An individual’s risk for Alzheimer’s disease is affected by a variety of genetic and environmental factors. While the causes of early-onset Alzheimer’s are well understood, the genetic factors underlying late-onset Alzheimer’s disease (LOAD), which makes up 95% of total cases, are less clear. The APOE4 allele is considered the major risk factor for this form of Alzheimer’s, as it can increase your risk by 2-3 times if you have one copy of the allele or up to 15 times if you have two copies. APOE4 does not guarantee that an individual will develop LOAD, and researchers have been searching for other genes that may be involved. (For more background see The Genetics of Alzheimer’s Disease).
Genome-wide association studies, which systematically analyze the 0.1% of DNA sequence that varies between individuals, have linked at least 21 other genes to an increased risk of LOAD. Individually, each of these genes has only a small influence in comparison to APOE4, often increasing one’s risk by only a few percentage points. However, when many of these small genetic risk factors are combined, they can greatly affect an individual’s chances of developing LOAD.
Overall, studies suggest that approximately 33% of an individual’s risk for developing LOAD is attributable to genetics, with the rest being due to lifestyle choices and environmental factors. Of this, APOE and the 21 already-identified genes account for less than 25% of the genetic risk, suggesting that the majority of genetic risk factors for Alzheimer’s disease remain unknown.
In a recent study published in the journal Neurology, a group of researchers from the Alzheimer’s Disease Neuroimaging Initiative searched for other genes, outside of the 21 already identified, that could also act as slight risk factors for Alzheimer’s. They used data collected from the International Genomics of Alzheimer’s Project to compute polygenetic risk scores, or PGRS, for both young and elderly adults who did not have dementia. Each person’s PGRS was calculated using his or her unique combination of small genetic risk factors (including many that were not statistically significant in genome-wide association studies) in order to estimate the genetic risk for LOAD. The researchers then analyzed whether PGRS were associated with biological markers of preclinical Alzheimer’s disease.
In elderly subjects who did not have dementia, high PGRS was associated with poorer memory, smaller volume of the hippocampus (the part of the brain that helps us form new memories), and increased levels of toxic beta-amyloid in the brain. High PGRS in these individuals also correlated with an increased rate of cognitive decline and a greater probability of later being diagnosed with Alzheimer’s disease. The researchers also computed PGRS for younger subjects under the age of 35. They found that a high PGRS was associated with reduced hippocampal volume, similarly to the older subjects.
Together, these results suggest that more genes besides the currently-identified 21 may need to be considered when evaluating an individual’s risk for LOAD. The researchers plan to repeat this study using a larger sample size to verify the results. Future studies also will track younger subjects to see if PGRS can predict their risk for Alzheimer’s as they age, and compare these results to less comprehensive systems of genetic prediction. The hope is that by refining PGRS, we may one day be able to develop better genetic tests for young people that yield more accurate predictions of future Alzheimer’s risk.