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Alzheimer's Disease-Related Proteins Picked up in Proteome-Wide Association Study

NEW YORK – By bringing together genetic and postmortem brain proteomic data, an Emory University team has tracked down almost a dozen genes that appear to influence Alzheimer's disease (AD) development by altering brain protein levels and may serve as potential treatment targets.

"Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies," senior and co-corresponding author Thomas Wingo, a researcher at Emory University School of Medicine, and his colleagues wrote in a paper published in Nature Genetics on Thursday.

For their proteome-wide association study (PWAS), the researchers searched for genetic loci linked to the levels of almost 8,400 proteins assessed by liquid chromatography and mass spectrometry in postmortem dorsolateral prefrontal cortex brain samples from 376 participants in the "Religious Orders Study/Memory Aging Project." Along with available genotyping data for those individuals, who had been profiled with genotyping arrays or whole-genome sequencing, they considered available data for more than 455,200 cases and controls included in a prior AD genome-wide association study.

The team's search led to 11 candidate genes that might be causal for AD, including one known and eight new AD risk genes, which they validated in a subsequent PWAS focused on more than 150 human brain proteomes. The risk gene set appeared to contribute to AD pathogenesis in a manner that was independent of the risk associated with the AD-related apolipoprotein E isoform APOE e4, pointing to new avenues for understanding and potentially treating the neurodegenerative disease.

For their follow-up experiments, the investigators went several steps further, exploring potential protein ties to other traits and symptoms before focusing on the transcripts coding for the PWAS proteins.

For example, in a transcriptome-wide association study that included nearly 900 brain samples from individuals of European ancestry — a set that was heavily skewed toward frontal cortex samples — they found five genes implicated by PWAS that also showed nominally-significant ties to AD in the TWAS. Three more genes had suggestive associations with AD in the transcriptome-centered analysis.

Half a dozen of the causal genes from the initial PWAS analysis were enriched in specific cell types in dorsolateral prefrontal cortex samples assessed by single-cell RNA sequencing, the team noted, including four genes enriched in excitatory neurons and individual genes that were overrepresented in oligodendrocyte cells or in astrocyte and microglia cell types.

The investigators also considered clusters of genes and proteins that tend to be expressed in concert to ensure that the range of proposed AD associations they picked up was not simply a reflection of activity within co-expression modules. Still, they cautioned that additional research will be needed to dig into the candidate causal gene set further and to search for targetable alterations in AD.

"[W]e identified 11 brain proteins that have evidence consistent with being causal in AD for further mechanistic studies to find new treatments for the disease," the authors concluded.