Given our previous findings of early changes to genes associated with the hypothalamus, it is possible that the downregulation of Irs4 (and other insulin signaling genes) is occurring in the HPA region, but it is also possible changes are occurring in the cortex directly and these may be key to the onset/progression of Alzheimer’s disease in these mice. The gene discussed is INS; the disease is early-onset autosomal dominant Alzheimer disease.