Fig. 6

Hypothetic timelines of late-onset AD and common comorbidity of stroke. Late-onset AD is a slow and progressive disease; its early pathophysiological cascades cultivate years to decades before clinical diagnosis and likely precede significant Aβ deposition which is a pathological event emerging in patients’ brains of around 50 years old [48]. Different from the most popular diagram showing the events after Aβ deposition [356], this graph emphasizes possible triggering mechanisms before Aβ and tau pathology. In this hypothetic model, neuronal hyperactivity and Ca²⁺-associated chronic excitotoxicity exist well before neuronal loss, functional deficits, increased APP processing, and Aβ/tau pathology. Meanwhile, these underlying mechanisms significantly increase the risk of stroke attacks accompanied by acute excitotoxicity. Accordingly, a preventive disease-modifying intervention such as MEM treatment is necessary in the preclinical phase, which can also serve as a preconditioning therapy against stroke that strikes more than 50% of AD patients