👤 Blossom Stephan

Personality traits are associated with cognitive resilience to dementia-related neuropathology. This study examines whether personality traits are related to cognitive resilience to accelerated epigenetic aging. Participants were adults aged from 50 to 98 years (N = 2926, 58% female, Mean age = 68.72, SD = 9.57) from the Health and Retirement Study (HRS). Data on cognition and epigenetic aging measures (GrimAge and DunedinPoAM38) were obtained in 2016. Data on personality, demographic factors, and clinical, behavioral, and psychological covariates were obtained in 2014/2016. Cognitive resilience was defined as the residual from the regression of cognition on epigenetic aging measures. Controlling for demographic factors, linear regression analyses indicated that higher neuroticism was associated with worse-than-expected cognition relative to one's epigenetic aging for both GrimAge and DunedinPoAM38 epigenetic measures. Higher conscientiousness and openness were related to better-than-expected cognition relative to one's epigenetic aging across the two measures. Logistic regression further indicated that higher neuroticism was associated with a lower likelihood of cognitive resilience to accelerated epigenetic aging, whereas higher conscientiousness and openness were related to a higher likelihood of cognitive resilience. These associations were partially accounted for by disease burden, sleep quality, physical activity, smoking, depressive symptoms, childhood adversity, lifetime trauma, and APOE e4 status, and persisted when participants with cognitive impairment were excluded. There was little evidence that age or sex moderated the associations. The present study expands the literature on resilience from neuropathology to a broader systemic impact of aging to provide novel evidence that personality traits are associated with cognitive resilience to accelerated epigenetic aging. Show less

A substantial proportion of dementia risk may be attributable to modifiable factors, yet these are often examined in isolation despite their interrelated nature and tendency to co-occur. It remains unclear whether the relationship between modifiable factors and dementia risk is influenced by individual characteristics such as sex and genetic susceptibility. We investigated longitudinal associations between the Lifestyle for Brain health (LIBRA) score and risk of dementia, cognitive performance, and brain structure, and whether relationships differed by sex and APOE ɛ4 carrier status.Participants were aged > 50 years, dementia-free at baseline, 50% female and predominantly (97%) white/Caucasian. The LIBRA score included 11 modifiable factors (e.g., hypertension, obesity, physical inactivity). Magnetic resonance imaging estimated brain volume, domain-specific cognitive composite scores were calculated, and dementia diagnoses were determined based on self-reported and linked healthcare data.Across a mean follow-up of 10.2 years, a higher LIBRA score was associated with greater odds of developing dementia (OR = 1.20, 95% CI 1.18-1.22). This association was stronger in APOE ɛ4 non-carriers compared to ɛ4 carriers. Cross-sectionally, higher LIBRA scores related to poorer cognition, smaller whole-brain gray and white matter volumes, and increased ventricular cerebrospinal fluid (CSF), however, only the association with increased ventricular CSF persisted longitudinally (mean follow-up 3.4 years).Each one-point increase on the LIBRA score was associated with 20% increased odds of developing dementia. These results reinforce the need to target modifiable dementia risk factors and to tailor dementia prevention strategies to individual risk profiles to maximize the impact on brain health. Show less

Accurate dementia risk prediction is critical for prevention, yet it remains unclear which predictors add meaningful value beyond chronological age. This review evaluates the extent to which multivariable dementia risk models identify modifiable risk factors that enhance prediction value. We systematically reviewed cohort studies reporting both age-only and multivariable dementia prediction models in the same population. Six age-only models across five cohorts were included. Age-only models achieved poor to good discrimination (C-statistics 0.66-0.84). Adding modifiable cardiovascular and lifestyle factors provided consistent, modest improvements of 0.02-0.05 in the UK Biobank, Atherosclerosis Risk in Communities (ARIC), and Rotterdam cohorts. Larger improvements of 0.07-0.12 were observed in models including cognitive testing or genetic factors [e.g., UK Biobank Dementia Risk Score (UKBDRS-APOE)] with the Hanley-McNeil z-test confirming the improvements were significant, indicating genuine improvement rather than random variation. While age is a significant risk factor for dementia, modifiable cardiovascular and lifestyle factors provide incremental predictive value beyond age and represent actionable targets for prevention. Despite modest statistical improvements, these factors offer the most clinically relevant targets for prevention strategies. Future efforts should prioritise interventions addressing these modifiable determinants to reduce dementia risk across populations. Show less

