Mid-to-Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals.

IMPORTANCE: Genetic and lifestyle factors contribute to an individual's risk of developing Alzheimer's disease. However, it is unknown whether and how adherence to healthy lifestyles can mitigate the genetic risk of Alzheimer's. OBJECTIVE: The aim of this study is to investigate whether adherence to healthy lifestyles can modify the impact of genetic predisposition to Alzheimer's disease on later-life cognitive decline. DESIGN SETTING AND PARTICIPANTS: This prospective cohort study included 891 adults of European ancestry, aged 40 to 65, who were without dementia and had complete healthy-lifestyle and cognition data during the follow-up. Participants joined the Wisconsin Registry for Alzheimer's Prevention (WRAP) beginning in 2001. We conducted replication analyses using a subsample with similar baseline age range from the Health and Retirement Study (HRS). EXPOSURES: We assessed participants' exposures using a continuous non-APOE polygenic risk score for Alzheimer's, a binary indicator for APOE-ε4 carrier status, and a weighted healthy-lifestyle score, including factors such as no current smoking, regular physical activity, healthy diet, light to moderate alcohol consumption, and frequent cognitive activities. MAIN OUTCOMES AND MEASURES: We z-standardized cognitive scores for global (Preclinical Alzheimer's Cognitive Composite score 3 - PACC3) and domain-specific assessments (delayed recall and immediate learning). RESULTS: We followed 891 individuals for up to 10 years (mean [SD] baseline age, 58 [6] years, 31% male, 38% APOE-ε4 carriers). After false discovery rate (FDR) correction, we found statistically significant PRS × lifestyle × age interactions on preclinical cognitive decline but the evidence is stronger among APOE-ε4 carriers. Among APOE-ε4 carriers, PRS-related differences in overall and memory-related domains between people scoring 0-1 and 4-5 regarding healthy lifestyles became evident around age 67 after FDR correction. These findings were robust across several sensitivity analyses and were replicated in the population-based HRS. CONCLUSION: A favorable lifestyle can mitigate the genetic risk associated with current known non-APOE genetic variants for longitudinal cognitive decline, and these protective effects are particularly pronounced among APOE-ε4 carriers.

Apolipoprotein E moderates the association between non-APOE polygenic risk score for Alzheimer's disease and aging on preclinical cognitive function.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (eg, a non-APOE polygenic risk score [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS × APOE ε4 × age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1190 individuals. RESULTS: We found statistically significant PRS × APOE ε4 × age interactions on immediate learning (P = 0.038), delayed recall (P < 0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P = 0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSIONS: APOE ε4 can modify the association between PRS and cognition decline. HIGHLIGHTS: APOE ε4 can modify the association between polygenic risk scores (PRSs) and longitudinal cognition decline, with the modifying effects more pronounced when the PRS is constructed using a conservative P threshold (eg, P < 5e-8 ). The adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental among APOE Îµ4 carriers around age 70. Individuals who are APOE Îµ4 carriers with high PRSs are the most vulnerable to the harmful effects caused by genetic burden.

The Big (Genetic) Sort? A Research Note on Migration Patterns and Their Genetic Imprint in the United Kingdom.

This research note reinvestigates Abdellaoui et al.'s (2019) findings that genetically selective migration may lead to persistent and accumulating socioeconomic and health inequalities between types (coal mining or non-coal mining) of places in the United Kingdom. Their migration measure classified migrants who moved to the same type of place (coal mining to coal mining or non-coal mining to non-coal mining) into "stay" categories, preventing them from distinguishing migrants from nonmigrants. We reinvestigate the question of genetically selective migration by examining migration patterns between places rather than place types and find genetic selectivity in whether people migrate and where. For example, we find evidence of positive selection: people with genetic variants correlated with better education moved from non-coal mining to coal mining places with our measure of migration. Such findings were obscured in earlier work that could not distinguish nonmigrants from migrants.

Understanding Internal Migration: A Research Note Providing an Assessment of Migration Selection With Genetic Data.

Migration is selective, resulting in inequalities between migrants and nonmigrants. However, investigating migration selection is empirically challenging because combined pre- and post-migration data are rarely available. We propose an alternative approach to assessing internal migration selection by integrating genetic data, enabling an investigation of migration selection with cross-sectional data collected post-migration. Using data from the UK Biobank, we utilized standard tools from statistical genetics to conduct a genome-wide association study (GWAS) for migration distance. We then calculated genetic correlations to compare GWAS results for migration with those for other characteristics. Given that individual genetics are determined at conception, these analyses allow a unique exploration of the association between pre-migration characteristics and migration. Results are generally consistent with the healthy migrant literature: genetics correlated with longer migration distance are associated with higher socioeconomic status and better health. We also extended the analysis to 53 traits and found novel correlations between migration and several physical health, mental health, personality, and sociodemographic traits.

