Abstract: More than 95% of Alzheimer’s disease (AD) is late-onset, in which patients show clinical cognition/behavior symptoms after age 65. Unlike early-onset AD that comes with mutations in genes directly involved in amyloid metabolism (APP, PSEN), genetic predispositions associated with late-onset AD are harder to pinpoint, and their mechanistic links to AD development need further investigation. Although the development mechanism of late-onset AD remains controversial, amyloid-beta accumulation, initiated in middle age, is widely accepted as the triggering event for early AD pathology (Du Bois et al., 2010; Sterling et al., 2011). In 2018, we reported a genomic instability mouse model (Sgo1–/+) in which amyloid-beta accumulates in the brain in old age without early-onset AD mutation (Rao et al., 2018). The identification led us to anticipate that the model may reveal the development mechanism of late-onset AD. In a new study that appeared in Aging Cell (Rao et al., 2020a), we identified GSK3 inactivation in middle age as a cause for triggering the amyloid-beta accumulation. Inactivation of GSK3 appeared to affect amyloid-beta generation in two ways: (i) via increasing ARC/Arg3.1, which can generate amyloid-beta in an activity-dependent manner, and (ii) via activating canonical Wnt signaling and driving the cell cycle in the brain, thus activating the “amyloid-beta accumulation cycle” (Rao et al., 2020b). Since the Sgo1–/+ condition prolongs mitosis, during which amyloid-beta generation and accumulation is facilitated, Sgo1–/+ may be mimicking the aneuploid condition prevalent in patients with mild cognitive impairment (MCI) and AD (Potter et al., 2019). Our studies (a) support the notion of the critical roles of genomic instability and aneuploidy in AD development, (b) suggest a role of GSK3 in the onset of amyloid-beta accumulation and onset of AD pathology in middle age, and (c) suggest the usefulness of the mouse model for testing drug candidates for late-onset AD.