MRC Unit for Lifelong Health and Ageing

To assess the impact of cardiorespiratory fitness (CRF) and muscle strength on depression and individual depression symptoms. Mendelian randomisation (MR) analysis was conducted in up to 341,326 participants of European ancestry from UK Biobank (aged 37-73years). Genetic variants from previous genome-wide association studies (GWAS) of CRF and grip strength (to proxy overall muscle strength) were utilised to instrument exposures. A broad depression phenotype based on self-report and hospital records, as well as individual measures of depression symptoms from the Patient Health Questionnaire-9 (PHQ-9) were used as outcomes. Analysis was repeated stratifying by sex and using summary statistics from a major depressive disorder (MDD) GWAS. There was no clear evidence for association between CRF and any depression outcome. There was robust evidence suggesting greater grip was associated with lower odds of broad depression (OR per 0.1kg increase in weight adjusted grip: 0.86, 95% CI:0.80,0.93), as well as the PHQ-9 items appetite changes (OR:0.56, 95% CI:0.49,0.65), and anhedonia (OR:0.79, 95% CI:0.69,0.90), a core symptom of depression. There was also some evidence for associations between greater grip and lower odds of depressed mood (OR:0.85, 95% CI:0.74,0.97), psychomotor changes (OR:0.79, 95% CI:0.64,0.97), fatigue (OR:0.83, 95% CI:0.74,0.93) and concentration problems (OR:0.85, 95% CI:0.74,0.98) in the MR-inverse variance weighted analysis. Effects were mostly driven by stronger associations in females and results replicated in the two-sample MR for MDD. Muscle strength may represent an important modifiable factor for preventing and treating depression and several specific symptoms, including core symptoms such as anhedonia.

Abstract The paper is structured around three main contributions. First, it takes advantage of a unique survey on Afghan asylum seekers in Germany to provide novel descriptive insights into asylum seekers’ beliefs about their outcomes and the associated intention to overstay. Second, it estimates asylum seekers’ perceived ex ante returns on overstaying and option values of regularisation, deportation, and experimentation. Third, it assesses and rejects the cost-effectiveness argument for assisted voluntary return policies. Instead, it estimates a sizeable willingness-to-pay of asylum seekers for investments that would guarantee their regularisation.

Background Early-life origins of late-life health are unclear. It is uncertain when in life risk-factors for dementia begin to exert effects. We examined childhood predictors of dementia and mortality in the world's longest continuously-running birth cohort. Methods Prospective cohort study, 78-year follow-up. Exposures assessed from birth-age 16. Dementia/death identified from national registries. Cox regression identified childhood predictors. Findings Of 5,046 participants, 121 (2.4%) were diagnosed with dementia and 1,243 (24.6%) died by age 78. Independent childhood predictors of dementia were low cognition (HR 2.06, 95% CI 1.31-3.24, P=0.002), pollution exposure (HR 2.05, 1.15-3.65, P=0.02), left-handedness/ambidexterity (HR 1.93, 1.15-3.23, P=0.01), sleep disturbance (HR 1.78, 1.00-3.17, P=0.049), nocturnal enuresis (HR 1.52, 1.06-2.17, P=0.02), and emotional problems (HR 1.38, 1.12-1.69, P=0.003). APOE ϵ4 (HR 3.38, 1.67-6.85, P=0.001), and BMI (HR 1.47, 1.17-1.84, P<0.001) associated with dementia only in females. Independent childhood predictors of mortality were BMI (HR 1.07, 1.01-1.14, P=0.02), lower socioeconomic position (HR 1.25, 1.09-1.42, P=0.001), sleep disturbance (HR 1.27, 1.05-1.53, P=0.02), nocturnal enuresis (HR 1.32, 1.04-1.68, P=0.02) emotional problems (HR males:1.09, 1.00-1.18, P=0.046, females:1.25, 1.14-1.36, P<0.0001), and conduct problems (HR 1.13, 1.06-1.20, P=0.0002). Female sex (HR 0.67, 0.59-0.75, P<0.001), education (HR 0.76, 0.67 to 0.87, P<0.001), and breastfeeding (HR 0.93/3-months, 0.89-0.98, P=0.002) associated with lower mortality. Interpretation Childhood factors predict a significant proportion of dementia and early mortality risk. While some associations are genetically determined or may relate to early brain development, the majority are potentially modifiable.

