Abstract: Alzheimer’s disease (AD), the most common form of neurodegeneration, is characterized by selective neuronal vulnerability and brain regionselective neuron demise. The entorhinal cortex and hippocampal CA1 projection neurons are at greater risk in AD whereas other regions display resistance to neurodegeneration. Interestingly, the cerebellum, a phylogenetically very old region, is affected only very late in the disease progression. Although AD has been investigated intensively for decades, the detailed causes of the observed selective neurodegeneration and the exact diseasedetermining factors remain enigmatic in larger parts. The fact that many elderly do show ADassociated neuropathological substrates, including amyloid plaques and neurofibrillary tangles, but display largely unimpaired cognitive functions suggests that the brain of some individuals shows effective adaptation and resistance to potentially challenging conditions (Zhang et al., 2023). In different neurodegenerative disorders, undiscovered resilience factors, and adaptive or stress-responsive mechanisms must exist and can maintain neuronal survival and functions. Uncovering such resistance factors and pathways could act as a blueprint to develop novel strategies for disease treatment and prevention. Multiomicstechnologies have been applied disclosing differential gene expressions and functions when disease-affected and disease-resistant brain areas are comparatively studied. An alternative approach to identify mediators of resistance is to mimic disease-relevant stress conditions in in vitro systems, for instance, via the generation of neuronal cell clones that are selected for partial or full resistance against disease-relevant challenges.