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Alzheimer's Disease Genomes Lead to Novel Loci Involved in Synaptic Function

NEW YORK – An international team led by investigators at Massachusetts General Hospital and Harvard Medical School has identified more than a dozen new Alzheimer's disease-related genetic loci containing rare risk variants. They made their discovery with the help of whole-genome sequencing of individuals with early-onset, familial forms of the neurodegenerative disease.

"With this study, we believe we have created a new template for going beyond standard GWAS and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease," senior author Rudolph Tanzi, director of the Mass General Hospital Genetics and Aging Research Unit and vice chair of neurology at MGH, said in a statement.

Tanzi, who is also affiliated with Harvard Medical School, noted that the team plans to build on the current findings for drug discovery by examining the consequences of the rare alterations with the help of so-called Alzheimer's-in-a-dish models, including three-dimensional cell culture and brain organoids.

"Together with the results of common variant [Alzheimer's disease] risk GWAS, our study highlights several novel promising routes of [Alzheimer's disease] research," he and his co-authors wrote, "and provides new potential targets for therapeutic interventions aimed at the early treatment or prevention of [Alzheimer's disease]."

To expand from Alzheimer's disease-focused genome-wide associations reported in the past, the researchers sequenced the genomes of 2,247 participants from more than 600 Alzheimer's disease-affected families, following up on suspicious sites in the genome in nearly 1,700 more unrelated individuals with or without Alzheimer's disease — an approach they outlined in a paper published in Alzheimer's & Dementia on Friday.

"This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants," first author Dmitry Prokopenko, a researcher affiliated with the MGH McCance Center for Brain Health and Harvard Medical School, said in a statement.

In the sequence data, the team saw rare Alzheimer's-associated variants at known risk loci involving genes such as apolipoprotein E and those involved in processes such as innate immunity, chronic neuroinflammation, and amyloid processing. But the investigators' single-variant and spatial clustering analysis also pointed to 13 loci not linked to Alzheimer's in the past.

In a series of follow-up analyses — including in silico functional, pathway, and network interaction analyses, as well as cell-type specific expression analyses using single-cell RNA sequencing data on samples from the mouse cortex and hippocampus — the researchers found that the newly-detected risk loci encompass rare variants in and around genes with apparent ties to neuronal synapse function, neuroplasticity, and related pathways. 

"Downstream analyses of these novel loci highlight synaptic function, in contrast to common [Alzheimer's disease]-associated variants, which implicate innate immunity and amyloid processing," the authors reported, noting that the study underscores "the ability of WGS to identify [Alzheimer's disease]-associated rare variants, particularly outside of the exome."

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