Abstract While significant progress has been made in understanding the genetic architecture of ageing in model organisms, our understanding of human ageing remains limited. We performed a multi-tissue Transcriptome-wide association study (TWAS) on human lifespan, integrating GWAS data from >1 million parental lifespans with gene expression prediction models derived from reference transcriptomic datasets; followed by replication using healthspan and longevity phenotypes as additional readouts of ageing. The TWAS uncovered 563 significant gene associations, of which 139 replicated. TOMM40 , encoding a component of the mitochondrial outer membrane translocase that is fundamental for mitochondrial function, had the strongest association with parental lifespan and longevity and was fine-mapped as a putatively causal lifespan gene at the APOE-TOMM40 region. Uniquely in our study, we identified fly orthologues of replicating genes and examined if modulating their expression impacts Drosophila longevity. The nine novel associations with all three ageing outcomes included COASY, encoding Coenzyme A synthase. Knocking down its fly orthologue, Ppat-dpck , resulted in significant lifespan extension in flies. Hence, in addition to discovering new genes associated with human ageing, by combining human TWAS with experimental Drosophila work, we provide evidence for the role of COASY ( Ppat-dpck ) in ageing across species. Significance statement Extensive research on ageing has been conducted in Drosophila and C.elegans due to their short lifespan and experimental tractability. However, in human genetic research, only a few loci have been consistently replicated. To bridge this gap, we conducted a transcriptome-wide association study (TWAS) followed by experimental validation in Drosophila . TWAS revealed 139 significant and replicating gene associations, including COASY. Knockdown of its fly orthologue ( Ppat-dpck ) significantly extended fly lifespan, validating its roles in ageing across species. Thus, integrating multiple ageing outcomes through TWAS in human genetic research can uncover robust associations and highlight genes involved in fundamental ageing mechanisms.

This study examines how different forms of social isolation, such as living alone, lack of community engagement, and unemployment, are associated with mental health in mid-life (ages 42-46), a life stage often overlooked when examining the impacts of social isolation. Using longitudinal data (1999-2016) from two British birth cohort studies: 1970 British Cohort Study N = 16,585 and the 1958 National Child Development Study N = 15,806, this study investigated whether different forms of isolation have independent effects, contribute to cumulative risk, or interact additively or multiplicatively. Effects varied by isolation type and mental health outcomes. Being out of employment was linked to higher psychological distress and lower life satisfaction and self-rated health, while living alone was only associated with lower life satisfaction. Limited contact with friends and relatives and a lack of community engagement were associated with lower life satisfaction and self-rated health. Greater social isolation corresponded to increased psychological distress, lower life satisfaction, and poorer self-rated health, demonstrating cumulative risk. Effects appeared additive rather than multiplicative. No consistent sex or cohort differences were observed. The study underscores the need to examine both separate and combined effects of social isolation across the complete mental health state. Isolation in its various forms was detrimental for mental health in mid-life and was most consistently linked to lower life satisfaction. Efforts to reduce isolation and its negative mental health impacts must recognise the complexity of these experiences.

Variation in the APOE gene strongly affects Alzheimer’s disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies. First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4415 participants of the A4 Study. Third, we analysed data from the Alzheimer’s Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% (95% confidence interval: 54.9%, 81.7%) in FinnGen to 92.7% in the ADGC (82.4, 96.5%). In A4, 85.4% (17.5, 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and Fin-Gen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.