Pervasive biases in proxy GWAS based on parental history of Alzheimer's disease.

Almost every recent Alzheimer's disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current AD GWAX provide highly misleading genetic correlations between AD risk and higher education which subsequently affects a variety of genetic epidemiologic applications involving AD and cognition. Our study sheds important light on the design and analysis of mid-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

Apolipoprotein E moderates the association between Non-APOE Polygenic Risk Score for Alzheimer's Disease and Aging on Preclinical Cognitive Function.

INTRODUCTION: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (e.g., a non-APOE polygenic risk scores [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS: We tested the PRS×APOE ε4×age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals. RESULTS: We found statistically significant PRS×APOE ε4×age interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSION: APOE ε4 can modify the association between PRS and cognition decline.

Higher educational attainment is associated with longer telomeres in midlife: Evidence from sibling comparisons in the UK Biobank.

Prior studies have established that higher educational attainment is associated with a longer telomere length (TL), a marker of cellular aging. However, it is unclear whether extant associations are causal, since they are likely confounded by unobserved genetic, early-life and family background factors that are correlated with education and TL. We leverage sibling differences in TL, education and measured genetics (polygenic scores for educational attainment and TL) to estimate associations between educational attainment and TL in midlife for European ancestry individuals in the UK Biobank, while controlling for unobserved confounders shared by siblings. After controlling for genetics and shared background between siblings, we find suggestive evidence that high school graduates have longer telomeres than high school dropouts, but we find no differences in TL between high school dropouts and college graduates.

Detecting genetic heterogeneities in response to trauma: The case of 9/11.

The current study evaluates genetic heterogeneities in response to trauma among U.S. young adults. Using Add Health Wave III, which coincidently overlapped with the September 11 attacks, and a depression mean and variance polygenic scores, we investigate how the polygenic scores moderate the causal effect of 9/11 on mental health. Our results show the presence of genetic heterogeneity, where those with high genetic plasticity experience an increase in depressive symptoms following trauma while those with low genetic plasticity do not. While the documented differences in reactions to trauma are important, we also note our ability to predict responses based only on genetic measures are too imprecise to identify susceptible clinical patients. We, therefore, contend that the expected benefits from genetic screening to identify susceptible individuals after trauma are limited. Our results provide novel evidence of a specific source of an additional heterogeneity contributing to the inequality of health following trauma.

Effects of a dammarane-type saponin, ginsenoside Rd, in nicotine-induced vascular endothelial injury.

BACKGROUND: Panax notoginseng (Burk.) F.H. Chen is a traditional medicinal plant widely used to prevent and treat cardiovascular diseases. Ginsenoside Rd (GRd) is a major bioactive component of P. notoginseng, but specific effects on cardiovascular disease-related pathogenic processes are rarely studied, especially vascular endothelial injury. PURPOSE: This study investigated the potential protective efficacy of GRd against nicotine-induced vascular endothelial cell injury, disruption of vascular nitric oxide (NO) signaling, aberrant endothelium-monocyte adhesion, platelet aggregation, and vasoconstriction. STUDY DESIGN/METHODS: Vascular endothelial injury and functional disruption were investigated in cultured human umbilical vein endothelial cells (HUVECs) by biochemical assays for nitric oxide (NO) and angiotensin II (Ang II), immunofluorescence (IF) and western blotting for expression analyses of apoptosis- related proteins, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Ang II type receptor 1 (AGTR1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). In addition, vascular protection by GRd was examined in nicotine-administered Sprague-Dawley (SD) rats by serum NO and Ang II assays, and by hematoxylin-eosin (HE) and immunostaining of aorta. We also examined effects of GRd on monocyte (THP-1 cells) adhesion assays, adenosine diphosphate (ADP)-induced platelet aggregation, and phenylephrine (PE)-induced vasoconstriction of isolated rat aortic rings. RESULTS: In HUVECs, nicotine significantly suppressed NO production, enhanced Ang II production, downregulated eNOS expression, and upregulated expression levels of AGTR1, TLR4, MyD88, NF-κB, iNOS, Bax/Bcl-2 ratio, cleaved caspase-3, and cytochrome c (cyt c). All of these changes were significantly reversed by GRd. In rats, oral GRd reversed the reduction NO and enhanced Ang II production in serum induced by nicotine administration, and HE staining revealed protection of aortic endothelial cells. In addition, GRd reversed nicotine-mediated enhancement of HUVECs-monocyte adhesion, inhibited ADP-induced platelet aggregation and PE-induced vasoconstriction. CONCLUSION: GRd may prevent nicotine-induced cardiovascular diseases by preserving normal vascular endothelial NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing endothelial cell-monocyte adhesion.