Although the hypothesis that many variants with small effect contribute in concert to AD is well established, no study has demonstrated that the sum of a multitude of non-significant effects contributes to the development of AD. Our group is the first to have found supportive evidence for such a contribution. This finding shows that many more genetic variants still await detection. We were able to show that these variants which may confer vulnerability through many different biological mechanisms, act across different samples. Since the effect sizes of individual risk alleles involved in polygenic susceptibility will be low, it will be difficult to distinguish true risk effects from false positives at the level of individual genes. Pathway-based analysis involving the incorporation of risk alleles from the multiple genes that contribute to a particular pathway may overcome this limitation, and allow the translation into a meaningful biological context.