ABSTRACT Background COVID-19 is associated with higher rates of gastrointestinal diseases, though the duration of this effect, and the role of vaccination and COVID-19 severity remain uncertain. Objective To investigate the relationship between COVID-19 and gastrointestinal diseases, by vaccination status in hospitalised and non-hospitalised patients. Design With NHS England approval, OpenSAFELY-TPP was used to access linked data from 24 million English adults. We defined three cohorts: “Pre-vaccination” (January 2020-June 2021), “vaccinated” and “unvaccinated” (June-December 2021). We estimated adjusted hazard ratios (aHRs) comparing the incidence of 10 gastrointestinal diseases, including upper and lower gastrointestinal bleeding, after versus before or without a COVID-19 diagnosis overall and by COVID-19 severity. Results COVID-19 diagnosis was associated with elevated incidence of gastrointestinal diseases, particularly after hospitalised disease. In the pre-vaccination cohort (n=18,422,781), the adjusted hazard ratios (aHRs) for upper gastrointestinal bleeding after hospitalised COVID-19 were 20.1 (95% CI 18.4–22.1) in weeks 1–4 and 1.90 (1.63–2.22) in weeks 53–102. The corresponding aHRs after non-hospitalised COVID-19 were 1.92 (1.74–2.11) and 1.34 (1.23– 1.45) respectively. Across time periods, aHRs for gastrointestinal diseases were lower in vaccinated (n=14,948,727) than in unvaccinated (n=3,479,043) individuals. These patterns were similar across gastrointestinal diseases. Conclusion The incidence of gastrointestinal disease is elevated for up to two years among individuals hospitalised following a COVID-19 diagnosis. Increases in incidence are attenuated among vaccinated individuals. Monitoring for gastrointestinal diseases after severe COVID-19 and promotion of vaccination in vulnerable groups are key to reducing long-term burden. KEY MESSAGES What is already known on this topic Acute symptoms of COVID-19 include gastrointestinal problems, and there is existing evidence that those with a COVID-19 diagnosis are more likely to experience long-term gastrointestinal complications, especially if they were hospitalised. Previous studies were either limited in size, lacked representativeness of the population, or had short follow-up (e.g. during hospitalisation). The role of vaccination, COVID-19 severity or peoples’ characteristics (e.g. age or sex) were not considered. What this study adds Based on population-wide data on 18.4 million individuals, rates of 10 gastrointestinal diseases are elevated after COVID-19, compared with rates before or without COVID-19 diagnosis. The elevation in rates of gastrointestinal diseases after COVID-19 diagnosis was less marked in people who were vaccinated before COVID-19 diagnosis. The elevation in rates was markedly higher, and persisted for up to two years, among individuals hospitalised with COVID-19, compared with those who were not hospitalised. How this study might affect research, practice or policy We show for the first time that the incidence of both acute and chronic gastrointestinal diseases remains elevated for up to two years after severe COVID-19 leading to hospitalisation. Our findings highlight the protective role of COVID-19 vaccination in reducing severe COVID-19 and its subsequent long-term gastrointestinal complications, reinforcing the importance of vaccination as a public health measure. Individuals who had severe COVID-19, regardless of vaccination status, should be prioritised for clinical monitoring for gastrointestinal diseases.

Gaucher disease (GD), the most common lysosomal storage disorder, is caused by bi-allelic mutations in the GBA1 gene. Variants in GBA1 also represent the most frequent genetic risk factor for Parkinson’s disease (PD). Although GD and PD are clinically distinct disorders, they share key pathological features, including lysosomal dysfunction, mitochondrial stress, and redox imbalance. While PD has traditionally been studied in the context of neuronal decline, the contribution of non-neuronal organ systems remains poorly understood. Here, we demonstrate that progressive renal dysfunction is a central, disease-modifying feature in Drosophila models of GD and PD. We show that Drosophila lacking either the main fly orthologue of GBA1, Gba1b, or the mitophagy regulator Parkin, exhibit age-dependent degeneration of the renal system. This includes disorganisation of the Malpighian tubules, impaired nephrocyte function, redox imbalance, and lipid accumulation. These renal defects contribute to systemic physiological decline, including water retention, ionic hypersensitivity, and exacerbation of neurodegenerative phenotypes. Importantly, we identify redox dyshomeostasis, rather than classical oxidative stress, as a central pathogenic driver, marked by paradoxical sensitivity to both oxidative and reductive interventions. Notably, treatment with the mTOR inhibitor rapamycin selectively restores renal structure and function in Gba1b mutants, but not in Parkin mutants, revealing mechanistic divergence between lysosomal and mitochondrial stress. These findings uncover redox imbalance as a biomarker of renal vulnerability and establish the renal system as a critical, potentially disease-modifying organ in the systemic progression of GD and PD.

