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Background  Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer’s disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD.    Methods  We have applied a newly developed protocol for deriving human basal forebrain cholinergic neurons (BFCN) from skin fibroblasts via induced pluripotent stem cell (iPSC) technology. We generated wildtype and familial AD mutant  PSEN2   N141I   (presenilin 2) BFCNs and assessed if insulin signaling, insulin regulation of the major AD proteins Aβ and/or tau, and/or calcium fluxes is altered by the  PSEN2   N141I   mutation.    Results  We report herein that wildtype,  PSEN2   N141I   and CRISPR/Cas9-corrected iPSC-derived BFCNs (and their precursors) show indistinguishable insulin signaling profiles as determined by the phosphorylation of canonical insulin signaling pathway molecules. Chronic insulin treatment of BFCNs of all genotypes led to a reduction in the Aβ42/40 ratio. Unexpectedly, we found a CRISPR/Cas9-correctable effect of  PSEN2   N141I   on calcium flux, which could be prevented by chronic exposure of BFCNs to insulin.    Conclusions  Our studies indicate that the familial AD mutation  PSEN2   N141I   does not induce neuronal insulin resistance in a cell autonomous fashion. The ability of insulin to correct calcium fluxes and to lower Aβ42/40 ratio suggests that insulin acts to oppose an AD-pathophysiology. Hence, our results are consistent with a potential physiological role for insulin as a mediator of resilience by counteracting specific metabolic and molecular features of AD.    Electronic supplementary material  The online version of this article (10.1186/s13024-018-0265-5) contains supplementary material, which is available to authorized users.

iPSC-derived familial Alzheimer’s PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling