effect in carriers and non-carriers. Rather, they showed that a CETPV405 by ApoE4 interaction was due to a stronger protective effect of the Valine allele on cognitive decline among ApoE4 carriers versus non-carriers (Lythgoe et al., 2015). Thus, the finding of a protective effect of the CETP Valine allele on brain-related outcomes among ApoE4 carriers seems to be consistent across studies; however, the effect of the Valine allele among non-carriers remains to be clarified.

In a case-control study of 286 AD patients and 315 healthy controls (mean age=75.4), Rodriguez et al. (2006) examined the interactive effects of ApoE and two CETP polymorphisms (V405 and TaqI B) on AD risk. They found that the TaqI B, but not the V405, polymorphism moderated the effect of ApoE on AD risk. Although the Rodriguez et al. (2006) findings were with the CETP TaqI B and not V405 SNP, we believe these results lend credence to the hypothesis that the ApoE and CETP genes interact to impact cognitive function likely through effects on cholesterol metabolism. Given that the V405 and TaqI B polymorphisms are in strong linkage disequilibrium and other studies have reported similar effects of the two polymorphisms on HDL levels (Thompson et al., 2008), it is likely that the V405 or TaqIB SNPs are linked mechanistically or one SNP is a marker for the other. Our study supports the ApoE by CETP interaction and further suggests that the interactive effects may not be specific to AD risk but also pertain to age-related memory decline.

There was a significant difference in the race distribution among ApoE and CETP genotype groups. Similar to previous reports, the proportion of CETPV405V homozygotes was higher among African Americans compared to Caucasians. This race difference may reflect a differential survival advantage in carriers of the beneficial CETP Valine allele that are African American, a group at higher risk for death from stroke (National Center for Health Statistics, 1997) and indicators of cardiovascular disease (Rooks et al., 2002). Additionally, race differences may be due, in part, to isolation by distance over evolutionary time scales. We attempted to account for the potential effects of race by including it as a confounder in our overall group analysis and by repeating analyses in a non-Hispanic, White-only subsample. Race was not a significant factor in the overall group analysis and similar results were found in the White-only subsample suggesting that results were not an artifact of a population stratification bias in an ethically/racially diverse population.

Previous research suggests that the effect of ApoE4 on risk of dementia tends to diminish with advanced age (Sulkava et al., 1996). It was speculated that the weakened effect of ApoE4 in the oldest old is due to survivor bias in that individuals who carry ApoE4 are likely to develop dementia in their 70s and 80s. Incident dementia cases in individuals 90 or older are less likely to be ApoE4-associated (Sulkava et al., 1996). ApoE4 is also associated with negative cardiac outcomes including atherosclerosis which adversely impact longevity and likely contribute to the increased risk of dementia (Sulkava et al., 1996). The frequency of CETPV405 alleles increases with age, likely due to the survival advantage it confers (Barziliai et al., 2003). We suggest that reduced influence of ApoE4 on the genetic risk of AD may be due, at least in part, to the increased frequency of the advantageous CETPV405 allele with age.

Despite a need for caution, the relationship between cerebral cholesterol metabolism and AD risk provides a plausible biological basis for the interactive effect of CETP and ApoE on memory. ApoE and CETP are expressed in the brain (Bu et al., 2009; Yamada et al., 1995) and impact cholesterol and lipid homeostasis. ApoE4 is associated with hyperlipidemia and hypercholesterolemia (Mahley & Rall, 2000) and promotes the production of amyloid beta (Aβ), a protein which in excessive amounts, may lead to amyloid plaques (Olesen & Dago, 2000). Evidence suggests that the CETPV405 allele leads to reduced local synthesis of CETP in the brain, with the associated increased level of brain high-density lipoprotein cholesterol (HDL-C) levels (Thompson et al., 2008). HDL-C reduces excess cellular cholesterol, and HDL particles interact with Aβ to hinder its aggregation into amyloid plaques (Olesen & Dago, 2000). The dose-dependent nature of the interactive effect of CETP and ApoE on memory decline further supports biological plausibility for a causal relationship. Therefore, it is plausible that the dose-dependent increase in HDL-C levels associated with the addition of a CETPV405 allele reflects an increasing buffering of the effect of ApoE4 allele on amyloid plaque formation, thereby decreasing AD-associated neuropathology. As an alternative, CETPV405 is associated with a reduced risk of vascular disease including stroke (Dullaart & Sluiter, 2008; Thompson et al., 2008). Therefore, the influence on cognitive decline could be mediated through reduced vascular disease as well.

