Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience.

Background: Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood.

Methods: APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80.

Proteogenomic signature of risk of Alzheimer's disease and related dementia risk in individuals with a history of major depression disorder.

The mechanisms linking a history of major depressive disorder (MDD) to an increased risk of Alzheimer's disease and related dementia (ADRD) are not fully understood. Using the UK Biobank available proteomic and genomic data, we evaluated the biological mechanisms linking both conditions. In participants with a history of MDD at baseline (n=3,615), we found that plasma levels of NfL, GFAP, PSG1 were associated with higher risk (HR=1.

Mitochondrial DNA copy number associated dementia risk by somatic mutations and frailty.

Mitochondrial dysfunction is linked to physical impairment and dementia. Mitochondrial DNA copy number (mtDNAcn) from blood may predict cognitive decline and dementia risk, but the effect of somatic mutations or frailty is unknown. We estimated mtDNAcn using fastMitoCalc and microheteroplasmies using mitoCaller, from Whole Genome Sequencing (WGS) data.

A proteomic signature of healthspan.

The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan (healthspan proteomic score (HPS)) using data from the UK Biobank Pharma Proteomics Project (53,018 individuals and 2920 proteins).

MRI-derived brain iron, grey matter volume, and risk of dementia and Parkinson's disease: Observational and genetic analysis in the UK Biobank cohort.

Background: Iron overload is observed in neurodegenerative diseases, especially Alzheimer's disease (AD) and Parkinson's disease (PD). Homozygotes for the iron-overload (haemochromatosis) causing HFE p.C282Y variant have increased risk of dementia and PD.

Proteomic aging clock (PAC) predicts age-related outcomes in middle-aged and older adults.

Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all-cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2923 plasma proteins assessed using the Olink Explore 3072 assay®.

Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.

The solute carrier organic anion transporter family member 1B1 () encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in , such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records.

Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone.

Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics.

genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank.

Objectives: haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.

Is Mitochondrial DNA Copy Number from Human Blood Associated with Iron Deposits in the Brain?

Iron overload is implicated in mitochondrial dysfunction. Some iron and mitochondria-related measures show sex differences. It is unclear whether mitochondrial DNA copy number (mtDNAcn) from blood associated with iron depositions in the brain or liver and whether the relationship differs by sex.

Proteomic aging clock (PAC) predicts age-related outcomes in middle-aged and older adults.

Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all-cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2,923 plasma proteins assessed using the Olink Explore 3072 assay.

Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.

Background: Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter.

Methods: We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project.

Hemochromatosis Genetic Variants and Musculoskeletal Outcomes: 11.5-Year Follow-Up in the UK Biobank Cohort Study.

The iron overload disorder hemochromatosis is primarily caused by the homozygous p.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain. We estimated hemochromatosis-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort.

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD.

Association between Residential Exposure to Air Pollution and Incident Coronary Heart Disease Is Not Mediated by Leukocyte Telomere Length: A UK Biobank Study.

Higher air pollution exposure and shorter leukocyte telomere length (LTL) are both associated with increased risk of coronary heart disease (CHD), and share plausible mechanisms, including inflammation. LTL may serve as a biomarker of air pollution exposure and may be intervened with to reduce the risk of CHD. To the best of our knowledge, we are the first to test the mediation effect of LTL in the relationship between air pollution exposure and incident CHD.

Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants.

Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.

Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.

Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e., osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.

Genomics and multimorbidity.

Multimorbidity has increased in prevalence world-wide. It is anticipated to affect over 1 in 6 of the UK population by 2035 and is now recognised as a global priority for health research. Genomic medicine has rapidly advanced over the last 20 years from the first sequencing of the human genome to integration into clinical care for rarer conditions.

Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults.

Background: A striking effect of old age is the involuntary loss of muscle mass and strength leading to sarcopenia and reduced physiological functions. However, effects of heavy-load exercise in older adults on diseases and functions as predicted by changes in muscle gene expression have been inadequately studied.

Methods: Thigh muscle global transcriptional activity (transcriptome) was analyzed in cohorts of older and younger adults before and after 12-13 weeks heavy-load strength exercise using Affymetrix microarrays.

Calcium-channel blockers: Clinical outcome associations with reported pharmacogenetics variants in 32 000 patients.

Aims: Pharmacogenetic variants impact dihydropyridine calcium-channel blockers (dCCBs; e.g., amlodipine) treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited.

Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank.

Background: In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations.

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.

Background: The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions.

Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men.

Objective: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications.

Methods And Analysis: This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years).