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Rare genetic variants may double risk for Alzheimer's disease

Scientists have identified several rare but influential variants in a gene not previously linked to Alzheimer’s that may double the risk for the disease in people who carry the gene. The results of the study, led by researchers at Washington University in St. Louis, adds phospholipase D3 (PLD3) to a growing list of genes thought to influence the risk of developing late-onset Alzheimer’s.

The researchers used whole exome sequencing and cellular models in the study published online Dec. 11, 2013, in Nature. They found that the PLD3 gene influences the processing of amyloid precursor protein (APP), a protein that plays a role in the development of amyloid plaques, a hallmark of Alzheimer’s. The findings show that lower PLD3 expression in brains of people with Alzheimer’s is correlated with higher APP and greater amyloid protein levels.

Supported in part by NIA, the scientists analyzed DNA samples of 14 families with 4 or more members affected by late-onset Alzheimer’s, plus more than 11,000 people of European descent and 302 African Americans, to find and confirm the PLD3 gene. The samples came from the National Cell Repository for Alzheimer’s Disease, Washington University, and other institutions.

Whole exome sequencing is a complex technique that identifies changes in an individual’s DNA that cause genetic disorders. The exome is the part of the human genome that contains key DNA sequences that tell the body to make proteins necessary for proper functioning. Analysis of these sequences can help researchers identify rare genetic disorders and, in this case, search vast amounts of genetic data efficiently to find new genetic variants that increase Alzheimer’s risk compared with those who do not have the variants.

The newly identified risk gene adds to growing knowledge of genetic variants thought to influence risk for and protection against late-onset Alzheimer’s disease. Results reported last fall by an international research consortium identified 11 new genes that offer new evidence about certain biological pathways involved in the development of Alzheimer’s. Together, the findings point to possible therapeutic targets to prevent or delay the disease’s progression.

Reference: Cruchaga C, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature, published online Dec. 11, 2013; DOI: 10.1038/nature12825.