A major strength of our study is the longitudinal design. In case-control studies of older adults, carriers of longevity genes such as CETPV405 may be over-represented by virtue of their longevity and perhaps extended disease duration. Therefore, in case-control studies of longevity genes in older adults, associations between longevity genes and prevalent dementia may be attenuated. However, similar to other longitudinal studies, we may have experienced selective attrition although the duration of follow-up minimizes this risk. Other study limitations include our specific assessment of episodic memory using the pFCSRT+ir, a list-learning task, which limits us in generalizing results to other types of memory including semantic, working or other episodic memory tasks such as paragraph recall. Secondly, the ApoE gene has three different allelic forms (ε2, ε3 and ε4) and, thus, six possible genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4 and ε4/ε4). Although, it would be informative to examine the interactive effects of CETP with the six possible ApoE genotypes, we lacked the statistical power to do so because of the small size of certain genotype groups after further stratification by CETP genotype. Thirdly, there were too few African-American CETPI405I homozygotes (N=48) to conduct analyses in an African-American-only subsample. Therefore, we are able to generalize our results to White, but not older African-American adults or other ethnicity/race groups. There is a need for further research to replicate our findings as well as investigate how ethnicity/race impacts the interactive effects of CETP and ApoE in larger samples.

In conclusion, the present report extends previous studies by suggesting that the interactive effects of CETPV405 and ApoE4 function in a dose-dependent manner in older adults and apply to the cognitive domain most closely associated with incipient dementia, episodic memory. We found that the CETPV405 variant allele buffers the negative effects of ApoE4 on memory decline in older adults in a dose-dependent manner. Our results highlight the importance of considering the CETP genotype in conjunction with ApoE when assessing risk of memory decline. Besides the functional difficulties and compromised quality of life that accompany cognitive decline, rapid decline in episodic memory can serve as a signal for incipient dementia, particularly AD (Salmon & Bondi, 2009). The protective interaction of the CETPV405 and ApoE4 alleles has implications for the discovery of genes linked to cognitive decline and incident AD. Identifying genetic variants associated with cognitive decline can inform intervention strategies that aim to diminish risk and help to direct intervention to individuals at high risk of dementia. These findings require replication in other samples and extension to other clinical endpoints including incidence of mild cognitive impairment, the transitional stage between healthy cognition and dementia.

Supplementary Material

supplement

  • A genetic variant of the CETP gene (CETPV405) is linked to cholesterol metabolism

  • We found a significant ApoE × CETP interaction on memory decline in in older adults

  • As CETPV405 alleles increased, ApoE4-associated memory decline decreased

  • Among CETPV405V homozygotes, ApoE4 allele status did not impact rates of decline

  • The CETPV405 allele buffers ApoE4-related memory decline in a dose-dependent manner

Acknowledgments

We thank the EAS research participants. We thank Charlotte Magnotta, Diane Sparracio and April Russo for assistance in participant recruitment; Betty Forro, Wendy Ramratan, and Mary Joan Sebastian for assistance in clinical and neuropsychological assessments; and Michael Potenza for assistance in data management. Funding/Support: This research was supported by the Einstein Aging Study (PO1 AG03949) from the National Institutes on Aging program; the National Institutes of Health CTSA (1UL1TR001073) from the National Center for Advancing Translational Sciences, the Sylvia and Lenard Marx Foundation, and the Czap Foundation. The contents of this manuscript are solely the responsibility of the authors and do not necessary represent the official view of the NCRR or NIH. Role of the Sponsor: The National Institutes on Aging had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

