Old age is the dominating risk factor for Alzheimer’s Disease (AD), which exclusively affects people at older ages. Sporadic AD represents the overwhelming majority of all cases, but most research on AD has been performed on genetic causes and their directly related pathways, also because we lacked models that can reflect complex human genetics and age in a neuronal context. 
Patient-specific iPSC models represent an attractive solution, but iPSC reprogramming results in cellular rejuvenation and thus yields phenotypically young neurons mirroring fetal development. By contrast, direct conversion of old patient fibroblasts into induced neurons (iNs) preserves endogenous signatures of aging and produces neurons that resemble the adult human brain on an epigenome- and transcriptome-wide scale. To control for the involvement of aging in AD, we generated age-equivalent fibroblast-derived iNs and rejuvenated iPSC-derived neurons from a cohort of AD patients and controls. Patient-derived AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, glycolytic reprogramming, and de-differentiation, which share similarities with malignant cancer transformation and age-dependent epigenetic erosion. We identified an isoform switch of pyruvate kinase M (PKM) to the PKM2 isoform as a trigger of a Warburg effect-like metabolic switch, and further as a key transcriptional regulator leading to cell fate instability. Using iNs from a variety of donors on the spectrum from healthy aging, to mild cognitive impairment (MCI), and AD, we currently seek to understand the early mechanisms that lead to these disease changes to identify means to preserve a mature and resilient neuronal state during aging. 
In summary, age-equivalent adult-like iNs from patients are a useful model to study age-dependent pathological signatures of AD. This iN model identifies AD-related neuronal changes as part of an active cellular program that impairs neuronal fate and resilience.