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Alzheimer disease (AD)-associated loci identified by genome-wide association studies (GWAS) only partly explain the genetic risk for this common neurodegenerative dementia. A recent GWAS of an alternative phenotype—cerebrospinal fluid tau levels—has uncovered new genetic variants that might further account for risk of AD and provide novel pathophysiological insights.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.

A multi-cohort genome-wide association study of tau PET, a brain imaging-based marker of Alzheimer’s disease, identifies a CYP1B1-RMDN2 locus as associated with higher tau and faster cognitive decline. These results suggest a new genetic contribution to cerebral tau and target for Alzheimer’s disease research.

Bioenergetic capacity, the ability to maintain energy balance under stress, can be monitored using blood acylcarnitine profiles. Improving this capacity may slow Alzheimer’s disease progression.

Alzheimer’s disease (AD) is typically associated with hippocampal and cortical pathology, although hippocampal sparing and limbic predominant forms exist. The authors use transcriptomic analysis and neuropathology to identify genes associated with selective hippocampal vulnerability in AD.

Resources reporting RNA editing sites from brain tissue have been published. Here, the authors provide an atlas of RNA editing events found in the aged and Alzheimer’s disease human brain tissue resulting in changes at protein level.

Multiancestry fine-mapping of brain protein quantitative trait loci coupled with Mendelian randomization analyses identifies protein–trait pairs consistent with causal effects across neurological and psychiatric conditions.

Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer’s disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.

Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.

Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years.

Genome-wide association studies have identified loci associated with neurodegenerative disease risk, but many of the implicated genetic variants are noncoding and their functional roles remain unclear. Using massively parallel reporter assays, CRISPR-based validation and genomic annotations, a new study functionally characterizes regulatory risk variants associated with Alzheimer disease and progressive supranuclear palsy.

APOE4 is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that APOE4 is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of APOE4 to APOE3 attenuates the AD-associated phenotype.

The limited understanding of the temporal molecular changes in late-onset Alzheimer’s disease hinder the development of therapeutic treatment. The authors use manifold learning to develop a molecular model for disease progression from RNASeq data from human postmortem brain samples.

Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.

Aging can lead to cognitive decline associated with neural pathology and Alzheimer's disease (AD). Here the authors scan the methylation status of CpGs across the entire genome of brain samples from aged subjects in an epigenome-wide association study (EWAS). Several loci, including ANK1, were associated with AD pathology, gene expression and AD genetic risk networks.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Large-scale, comprehensive proteomic profiling of Alzheimer’s disease brain and cerebrospinal fluid reveals disease-associated protein coexpression modules and highlights the importance of glia and energy metabolism in disease pathogenesis.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

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.

Steve Younkin and colleagues report the results of a genome-wide association study for late-onset Alzheimer's disease. A variant on the X chromosome in PCDH11X is associated with increased risk of the disorder. PCDH11X encodes a protocadherin and is a member of a cell surface receptor molecule family.

APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.

Combining a novel, biophysically plausible clustering scheme with statistics and interpretable machine learning yields insights into microglia dysfunction in Alzheimer’s disease.

A network analysis on deconvoluted bulk transcriptomic data from human Alzheimer’s disease cohorts identifies several potential key disease drivers, including JMJD6.

David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption.