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• Abscisic Acid (ABA) treatment can effectively prevent memory impairment in a murine model of Alzheimer disease (AD). • ABA treatment can prevent microglia transition to inflammatory state in transgenic model of AD. • The beneficial effects of ABA, PPARᵧ agonist and an insulin sensitizer in the central nervous system are independent of peripheral insulin resistance. • Further studies will establish whether later intervention (when the disease may be in initial stages), but longer treatments can guarantee better rescue of memory impairment. Neuroinflammation and insulin resistance in the brain are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Even though traditionally Alzheimer´s disease has been associated to Aβ deposits and hyperphosphorylated Tau intracellular tangles, several studies show that neuroinflammation may be the initial cause that triggers degeneration. Accordingly, a number of natural supplements that improves brain insulin sensitivity and reduce neuroinflammation have been proposed as good choices in the therapeutic prevention of cognitive decline. Further supporting this evidence, we show that phytohormone Abscisic Acid, can prevent memory impairment and neuroinflammation markers in a triple transgenic mouse model, where no peripheral inflammatory changes have occurred. Moreover, our data strongly suggests that early intervention is critical for good prognosis, and that cognitive improvement requires longer treatment than recovering neuroinflammation markers. [ABSTRACT FROM AUTHOR]