Genetic and cardiometabolic contributions to cognitive, structural brain and biomarker phenotypes

The number of individuals experiencing abnormal cognitive ageing is rapidly increasing, which can only in part be explained by an ageing population. Prevention of considerable cognitive decline is complicated by its heterogeneity and numerous risk factors. The most significant contributions to brain health and cognitive decline outside of age are higher genetic risk and poor cardiometabolic health. There are gaps in the literature and understanding regarding the extent to which common genetic or cardiometabolic conditions contribute to and interact with one another to influence brain health. Therefore, the overall aim of this PhD project is to explore genetic and cardiometabolic risks in relation to structural brain MRI measures, cognitive assessments, and blood biomarkers. This thesis used large-scale secondary data from the UK Biobank in which several analyses investigating associations between cardiometabolic conditions, genetic risks, cognition, and brain MRI data are the largest to date. The use of the UK Biobank cohort also allowed for controlling of confounders that have not been considered or accounted for in previous studies. The primary focus of this thesis was on genetic and cardiometabolic contributions to cognition and brain MRI. The main objectives were: (1) Contribute to the understanding of cardiovascular to brain health and (2) Determine the role of genetic risk factors on the brain and physical health in healthy adults. When examining multimorbidity, there were no clear trends between cardiometabolic groups and brain MRI metrics. However, this may have been due to a healthy selection bias in which those with multimorbidity were healthy enough for MRI assessments. When examining genetically elevated risk of cardiovascular disease (CVD) indexed by lipoprotein A (), we found associations with mean diffusivity and fractional anisotropy, suggesting a potential role of LpA in brain ageing. However, we found discrepancies between genetically elevated LpA and blood LpA, which should be further investigated. When calculating genetic risk scores for Alzheimer’s disease (AD) in healthy midlife adults, we found evidence for potential early ageing pathology within subfields of the hippocampus prior to significant cognitive impairments. We also found that this elevated genetic risk for AD was associated with elevated cystatin c. Elevated genetic risk of AD also showed significant sex differences in biomarker analyses. Creatinine and oestradiol were significantly associated with an elevated risk of Alzheimer’s in women but not men. These findings support routine stratification in exploratory research. This thesis emphasises the importance of epidemiological research that considers cardiometabolic, lifestyle and genetic risk factors together in the context of cognitive health. There is scope to build on this work in omics and cohort studies

Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank

Previous studies testing associations between polygenic risk for late-onset Alzheimer’s disease (LOAD-PGR) and brain magnetic resonance imaging (MRI) measures have been limited by small samples and inconsistent consideration of potential confounders. This study investigates whether higher LOAD-PGR is associated with differences in structural brain imaging and cognitive values in a relatively large sample of non-demented, generally healthy adults (UK Biobank). Summary statistics were used to create PGR scores for n = 32,790 participants using LDpred. Outcomes included 12 structural MRI volumes and 6 concurrent cognitive measures. Models were adjusted for age, sex, body mass index, genotyping chip, 8 genetic principal components, lifetime smoking, apolipoprotein (APOE) e4 genotype and socioeconomic deprivation. We tested for statistical interactions between APOE e4 allele dose and LOAD-PGR vs. all outcomes. In fully adjusted models, LOAD-PGR was associated with worse fluid intelligence (standardised beta [β] = −0.080 per LOAD-PGR standard deviation, p = 0.002), matrix completion (β = −0.102, p = 0.003), smaller left hippocampal total (β = −0.118, p = 0.002) and body (β = −0.069, p = 0.002) volumes, but not other hippocampal subdivisions. There were no significant APOE x LOAD-PGR score interactions for any outcomes in fully adjusted models. This is the largest study to date investigating LOAD-PGR and non-demented structural brain MRI and cognition phenotypes. LOAD-PGR was associated with smaller hippocampal volumes and aspects of cognitive ability in healthy adults and could supplement APOE status in risk stratification of cognitive impairment/LOAD

Carotid intima-media thickness novel loci, sex-specific effects, and genetic correlations with obesity and glucometabolic traits in UK Biobank

Objective: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease. Conclusions: These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression

Alzheimer’s disease susceptibility gene apolipoprotein e (APOE) and blood biomarkers in UK Biobank (N=395,769)

