Gerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 associated with LOAD. The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (PM) = 1.7 × 10−9, joint analysis P (PJ) = 1.7 × 10−9; stages 1, 2 and 3, PM = 8.2 × 10−12), CD2AP (rs9349407; stages 1, 2 and 3, PM = 8.6 × 10−9), EPHA1 (rs11767557; stages 1, 2 and 3, PM = 6.0 × 10−10) and CD33 (rs3865444; stages 1, 2 and 3, PM = 1.6 × 10−9). We also replicated previous associations at CR1 (rs6701713; PM = 4.6 × 10−10, PJ = 5.2 × 10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9 × 10−8), BIN1 (rs7561528; PM = 4.0 × 10−14, PJ = 5.2 × 10−14) and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0 × 10−10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility1,2,3.

Alzheimer disease (AD) is the most common causes of neurodegenerative disorder in the elderly individuals. Clinically, patients initially present with short-term memory loss, subsequently followed by executive dysfunction, confusion, agitation, and behavioral disturbances. Three causative genes have been associated with autosomal dominant familial AD (APP, PSEN1, and PSEN2) and 1 genetic risk factor (APOEε4 allele). Identification of these genes has led to a number of animal models that have been useful to study the pathogenesis underlying AD. In this article, we provide an overview of the clinical and genetic features of AD.

Lewy body disease (LBD) encompasses a spectrum of clinicopathologic entities that include Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). Dementia with Lewy bodies and PDD are differentiated from one another based on clinical criteria. Dementia with Lewy bodies is diagnosed when dementia occurs before or concurrently with parkinsonism, whereas in PDD, parkinsonism precedes dementia by at least 12 months.¹ Lewy body disease neuropathologic changes (NCs) include classic histologic inclusions (Lewy bodies) and α-synuclein immunopositive neuronal inclusions and processes (Lewy neurites) in partially overlapping regions of the brain. However, the pathologic classification of DLB is complex because some cases show LBDNCs with no or low levels of Alzheimer disease (AD) NCs, which we refer to as pure DLB (pDLB), while many other cases show LBDNCs with coexistent high levels of ADNCs (LBD-AD). Importantly, the pathophysiologic relationship between LBD-AD, pDLB, and PDD has not been delineated, and whether these disorders share common risk factors remains unclear.