Modeling early-onset sporadic Alzheimer’s disease using iPSC-derived neurons

Non-familial Alzheimer’s disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer’s disease (EOAD) and constitutes ~5-6% of all Alzheimer’s disease (AD) cases. While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and motor dysfunction. Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2, but have been seldom used for sporadic forms of AD that display more heterogeneous disease manifestation. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA-sequencing. A modest difference in expression profiles between EOAD patients and non-demented control subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures during the iPSC reprogramming, are not an ideal model system to study sporadic AD. iPSC Neurons: The 4 non-demented control (NDC) subject iPSC neurons and the 4 early-onset Alzheimer's disease (EOAD) patient iPSC neurons were generated from reprogrammed iPSCs, originated from skin-derived fibroblasts. All neurons were differentiated from iPSCs using SMAD inhibition in neural maintenance media and converted to NPCs by bFGF. Neurons that were pelleted down and frozen per NDC subject or EOAD patient each contained roughly 150,000-2 million cells. RNA-seq data: Biological differentiation replicates (n=3) of neurons generated from NPCs derived from human iPSCs using paired-end sequencing runs orignating from 4 NDC subjects (n=24) and 4 EOAD patients (n=24).