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Background: Despite decades of research, the mechanisms linking APOE to Alzheimer's disease (AD) remain poorly understood. Finding additional risk variants at the APOE locus, beyond the common APOE‐ε2 and APOE‐ε4 alleles, may help elucidate how APOE is involved in the disease. Method: Association with case‐control status was tested in a sequenced discovery sample (Stage 1) and followed‐up in several microarray imputed cohorts as well as the UK Biobank whole‐exome sequencing resource using a proxy‐AD phenotype (Stages 2+3) (Table 1). Stage 1 included 37,409 non‐unique participants of European or Admixed‐European ancestry, with 11,868 cases and 11,934 controls passing analysis inclusion criteria. In Stages 2+3, 475,473 participants were considered across 8 cohorts, of which 56,029 cases, 28,484 proxy‐AD cases, and 328,372 healthy‐controls passed inclusion criteria, and were of European ancestry. Result: Two missense variants were associated with a two to three‐fold decreased AD risk: R251G (odds ratio, 0.44; 95% confidence interval [CI], 0.33‐0.59; P = 4.7×10‐8) and V236E (odds ratio, 0.37; 95% CI, 0.25‐0.56; P = 1.9×10‐6) (Table 2, Figures 1, 2). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared to non‐carriers (Table 3). Conclusion: We identified a novel variant associated with AD, R251G, which mitigates the ε4 associated AD risk, and confirmed the protective effect of the V236E variant. The location of the variants confirms that the carboxyl‐terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here, suggest that protein chemistry and functional assays of these variants have the potential to identify novel pathways for drug development. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid‐β‐rich (amyloid plaques) aggregates in AD, α‐synuclein‐rich aggregates (Lewy bodies) in PD and TDP‐43 aggregates in ALS, although co‐presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS. Method: Using genome‐wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer's AD disease versus controls across ancestry groups. Result: A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10‐13; AD: OR=0.91[0.89; 0.93]; p=1.8x10‐22), and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA‐DRB1*04 subtypes best accounted for the association, strongest with HLA‐DRB1*04:04 and HLA‐DRB1*04:07, intermediary with HLA‐DRB1*04:01 and HLA‐DRB1*04:03, and absent for HLA‐DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA‐DRB1*04 subtypes strongly bound the aggregation‐prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. Conclusion: An HLA‐DRB1*04‐mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk.Methods: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median (PWM)-based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments.Results: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88-1.20) per 1-standard-deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83-1.17] and 0.99 [95% CI, 0.86-1.14], respectively).Interpretation: We did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191-199. [ABSTRACT FROM AUTHOR]