Rare Gene Variants Doubles Alzheimer's Disease Risk

Variations in a gene have been identified that doubles a person's risk of developing Alzheimer's disease later in life.

A number of common genetic variants have been linked to early-onset, which strikes before age 65, and the more common late-onset forms of Alzheimer's disease, but those variants account for only a fraction of Alzheimer's cases.


A team led by scientists at the Washington University School of Medicine (St. Louis, MO, USA) analyzed DNA from people in families in which multiple members were affected by Alzheimer's disease. They sequenced all the protein-coding genes from several individuals in each of 14 families, using a technique called whole exome sequencing. Some of these family members had an Alzheimer's diagnosis, but others did not.

After the initial exome sequencing, the team used more detailed sequencing to look closely at the phospholipase-D 3 (PLD3) gene in another 4,000 people of the same age, some of whom had Alzheimer's disease. This study helped them identify additional variants in the gene that increased risk for Alzheimer's, indicating that the PLD3 gene clearly had a role in the development of late-onset Alzheimer's disease.

Additional analyses conducted in the laboratory showed that when the PLD3 gene is active, levels of amyloid-beta decline. This substance aggregates in the brains of Alzheimer's patients to form plaques. When the scientists decreased expression of PLD3, levels of amyloid-beta increased.

Carlos Cruchaga, PhD, the lead author of the study, said, “We were very excited to be able to identify a gene that contains some of these rare variants and we were surprised to find that the effect of the gene was so large. After adjusting for other factors that can influence risk for the disease, we found that people with certain gene variants were twice as likely as those who didn't have the variants to develop Alzheimer's. We studied 11,000 other people with and without the disease and found that a PLD3 gene variant doubled the risk for Alzheimer's disease.” The study was published on December 11, 2013, in the journal Nature.

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