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We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed(More)
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants(More)
Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison(More)
Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of(More)
Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of(More)
Under physiological conditions, the number and function of microglia--the resident macrophages of the CNS--is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state--a process referred to as priming. Studies using(More)
BACKGROUND Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and(More)
BACKGROUND Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes. METHODS In June, 2003, consent for long-term clinical follow-up,(More)
It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an(More)
BACKGROUND Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.(More)