We believe that our model helps to clarify one of the reasons for current controversy regarding the levels and role of TGF-β signaling in disease, aging, and Alzheimer’s disease (AD), which could be at least partially a result of the focus solely on serum or cerebrospinal fluid (CSF) TGF-β levels, which according to our results might not be biologically relevant to local microglia status. Here, TGFB1 is linked to early-onset autosomal dominant Alzheimer disease.