Background: Alzheimer’s disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Objective: Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. Methods:After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers. Results: Several biomarkers significantly associated with APOE ɛ4 ‘risk’ and ɛ2 ‘protective’ genotypes (versus neutral ɛ3/ɛ3). Most associations supported previous data: for example, ɛ4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p < 0.001) and ɛ2 with lower LDL (b = –0.456 SDs, p < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ4 and increased insulin-like growth factor (IGF-1) (b = 0.017, p < 0.001) where lower levels have been previously suggested as an AD risk factor. Conclusion: These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways

Testing for Interactions Between APOE and Klotho Genotypes on Cognitive, Dementia, and Brain Imaging Metrics in UK Biobank

Recent research suggests genetic variation in the Klotho locus may modify the association between APOE ɛ4 and cognitive impairment. We tested for associations and interactions between these genotypes versus risk of dementia, cognitive abilities, and brain structure in older UK Biobank participants. Klotho status was indexed with rs9536314 heterozygosity (versus not), in unrelated people with versus without APOE ɛ4 genotype, corrected for various confounders. APOE ɛ4 associated with increased risk of dementia, worse cognitive abilities, and brain structure. Klotho was associated with better reasoning. There were no interactions; potentially suggesting an age- and pathology-dependent Klotho effect

Association of SBP and BMI with cognitive and structural brain phenotypes in UK Biobank

Objective: To test for associations between SBP and BMI, with domain-specific cognitive abilities and examine which brain structural phenotypes mediate those associations. Methods: Using cross-sectional UK Biobank data (final N = 28 412), we examined SBP/BMI vs. cognitive test scores of pairs-matching, matrix completion, trail making test A/B, digit symbol substitution, verbal–numerical reasoning, tower rearranging and simple reaction time. We adjusted for potential confounders of age, sex, deprivation, medication, apolipoprotein e4 genotype, smoking, population stratification and genotypic array. We tested for mediation via multiple structural brain imaging phenotypes and corrected for multiple testing with false discovery rate. Results: We found positive associations for higher BMI with worse reaction time, reasoning, tower rearranging and matrix completion tasks by 0.024–0.067 SDs per BMI SD (all P < 0.001). Higher SBP was associated with worse reasoning (0.034 SDs) and matrix completion scores (−0.024 SDs; both P < 0.001). Both BMI and SBP were associated with multiple brain structural metrics including total grey/white matter volumes, frontal lobe volumes, white matter tract integrity and white matter hyperintensity volumes: specific metrics mediated around one-third of the associations with cognition. Conclusion: Our findings add to the body of evidence that addressing cardiovascular risk factors may also preserve cognitive function, via specific aspects of brain structure

Participant completion of longitudinal assessments in an online cognitive aging registry: The role of medical conditions

IntroductionThis study aimed to understand whether older adults' longitudinal completion of assessments in an online Alzheimer's disease and related dementias (ADRD)-related registry is influenced by self-reported medical conditions.MethodsBrain Health Registry (BHR) is an online cognitive aging and ADRD-related research registry that includes longitudinal health and cognitive assessments. Using logistic regressions, we examined associations between longitudinal registry completion outcomes and self-reported (1) number of medical conditions and (2) eight defined medical condition groups (cardiovascular, metabolic, immune system, ADRD, current psychiatric, substance use/abuse, acquired, other specified conditions) in adults aged 55+ (N = 23,888). Longitudinal registry completion outcomes were assessed by the completion of the BHR initial questionnaire (first questionnaire participants see at each visit) at least twice and completion of a cognitive assessment (Cogstate Brief Battery) at least twice. Models included ethnocultural identity, education, age, and subjective memory concern as covariates.ResultsWe found that the likelihood of longitudinally completing the initial questionnaire was negatively associated with reporting a diagnosis of ADRD and current psychiatric conditions but was positively associated with reporting substance use/abuse and acquired medical conditions. The likelihood of longitudinally completing the cognitive assessment task was negatively associated with number of reported medical conditions, as well as with reporting cardiovascular conditions, ADRD, and current psychiatric conditions. Previously identified associations between ethnocultural identity and longitudinal assessment completion in BHR remained after accounting for the presence of medical conditions.DiscussionThis post hoc analysis provides novel, initial evidence that older adults' completion of longitudinal assessments in an online registry is associated with the number and types of participant-reported medical conditions. Our findings can inform future efforts to make online studies with longitudinal health and cognitive assessments more usable for older adults with medical conditions. The results need to be interpreted with caution due to selection biases, and the under-inclusion of minoritized communities