Sex, Body Mass Index, and APOE4 Increase Plasma Phospholipid-Eicosapentaenoic Acid Response During an ω-3 Fatty Acid Supplementation: A Secondary Analysis.

BACKGROUND: The brain is concentrated with omega (ω)-3 (n-3) fatty acids (FAs), and these FAs must come from the plasma pool. The 2 main ω-3 FAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), must be in the form of nonesterified fatty acid (NEFA) or esterified within phospholipids (PLs) to reach the brain. We hypothesized that the plasma concentrations of these ω-3 FAs can be modulated by sex, body mass index (BMI, kg/m2), age, and the presence of the apolipoprotein (APO) E-ε4 allele in response to the supplementation. OBJECTIVES: This secondary analysis aimed to determine the concentration of EPA and DHA within plasma PL and in the NEFA form after an ω-3 FA or a placebo supplementation and to investigate whether the factors change the response to the supplement. METHODS: A randomized, double-blind, placebo-controlled trial was conducted. Participants were randomly assigned to either an ω-3 FA supplement (DHA 0.8 g and EPA 1.7 g daily) or to a placebo for 6 mo. FAs from fasting plasma samples were extracted and subsequently separated into PLs with esterified FAs and NEFAs using solid-phase extraction. DHA and EPA concentrations in plasma PLs and as NEFAs were quantified using gas chromatography. RESULTS: EPA and DHA concentrations in the NEFA pool significantly increased by 31%-71% and 42%-82%, respectively, after 1 and 6 mo of ω-3 FA supplementation. No factors influenced plasma DHA and EPA responses in the NEFA pool. In the plasma PL pool, DHA increased by 83%-109% and EPA by 387%-463% after 1 and 6 mo of ω-3 FA supplementation. APOE4 carriers, females, and individuals with a BMI of ≤25 had higher EPA concentrations than noncarriers, males, and those with a BMI of >25, respectively. CONCLUSIONS: The concentration of EPA in plasma PLs are modulated by APOE4, sex, and BMI. These factors should be considered when designing clinical trials involving ω-3 FA supplementation. This trial was registered at clinicaltrials.gov as NCT01625195.

An Exploratory Analysis of Changes in Mental Wellbeing Following Curcumin and Fish Oil Supplementation in Middle-Aged and Older Adults.

Curcumin has previously been shown to enhance mood in non-depressed older adults. However, observed benefits were limited to short-term supplementation (4 weeks). In a 16 week randomized, double-blind, placebo-controlled, 2 × 2 factorial design trial, we supplemented overweight or obese non-depressed adults (50-80 years) with curcumin (160 mg/day), fish oil (2000 mg docosahexaenoic acid +400 mg eicosapentaenoic acid/day), or a combination of both. Secondary outcomes included mental wellbeing measures (mood states and subjective memory complaints (SMCs)) and quality of life (QoL). Furthermore, plasma apolipoprotein E4 (APOE4) was measured to determine whether APOE4 status influences responses to fish oil. Curcumin improved vigour (p = 0.044) compared to placebo and reduced SMCs compared to no curcumin treatment (p = 0.038). Fish oil did not affect any mood states, SMCs or QoL; however, responses to fish oil were affected by APOE4 status. In APOE4 non-carriers, fish oil increased vigour (p = 0.030) and reduced total mood disturbances (p = 0.048) compared to placebo. Improvements in mental wellbeing were correlated with increased QoL. Combining curcumin with fish oil did not result in additive effects. This exploratory analysis indicates that regular supplementation with either curcumin or fish oil (limited to APOE4 non-carriers) has the potential to improve some aspects of mental wellbeing in association with better QoL.

Tea Consumption Reduces the Incidence of Neurocognitive Disorders: Findings from the Singapore Longitudinal Aging Study.

OBJECTIVES: To examine the relationships between tea consumption habits and incident neurocognitive disorders (NCD) and explore potential effect modification by gender and the apolipoprotein E (APOE) genotype. DESIGN: Population-based longitudinal study. SETTING: The Singapore Longitudinal Aging Study (SLAS). PARTICIPANTS: 957 community-living Chinese elderly who were cognitively intact at baseline. MEASUREMENTS: We collected tea consumption information at baseline from 2003 to 2005 and ascertained incident cases of neurocognitive disorders (NCD) from 2006 to 2010. Odds ratio (OR) of association were calculated in logistic regression models that adjusted for potential confounders. RESULTS: A total of 72 incident NCD cases were identified from the cohort. Tea intake was associated with lower risk of incident NCD, independent of other risk factors. Reduced NCD risk was observed for both green tea (OR=0.43) and black/oolong tea (OR=0.53) and appeared to be influenced by the changing of tea consumption habit at follow-up. Using consistent non-tea consumers as the reference, only consistent tea consumers had reduced risk of NCD (OR=0.39). Stratified analyses indicated that tea consumption was associated with reduced risk of NCD among females (OR=0.32) and APOE ε4 carriers (OR=0.14) but not males and non APOE ε4 carriers. CONCLUSION: Regular tea consumption was associated with lower risk of neurocognitive disorders among Chinese elderly. Gender and genetic factors could possibly modulate this association.