CW receives research support from NIH P01 AG039409 (investigator), R01 AG039330 (investigator), R01 AG036921 (investigator), R01 HL094581 (investigator), and Bristol-Myers Squibb. MJK receives research support from NIH-NIA P01 AG027734 (investigator), R01 AG022374 (investigator), NIH-NIA R01 AG034119 (investigator), NIH-NIA P01 AG039409 (investigator), NIH-NIA AG038651 (investigator), R01AG042595 (investigator) and R03AG045474 (Principal investigator). MEZ receives research support from the NIH P01 AG03949 (coinvestigator). CAD receives research support from NIH P01 AG039409 (project leader), P01AG027734 (coinvestigator), 5R01 AG22374 (site principal investigator), 2U01AG012535-16 (principal investigator), NCRR 5UL1RR025750-03 (investigator), Bristol-Myers Squibb, and the S and L Marx Foundation. CH has received research support from the National Institute of Aging (P01 AG03949, P01 AG027734, R01 AG022092, R01 AG034087, R01 AG034119, R21 AG036935), the National Center for Research Resources (1-UL1-RR025750-01), the National Cancer Institute (P30 CA13330-35), the National Institute of Occupational Safety and Health (5-U011O-OH008242, U01 OH010411, U01 OH010412, and contracts 200-2011-39378 and 200-2011-39489), and Endo Pharmaceuticals, has consulted to research projects at the University of Connecticut Health Center, is and has been a member of Data and Safety Monitoring Committees at Columbia University, received honoraria from Washington University St. Louis and from Oregon Health and Science University, has received travel funding from Washington University St. Louis, Yale University, Oregon Health and Science University, and the University of Victoria, and is a member of the American Statistical Association Media Experts Panel. LJO received research funding from NIH (DC011805, NS037409, NS081282) and Foundation for Dystonia Research, she also receives patent royalties from Athena Diagnostics. Dr. Richard B. Lipton receives research support from the NIH: PO1 AG003949 (Program Director), PO1AG027734 (Project Leader), RO1AG025119 (Investigator), RO1AG022374-06A2 (Investigator), RO1AG034119 (Investigator), RO1AG12101 (Investigator), K23AG030857 (Mentor), K23NS05140901A1 (Mentor), and K23NS47256 (Mentor), the National Headache Foundation, and the Migraine Research Fund; serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache, has reviewed for the NIA and NINDS, holds stock options in eNeura Therapeutics (a company without commercial products); serves as consultant, advisory board member, or has received honoraria from: Alder, Allergan, American Headache Society, Autonomic Technologies, Avanir, Boston Scientific, Bristol Myers Squibb, Colucid, Dr. Reddy’s, Electrocore, Eli Lilly, Endo, eNeura Therapeutics, Informa, Labrys, Merck, Novartis, Teva, Vedanta.

Abbreviations

ApoE4

apolipoprotein ε4 allele

CETP

cholesteryl ester transfer protein

CETPI405I

CETPV405 polymorphism Isoleucine homozygote

CETPV405V

CETPV405 polymorphism Valine homozygote

CETPI405V

CETPV405 polymorphism Valine heterozygote

HDL-C

high density lipoprotein cholesterol

MTL

medial temporal lobe

EAS

Einstein Aging Study

FCSRT

Free and Cued Selective Reminding Test

pFCSRT+ir

Picture Version of the Free and Cued Selective Reminding Test with Immediate Recall

IADL

Instrumental Activities of Daily Living

Footnotes

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Disclosure statement

EES reports no disclosures

Data presented in this manuscript has not published or submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging. The use of human subjects and the study protocol were approved by the local institutional review board (IRB), and IRB-approved informed consent forms were obtained at clinic visits. All authors have reviewed the contents of the manuscript, approve of its contents and validate the accuracy of the data.

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