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A number of tyrosine phosphatases act to reduce PI3K\/Akt activity, and inhibition of tyrosine phosphatases is protective against A\u03b2 toxicity in cell cultures and whole animals. Results from analysis of exome sequenced late onset AD cases and controls similarly show that rare coding variants predicted to damage PI3K functioning increase AD risk, whereas those which are predicted to damage genes for tyrosine phosphatase genes are protective. 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