A global team of researchers has linked a rare change in a gene called PLD3 to a doubling in the risk of the most common, late-onset form of Alzheimer’s disease. The discovery adds to the growing number of genes linked to Alzheimer’s, helping researchers to map the risk factors for the disease. The research, co-funded by Alzheimer’s Research UK, is published on 11 December in the journal Nature.
Until today, DNA changes in 21 different parts of the genome have been linked to an altered risk of Alzheimer’s. Many of these changes are common in the population, and associated with a low risk of developing the disease. However, researchers believe that the heritability of late-onset Alzheimer’s – which affects people over the age of 65 – cannot be fully explained by the changes discovered so far. Scientists believe that the remaining heritability may be accounted for by rare genetic changes that are hard for researchers to find but have big effects on risk.
Recent advances in genetic technologies are helping researchers to find these ‘rare variants’, leading to the discovery in 2012 of a change in a gene called TREM2, associated with a three-fold increased risk of the disease.
To search for more rare variants, a group of researchers from across the UK and the world joined forces. They started by studying 14 families with a history of late-onset Alzheimer’s, comparing the DNA sequence between affected and unaffected family members. They found a particular change in a gene called phospholipase D3 (PLD3) in two of the families, and followed this up by looking for the same change in data from more than 11,000 unrelated individuals, with and without Alzheimer’s. They found that the change in PLD3 (present in around 0.8% of the population) was associated with around a two-fold higher risk of Alzheimer’s. When the researchers studied the DNA sequence of PLD3 in more detail, they discovered a total of 14 changes associated with an altered risk.
The researchers found that the PLD3 protein is found in areas of the brain particularly vulnerable to Alzheimer’s. Levels of PLD3 inside nerve cells were also lower in people with Alzheimer’s compared to those without. In laboratory experiments, lower levels of PLD3 were associated with higher levels of the hallmark Alzheimer’s protein, amyloid, suggesting that the gene changes may contribute to the disease by driving up levels of this protein in the brain.
Rebecca Wood, Chief Executive of Alzheimer’s Research UK, the UK’s leading dementia research charity, said:
“Advances in genetic technology are allowing researchers to understand more than ever about the genetic risk factors for the most common form of Alzheimer’s. This announcement, made just off the back of the G8 dementia research summit, is a timely reminder of the progress that can be made by worldwide collaboration.
“We know that late-onset Alzheimer’s is caused by a complex mix of risk factors, including both genetic and lifestyle. Understanding all of these risk factors and how they work together to affect someone’s likelihood of developing Alzheimer’s is incredibly important for developing interventions to slow the onset of the disease. Alzheimer’s Research UK is proud to have contributed to this discovery, both by funding researchers and through the establishment of a DNA collection that has been used in many of the recent genetic discoveries in Alzheimer’s.”