Gaucher disease (GD), the most common lysosomal storage disorder, is caused by bi-allelic mutations in the GBA1 gene. Variants in GBA1 also represent the most frequent genetic risk factor for Parkinson’s disease (PD). Although GD and PD are clinically distinct disorders, they share key pathological features, including lysosomal dysfunction, mitochondrial stress, and redox imbalance. While PD has traditionally been studied in the context of neuronal decline, the contribution of non-neuronal organ systems remains poorly understood. Here, we demonstrate that progressive renal dysfunction is a central, disease-modifying feature in Drosophila models of GD and PD. We show that Drosophila lacking either the main fly orthologue of GBA1, Gba1b, or the mitophagy regulator Parkin, exhibit age-dependent degeneration of the renal system. This includes disorganisation of the Malpighian tubules, impaired nephrocyte function, redox imbalance, and lipid accumulation. These renal defects contribute to systemic physiological decline, including water retention, ionic hypersensitivity, and exacerbation of neurodegenerative phenotypes. Importantly, we identify redox dyshomeostasis, rather than classical oxidative stress, as a central pathogenic driver, marked by paradoxical sensitivity to both oxidative and reductive interventions. Notably, treatment with the mTOR inhibitor rapamycin selectively restores renal structure and function in Gba1b mutants, but not in Parkin mutants, revealing mechanistic divergence between lysosomal and mitochondrial stress. These findings uncover redox imbalance as a biomarker of renal vulnerability and establish the renal system as a critical, potentially disease-modifying organ in the systemic progression of GD and PD.

Complex socio-cultural, psychological, geographical, and service-related challenges are faced when recruiting people with dementia for clinical trials. The aim of Phase 1 of the Dementia PersonAlised Care Team (D-PACT) project was to assess the feasibility of recruiting (identifying, approaching and consenting) people with dementia, including those without capacity to consent, to a cluster randomized controlled trial of a primary care-based personalized dementia support intervention in England. COVID-19 necessitated a shift to remote working, creating the opportunity to compare recruitment strategies before and under lockdown constraints. This paper shares the adaptations made to enable remote consent and capacity judgement with people with dementia, as well as lessons learned. Consent was conducted in person from September 2019 to March 2020. Remote consent was implemented from September 2020 to March 2021 after an enforced pause. Both quantitative and qualitative data were collected. Recruitment rates (proportion consented from eligible patients approached), mean monthly consent rates, and time spent on consent-related activities (tasks before and after consent/capacity-judgment meetings, miscellaneous tasks, travel) were compared. Participant experiences with remote recruitment were examined through thematic analysis of qualitative interviews. Pre-COVID-19, 22 participants (9.9%) out of 228 approached were consented in person. During the pandemic, 19 participants (9.6%) out of 198 were consented remotely, excluding 15 participants initially approached pre-pandemic and later consented via remote means. Mean monthly consent rates increased from 3.6 (in person) to 5.6 (remote). However, remote consent required more time (mean 14 researcher-hours per participant vs. 9 in person), with 75% of time spent on consent-related tasks compared to 20% in person. Travel accounted for 40% of in-person consent time. Interviews (n = 13) showed general acceptability of remote processes. However pre-consent information was perceived as excessive and led some participants to skim materials, potentially reducing understanding. While remote consent is time-intensive, it achieves comparable rates (proportion consented/total approached) to in-person methods and higher monthly consent rates. A flexible, hybrid approach can enhance participation, offer choice, and increase person-centredness. Realistic planning for time and resources is crucial for inclusive dementia research. Funders should support these needs to ensure effective recruitment. ISRCTN80204146.