Suchergebnisse

The possible role of aluminium in the pathogenesis of Alzheimer's disease (AD) has been hotly debated over the past few decades. Although the so‐called 'aluminium hypothesis' was popular in the 1970s and 1980s, it has gradually fallen out of favour in the past few years possibly following a number of inconclusive and contradictory human environmental/clinical studies. Nevertheless, there have from time to time been reminders in the media of environmental accidents; these have prevented the topic from disappearing completely from public memory. One such accident occurred on July 6th 1988 in Camelford, Cornwall when 20 tonnes of aluminium sulphate was mistakenly discharged into the mains water supply. Twenty thousand people were exposed to concentrations of aluminium which were 500–3000 times the acceptable limit under European Union legislation. Over the subsequent years there have been UK government inquiries into the supposed environmental impact and occasional clinical follow‐up studies documenting declining cerebral function in those exposed to the contaminated water but very little neuropathological data has been published. To our knowledge, the case described here is only the second neuropathological description.

This is the final version. Available from Elsevier via the DOI in this record. ; Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies. ; This study was supported by the Alzheimer's Research UK, the Medical Research Council (MRC), the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (whose members are from the University College London Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee), grants (P50 AG016574, U01 AG006786, and R01 AG18023), the National Institute for Health Research Biomedical Research Unit in Dementia at University College London Hospitals, University College London; an anonymous donor, the Big Lottery (to Dr. Morgan); a fellowship from Alzheimer's Research UK (to Dr. Guerreiro); and the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disease and Stroke, National Institutes of Health (Department of Health and Human Services Project number, ZO1 AG000950-10). The MRC London Neurodegenerative Diseases Brain Bank and the Manchester Brain Bank from Brains for Dementia Research are jointly funded from ARUK and AS. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project number ZO1 AG000950-10. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. NIH grant R01 AG042611 to Kauwe J.