Self-Reported Sleep Apnea and Dementia Risk: Findings from the Prevention of Alzheimer's Disease with Vitamin E and Selenium Trial.

OBJECTIVES: To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADViSE) study and to explore whether the association depends on apolipoprotein E (APOE) ɛ4 allele status. DESIGN: Secondary analysis based on data collected during PREADViSE. SETTING: Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location. PARTICIPANTS: Men enrolled in PREADViSE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = 7,547). MEASUREMENTS: Participants were interviewed at baseline for sleep apnea. The Memory Impairment Screen (MIS) was administered to each participant annually. Subjects who failed this initial screen were tested with secondary screening tests. Medical history and medication use were determined, and the AD8 dementia screening instrument was used. RESULTS: The effect of self-reported sleep apnea on dementia risk depended on APOE ɛ4 status. When the allele was absent, baseline self-reported sleep apnea was associated with a 66% higher risk of developing dementia (95% confidence interval = 2-170%), whereas self-reported sleep apnea conferred no additional risk for participants with an ɛ4 allele. CONCLUSION: Sleep apnea may increase risk of dementia in the absence of APOE ɛ4. This may help inform prevention strategies for dementia or AD in older men with sleep apnea. Registration: PREADViSE is registered at ClinicalTrials.gov: NCT00040378.

Human apolipoprotein E allele and docosahexaenoic acid intake modulate peripheral cholesterol homeostasis in mice.

Carrying at least one apolipoprotein E ε4 allele (E4+) is the main genetic risk factor for Alzheimer's disease (AD). Epidemiological studies support that consuming fatty fish rich in docosahexaenoic acid (DHA; 22:6ω3) is protective against development of AD. However, this protective effect seems not to hold in E4+. The involvement of APOE genotype on the relationship between DHA intake and cognitive decline could be mediated through cholesterol. Many studies show a link between cholesterol metabolism and AD progression. In this study, we investigated whether cholesterol metabolism is improved in E3+ and E4+ mice consuming a diet rich in DHA. Plasma cholesterol was 36% lower in E4+ mice compared to E3+ mice fed the control diet (P=.02), and in the liver, there was a significant genotype effect where cholesterol levels were 18% lower in E4+ mice than E3+ mice. The low-density lipoprotein receptor was overexpressed in the liver of E4+ mice. Plasma cholesterol levels were 33% lower after the DHA diet (P=.02) in E3+ mice only, and there was a significant diet effect where cholesterol level was 67% lower in the liver of mice fed DHA. Mice fed the DHA diet also had 62% less lipolysis stimulated lipoprotein receptor expression in the liver compared to mice fed the control diet (P<.0001), but there was no genotype effect. These findings suggest that plasma and liver cholesterol homeostasis and the receptors regulating uptake of cholesterol in the liver are modulated differently and independently by APOE allele and DHA intake.

Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment.

BACKGROUND: Low-normal concentrations of vitamin B-12 (VitB12) may be associated with worse cognition. However, previous evidence has been mixed, and the underlying mechanisms remain unclear. OBJECTIVE: We determined whether serum VitB12 concentrations within the normal range were linked to memory functions and related neuronal structures in patients with mild cognitive impairment (MCI). DESIGN: In a cross-sectional design, we assessed 100 amnestic MCI patients (52 women; age range: 50-80 y) with low- and high-normal VitB12 concentration (median split: 304 pmol/L) for memory functions with the use of the Auditory Verbal Learning Test. MRI was performed at 3 tesla (n= 86) for the estimation of the volume and microstructure of the hippocampus and its subfields as indicated by the mean diffusivity on diffusion-weighted images. With the use of a mediation analysis, we examined whether the relation between VitB12 and memory performance was partially explained by volume or microstructure. RESULTS: MCI patients with low-normal VitB12 showed a significantly poorer learning ability (P= 0.014) and recognition performance (P= 0.008) than did patients with high-normal VitB12. Also, the microstructure integrity of the hippocampus was lower in patients with low-normal VitB12, mainly in the cornu ammonis 4 and dentate gyrus region (P= 0.029), which partially mediated the effect of VitB12 on memory performance (32-48%). Adjustments for age, sex, education, apolipoprotein E e4 status, and total homocysteine, folate, and creatinine did not attenuate the effects. CONCLUSIONS: Low VitB12 concentrations within the normal range are associated with poorer memory performance, which is an effect that is partially mediated by the reduced microstructural integrity of the hippocampus. Future interventional trials are needed to assess whether supplementation of VitB12 may improve cognition in MCI patients even in the absence of clinically manifested VitB12 deficiency. This trial was registered at clinicaltrials.gov as NCT01219244.

Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease.

An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer's disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer's disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE ε4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs.

Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms.

BACKGROUND AND AIMS: The polyphenol quercetin may prevent cardiovascular diseases due to its vasorelaxant and anti-oxidative properties. We investigated the effects of quercetin on risk factors of atherosclerosis, biomarkers of inflammation and oxidative stress, depending on the apolipoprotein E (APOE) genotype. METHODS AND RESULTS: In a double-blind crossover study 49 healthy male subjects with APOE genotype 3/3 (n = 19), 3/4 (n = 22) and 4/4 (n = 8) consumed 150 mg/d quercetin or placebo for 8 weeks each, intermitted by a three-week washout phase. After each intervention, endothelial function, anthropometry, metabolic and inflammatory parameters were measured in the fasting and postprandial state following a standardized lipid-rich meal. Endothelial function was not changed. In all subjects combined, quercetin significantly decreased waist circumference (P = 0.004) and postprandial systolic blood pressure (P = 0.044). Postprandial triacylglycerol concentrations were significantly decreased and HDL-cholesterol concentrations increased after quercetin as compared to placebo consumption (P = 0.025). Quercetin also moderately increased levels of TNFα (P = 0.024). There was a significant gene-diet interaction for waist circumference and for body mass index (BMI). CONCLUSIONS: Quercetin supplementation improved some risk factors of cardiovascular disease, yet exerted slightly pro-inflammatory effects. Genotype-dependent effects were seen only on waist circumference and BMI.

Selenium level is associated with apoE epsilon4 in rural elderly Chinese.

OBJECTIVE: Se is an essential trace element in human nutrition associated with antioxidant activity. Previous studies on predictors of toenail Se or serum Se have mostly concentrated on demographic factors such as age and gender. The present paper examines the association between apoE genotype and Se levels in nail samples in a rural elderly Chinese cohort. DESIGN: Two thousand Chinese aged 65 years and over from four counties in China were enrolled in a cohort to study the association of Se with cognitive decline. Nail samples were collected from each participant and analysed for Se levels. Dietary Se intake was estimated from an FFQ using Se contents measured in food items collected from each village. Blood samples on filter cards were collected and analysed for apoE genotype. Mixed-effect models were constructed with nail Se level as the dependent variable and each village as the random effect, which controlled for the potential confounding effect from correlation in Se measures obtained from participants residing in the same village. RESULTS: In this elderly Chinese cohort, carriers of the apoE epsilon4 allele had significantly lower Se levels measured in nail samples than non-carriers after adjusting for other significant covariates and controlling for estimated dietary Se intake. There was no significant difference between the two genotypes on estimated Se dietary intake (P = 0.6451). CONCLUSIONS: Future studies are needed to examine the mechanism underlying the association between the apoE epsilon4 allele and Se levels, including the role of oxidative stress and that of reduced lipid metabolism in the apoE epsilon4 carriers.

Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer's disease: the omega-3 Alzheimer's disease study.

OBJECTIVES: To study the effects of omega (Omega)-3 fatty acid (FA) supplements on weight and appetite in patients with mild to moderate Alzheimer's disease (AD) in relation to inflammatory biomarkers and apolipoprotein E epsilon4 (APOEepsilon4). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Specialist memory clinics in the Stockholm catchment area. PARTICIPANTS: Two hundred four patients (aged 73+/-9, 52% women) with mild to moderate AD. INTERVENTION: Patients with AD received 1.7 g of docosahexaenoic acid (DHA) and 0.6 g of eicosapentaenoic acid (EPA) (Omega-3/Omega-3 group; n=89, aged 73+/-9, 57% women) or placebo 0.6 g of linoleic acid per day (placebo/Omega-3 group; n=85, aged 73+/-9, 46% women) for 6 months. After 6 months, all patients received DHA and EPA for another 6 months. MEASUREMENTS: Anthropometry, biochemical nutritional and inflammatory markers, and appetite assessed by caregiver. RESULTS: Mean weight and body mass index (kg/m(2)) at baseline were 70.0+/-11.8 kg and 24.3+/-3.0 kg/m(2), respectively. At 6- and 12-month follow-up, weight had increased 0.7+/-2.5 kg (P=.02) and 1.4+/-2.9 kg (P<.001) in the Omega-3/Omega-3 group. In the placebo group, weight was unchanged at 6 months but had increased (P=.01) at 12 months follow-up after Omega-3 supplementation was initiated. Appetite improved in the Omega-3/Omega-3 group over the treatment period (P=.01). In logistic regression analyses, not carrying the APOEepsilon4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up. CONCLUSION: A DHA-enriched Omega-3 FA supplement may positively affect weight and appetite in patients with mild to moderate AD. Not carrying the APOEepsilon4 allele and high DHA were independently associated with weight gain.