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.

Gerard Schellenberg and colleagues report a genome-wide association study for progressive supranuclear palsy, a movement disorder with prominent tau neuropathology. They identified three new risk loci and confirmed the known risk locus at MAPT. Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.