A similar pattern of staining was observed with pIRS1 S636/639; in control brain IRS1 pS636/639 was predominantly nuclear, and was present in both neurons and small cells (Fig. 5g-h), in AD nuclei were predominantly negative, with this being particularly apparent in neurons which had evidence of cytoplasmic staining associated with tangles, and tau pathology including NFTs and GVD were pIRS1 S636/639 positive (Fig. 5i). Here, IRS1 is linked to Alzheimer disease.