Anticholinergic burden in middle and older age is associated with lower cognitive function, but not with brain atrophy.

AIMS: The aim of this study is to estimate the association between anticholinergic burden, general cognitive ability and various measures of brain structural MRI in relatively healthy middle-aged and older individuals. METHODS: In the UK Biobank participants with linked health-care records (n = 163,043, aged 40-71 at baseline), of whom about 17 000 had MRI data available, we calculated the total anticholinergic drug burden according to 15 different anticholinergic scales and due to different classes of drugs. We then used linear regression to explore the associations between anticholinergic burden and various measures of cognition and structural MRI, including general cognitive ability, 9 separate cognitive domains, brain atrophy, volumes of 68 cortical and 14 subcortical areas and fractional anisotropy and median diffusivity of 25 white-matter tracts. RESULTS: Anticholinergic burden was modestly associated with poorer cognition across most anticholinergic scales and cognitive tests (7/9 FDR-adjusted significant associations, standardised betas (ß) range: -0.039, -0.003). When using the anticholinergic scale exhibiting the strongest association with cognitive functions, anticholinergic burden due to only some classes of drugs exhibited negative associations with cognitive function, with ß-lactam antibiotics (ß = -0.035, PFDR < 0.001) and opioids (ß = -0.026, PFDR < 0.001) exhibiting the strongest effects. Anticholinergic burden was not associated with any measure of brain macrostructure or microstructure (PFDR > 0.08). CONCLUSIONS: Anticholinergic burden is weakly associated with poorer cognition, but there is little evidence for associations with brain structure. Future studies might focus more broadly on polypharmacy or more narrowly on distinct drug classes, instead of using purported anticholinergic action to study the effects of drugs on cognitive ability.

Increase in anticholinergic burden from 1990 to 2015: Age-period-cohort analysis in UK biobank.

BACKGROUND: The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence suggests that associated adverse effects may occur even decades after stopping anticholinergic use. Despite the implicated importance of examining longitudinal patterns of anticholinergic prescribing for different age groups, few such data are available. METHODS: We performed an age-period-cohort (APC) analysis to study trends in an aggregate measure of anticholinergic burden between the years 1990 and 2015, utilising data from >220 000 UK Biobank participants with linked prescription data from primary care. RESULTS: Anticholinergic burden in the sample increased up to 9-fold over 25 years and was observed for both period and age effects across most classes of drugs. The greatest increase was seen in the prescribing of antidepressants. Female sex, lower education and greater deprivation were associated with greater anticholinergic burden. CONCLUSIONS: The increase in anticholinergic prescribing is mostly due to an increase in polypharmacy and is attributable to both ageing of participants and period-related changes in prescribing practices. Research is needed to clarify the implications of rising anticholinergic use for public health and to contextualise this rise in light of other relevant prescribing practices.

An integrative approach for the analysis of risk and health across the life course: challenges, innovations, and opportunities for life course research.

Life course epidemiology seeks to understand the intricate relationships between risk factors and health outcomes across different stages of life to inform prevention and intervention strategies to optimize health throughout the lifespan. However, extant evidence has predominantly been based on separate analyses of data from individual birth cohorts or panel studies, which may not be sufficient to unravel the complex interplay of risk and health across different contexts. We highlight the importance of a multi-study perspective that enables researchers to: (a) Compare and contrast findings from different contexts and populations, which can help identify generalizable patterns and context-specific factors; (b) Examine the robustness of associations and the potential for effect modification by factors such as age, sex, and socioeconomic status; and (c) Improve statistical power and precision by pooling data from multiple studies, thereby allowing for the investigation of rare exposures and outcomes. This integrative framework combines the advantages of multi-study data with a life course perspective to guide research in understanding life course risk and resilience on adult health outcomes by: (a) Encouraging the use of harmonized measures across studies to facilitate comparisons and synthesis of findings; (b) Promoting the adoption of advanced analytical techniques that can accommodate the complexities of multi-study, longitudinal data; and (c) Fostering collaboration between researchers, data repositories, and funding agencies to support the integration of longitudinal data from diverse sources. An integrative approach can help inform the development of individualized risk scores and personalized interventions to promote health and well-being at various life stages.

Association between anticholinergic burden and dementia in UK Biobank.

Background: Previous studies on the relationship between anticholinergic drugs and dementia have reported heterogeneous results. This variability could be due to different anticholinergic scales and differential effects of distinct classes of drugs. Methods: Using Cox proportional hazards models, we computed the association between annual anticholinergic burden (AChB) and the risk of dementia in UK Biobank with linked general practitioner prescription records between the years 2000 and 2015 (n = 171,775). Results: AChB according to most anticholinergic scales (standardized odds ratio range: 1.027-1.125) and the slope of the AChB trajectory (hazard ratio = 1.094; 95% confidence interval: 1.068-1.119) were predictive of dementia. However, the association between AChB and dementia held only for some classes of drugs, especially antidepressants, antiepileptics, and antidiuretics. Discussion: The heterogeneity in previous findings may partially be due to different effects for different classes of drugs. Future studies should establish differences in more detail and further examine the practicality of a general measure of AChB relating to the risk of dementia.

Variation in VKORC1 Is Associated with Vascular Dementia.

BACKGROUND: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer's disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10-7), which was included in the genome-wide significant KAT8 locus. OBJECTIVE: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. METHODS: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. RESULTS: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10-6). The T-allele in rs9923231 was linked to a lower warfarin dose (ßperT - allele = -0.29, p < 2×10-16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. CONCLUSION: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.

DNA methylation in APOE: The relationship with Alzheimer's and with cardiovascular health.

INTRODUCTION: Genetic variation in the apolipoprotein E (APOE) gene is associated with Alzheimer's disease (AD) and risk factors for cardiovascular disease (CVD). DNA methylationat APOE has been associated with altered cognition and AD. It is unclear if epigenetic marks could be used for predicting future disease. METHODS: We assessed blood-based DNA methylation at 13 CpGs in the APOE gene in 5828 participants from the Generation Scotland (GS) cohort. Using linear mixed models regression, we examined the relationships among APOE methylation, cognition, cholesterol, the family history of AD and the risk for CVD. RESULTS: DNA methylation at two CpGs was associated with the ratio of total cholesterol and HDL cholesterol, but not with cognition, family history of AD, or the risk of CVD. DISCUSSION: APOE methylation is associated with the levels of blood cholesterol, but there is no evidence for the utility of APOE methylation as a biomarker for predicting AD or CVD.