An analysis of exome sequencing data from more than 10,000 individuals with late onset Alzheimer’s disease (AD; LOAD) suggests that natural variants in tyrosine phosphatase genes may protect against the neurodegenerative disorder by impacting on the PI3K/Akt/GSK-3β signaling pathway. This pathway is important for cell survival.
Previous studies in mice and rats have suggested that inhibiting the function of these proteins might be protective against Alzheimer’s disease, and the reported study by researchers at University College London (UCL) represents the first demonstration that the same effect may occur in humans. The results also point to new potential therapeutic strategies against AD that target the PI3K/Akt/GSK-3β pathway.
“These results are quite encouraging,” said lead study author David Curtis, PhD, honorary professor at the UCL Genetics Institute. “It looks as though when naturally occurring genetic variants reduce the activity of tyrosine phosphatases then this makes Alzheimer’s disease less likely to develop, suggesting that drugs which have the same effect might also be protective.”
The findings also strengthen existing evidence that other genes could be linked to either elevated or reduced risk of Alzheimer’s disease. Curtis and colleagues reported on their study in Annals of Human Genetics, in a paper titled, “Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of PI3K/Akt/GSK-3β and Wnt signaling pathways.”
For their study, the UCL researchers turned to the Alzheimer’s Disease Sequencing Project (ADSP), an initiative that aims to identify rare genetic variants that increase or decrease the risk of LOAD. A number of analyses utilizing the ADSP dataset have already been reported, with results pointing to associations between AD and novel, as well as previously implicated genes and variants. However, the authors noted, “A limitation of these previous studies is that they focus on specific genes and/or types of variant.” For their newly reported study, the scientists used a method for carrying out weighted burden analysis of all variant within a gene, which assigns more weight to variants that are rare, and to those that are predicted to have a functional effect. “This method was applied to the ADSP sample in the hope that it would more completely capture the effect of variants influencing susceptibility to LOAD.” The researchers used their method to analyze DNA from 4,600 AD patients and 6,100 controls.
In total the weighted burden tests evaluated 1,217,860 individual variants in 15,777 genes, to identify which damaging variants were more common in people with or without Alzheimer’s disease.
The results highlighted a number of genes that had previously been linked with AD, including TREM2, ABCA7, and SORL1. These genes, in particular, are “well-established susceptibility genes for LOAD, which inspires some confidence in the validity of the approach,” the authors stated. There was also additional support provided for PSEN1, “which previously had been only weakly implicated in LOAD,” the team noted. There was also “suggestive evidence” that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk.
Interestingly, C1R is known to affect periodontal Ehlers-Danlos syndrome, a disease involving chronic gum inflammation. Some previous research suggests that gum infections may increase the risk of Alzheimer’s disease, so Curtis speculated there may be a mechanism whereby genetic variants in C1R lead to some degree of gum disease, which in turn predisposes to Alzheimer’s disease.
The study results, in addition, pointed to genes that may protect against LOAD. “Perhaps the most plausible result is for TIAF1,” the investigators wrote, as this gene self-aggregates and leads to apoptosis, amyloid-beta formation, and plaque formation. “… variants which interfered with this process would be expected to reduce LOAD risk.” The data also pointed to a protective effect for variants of NDRG2, although the team noted that further studies would be needed to verify this finding.
The “most striking result,” the authors reported, was the strong evidence that variants of genes encoding tyrosine phosphatases were protective against LOAD. “Given the established role of tyrosine phosphatase processes in the development of AD this result is eminently plausible but has not been described previously,” they wrote.” Taken in context with the results for PIK3RI, the findings “suggest that increased activity of the PI3K/Akt signaling pathway is protective against LOAD whereas reduced activity increases risk … Since PIK3R1 variants are expected to impair PI3K/Akt/GSK-3β signaling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models suggesting that this pathway is protective against AD.” Curtis added, “There is a consistent story in our results that the activity of the PI3K/Akt/GSK-3β signaling pathway is protective, which is exactly in line with findings from animal studies.”
The researchers say it is feasible that drugs which have the same effect as the tyrosine phosphatase variants might also be able to reduce the risk of Alzheimer’s disease. Curtis pointed out that some drugs which act on tyrosine phosphatases have already been developed, but have not yet been tested in clinical trials.
“Analyzing all variants together in a single joint analysis makes good use of the available data while avoiding problems due to multiple testing issues,” the authors concluded. “The results obtained serve to highlight genes rather than individual variants, which tend to be too rare for individual inferences to be made. The results reported here serve to reinforce some known aspects of LOAD biology and to suggest additional leads which might profitably be pursued.”
“Here’s a natural experiment in people that helps us understand how Alzheimer’s disease develops: as some people have these genetic variants and some don’t, we can see that the impact of having particular variants is a reduced likelihood of developing Alzheimer’s disease,” Curtis added.
“Finding DNA variants that modify the risk of Alzheimer’s disease is useful as it may help us develop drugs that target the same proteins. Simultaneously, researchers at UCL and across the globe are finding ways to detect the earliest stages of Alzheimer’s disease, before it causes any problems. As our understanding improves, there may be opportunities to intervene with treatments to prevent the disease from progressing.”