Where and when do changes in ins and IS affect AD? Colored lines represent our current understanding of the pathological timeline in AD. It is currently unclear when and where changes in ins/IS occur in this timeline. If changes in ins/IS happen early, (1) they could initiate or potentiate amyloid accumulation to casually influence AD. If ins/IS changes appear around the time of symptoms (4), this could be a consequence of years of pathological changes and may be directly related to cognitive decline. If changes in ins/IS occur in the presymptomatic period (2 and 3), they could be interacting with Aβ, tau, or metabolism to contribute to disease progression. Conversely, presymptomatic changes could be a result of tau or Aβ accumulation or metabolic perturbation. Additionally, it is possible that changes in ins/IS could simply push the symptomatic period to the left (earlier) without directly interacting with these pathologies.