New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Association between anticholinergic burden and dementia in UK Biobank

Abstract 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

Active Cognitive Lifestyle Associates with Cognitive Recovery and a Reduced Risk of Cognitive Decline

Education and lifestyle factors linked with complex mental activity are thought to affect the progression of cognitive decline. Collectively, these factors can be combined to create a cognitive reserve or cognitive lifestyle score. This study tested the association between cognitive lifestyle score and cognitive change in a population-based cohort of older persons from five sites across England and Wales. Data came from 13,004 participants of the Medical Research Council Cognitive Function and Ageing Study who were aged 65 years and over. Cognition was assessed at multiple waves over 16 years using the Mini-Mental State Examination. Subjects were grouped into four cognitive states (no impairment, slight impairment, moderate impairment, severe impairment) and cognitive lifestyle score was assessed as a composite measure of education, mid-life occupation, and current social engagement. A multi-state model was used to test the effect of cognitive lifestyle score on cognitive transitions. Hazard ratios for cognitive lifestyle score showed significant differences between those in the upper compared to the lower tertile with a more active cognitive lifestyle associating with: a decreased risk of moving from no to slight impairment (0.58, 95% CI (0.45, 0.74)); recovery from a slightly impaired state back to a non-impaired state (2.93 (1.35, 6.38)); but an increased mortality risk from a severely impaired state (1.28 (1.12, 1.45)). An active cognitive lifestyle is associated with a more favorable cognitive trajectory in older persons. Future studies would ideally incorporate neuroradiological and neuropathological data to determine if there is causal evidence for these associations

Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study.

BACKGROUND: Identifying modifiable lifestyle correlates of cognitive decline and risk of dementia is complex, particularly as few population-based longitudinal studies jointly model these interlinked processes. Recent methodological developments allow us to examine statistically defined sub-populations with separate cognitive trajectories and dementia risks. METHODS: Engagement in social, physical, or intellectual pursuits, social network size, self-perception of feeling well understood, and degree of satisfaction with social relationships were assessed in 2854 participants from the Paquid cohort (mean baseline age 77 years) and related to incident dementia and cognitive change over 20-years of follow-up. Multivariate repeated cognitive information was exploited by defining the global cognitive functioning as the latent common factor underlying the tests. In addition, three latent homogeneous sub-populations of cognitive change and dementia were identified and contrasted according to social environment variables. RESULTS: In the whole population, we found associations between increased engagement in social, physical, or intellectual pursuits and increased cognitive ability (but not decline) and decreased risk of incident dementia, and between feeling understood and slower cognitive decline. There was evidence for three sub-populations of cognitive aging: fast, medium, and no cognitive decline. The social-environment measures at baseline did not help explain the heterogeneity of cognitive decline and incident dementia diagnosis between these sub-populations. CONCLUSIONS: We observed a complex series of relationships between social-environment variables and cognitive decline and dementia. In the whole population, factors such as increased engagement in social, physical, or intellectual pursuits were related to a decreased risk of dementia. However, in a sub-population analysis, the social-environment variables were not linked to the heterogeneous patterns of cognitive decline and dementia risk that defined the sub-groups