Dysregulated blood lipids are a major predictor of cardiovascular events. A recent genome-wide association study (GWAS) with five clinically relevant lipid traits in 1.65 million individuals implicated over 770 genomic regions in regulating blood lipid metabolism. To translate these associations into clinical applications, a functional understanding of their roles in lipoprotein metabolism, transport and remodeling (LPmtr) is required. Here, we report the deep molecular fine-mapping of 554 of these lipid risk loci using 168 lipoprotein-related traits and all possible ratios between them in over 273,000 participants of the UK Biobank. We identified new ratio-based markers of pathways shared by multiple LPmtr genes, such as the linoleic acid fraction of the polyunsaturated fatty acid pool to reveal potential causal genes at poorly characterized lipid risk loci, the percentage of esterified cholesterol moieties in LDL particles as a proxy for soluble LDL receptor levels, and the HDL fraction of total lipoprotein particle number as a predictor of incident myocardial infarction. We demonstrate how lipoprotein fine-mapping can generate new hypotheses for drug target development while uncovering new mechanisms relevant to hyperlipidemia. Ratio-driven clustering further implicated miR-148 in TG secretion, linking ER-stress responses at postprandial state to VLDL metabolism via mTORC1, shown through series of integrated cellular assays and mouse studies. Moreover, consistent with its regulatory influence on lipid flux we identify miR-148a a previously unrecognized determinat of Show less

The present study explores how family relationship quality is associated with psychological and cognitive health among grandparents who had primary responsibility in raising their grandchildren and examines whether co-residence with adult children moderates this relationship. The study uses data from 589 grandparents who completed the Midlife Development in the United States (MIDUS) survey. Latent profile analysis (LPA) is used to identify grandparent-family relationship types. Ordinary Least Squares (OLS) regression models are used to estimate the association between relationship types and psychological and cognitive health (i.e., psychological distress, psychological well-being, episodic memory, and executive function). LPA identified four grandparent-family relationship types: amicable, ambivalent, neutral, and disharmonious. Compared to grandparents with amicable family relationships, those with ambivalent family relationships had significantly higher levels of psychological distress, reduced psychological well-being, and poorer episodic memory. Further, the association between ambivalent relationships and episodic memory was stronger among respondents who co-resided with their adult children. Emotional closeness with family is essential for grandparents who are raising their grandchildren. This study contributes to a more detailed understanding of the role of relationships with family and suggests that emotional and instrumental support from family is important for increasing grandparent caregivers' psychological and cognitive well-being. Show less

Saccharomyces cerevisiae cells control their cell size at a point in late G(1) called Start. Here, we describe a negative role for the Sin3/Rpd3 histone deacetylase complex in the regulation of cell size at Start. Initiation of G(1)/S-specific transcription of CLN1, CLN2 and PCL1 in a sin3Delta strain occurs at a reduced cell size compared with a wild-type strain. In addition, inactivation of the transcriptional regulator SIN3 partially suppressed a cln3Delta mutant, causing sin3Deltacln3Delta double mutants to start the cell cycle at wild-type size. Chromatin immunoprecipitation results demonstrate that Sin3 and Rpd3 are recruited to promoters of SBF (Swi4/Swi6)-regulated genes, and reveal that binding of Sin3 to SBF-specific promoters is cell-cycle regulated. We observe that transcriptional repression of SBF-dependent genes in early G(1) coincides with the recruitment of Sin3 to specific promoters, whereas binding of Sin3 is abolished from Swi4/Swi6-regulated promoters when transcription is activated at the G(1) to S phase transition. We conclude that the Sin3/Rpd3 histone deacetylase complex helps to prevent premature activation of the S phase in daughter cells. Show less

To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease. Show less