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Alzheimer’s disease (AD) manifested before 65 years of age is commonly referred to as early-onset AD (EOAD)[1]. Significant research on EOAD has focused on autosomal-dominant familial mutations in PSEN1, PSEN2, and APP; however, these mutations only represent 5–10% of EOAD cases. Although EOAD has a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%), which is polygenic, EOAD may be due to autosomal recessive inheritance or combinatorial polygenic risk [2, 3]. Even though the endpoint clinicopathological changes, ie, Aβ plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous [4]. The heterogeneity, leading to temporally distinct age of onset (AOO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes [5–7]. Further, analyses of large cohorts of postmortem brains demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling [4]. Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected, and therefore may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology [8]. To this end, we analyzed AD patient samples …