Recent decades have produced numerous findings challenging the amyloid cascade hypothesis of AD, leading to a widely accepted view that the etiology of AD is multifactorial. Despite this consensus, ongoing attempts have sought to unify AD’s causal basis within broader explanatory frameworks. A leading candidate has been the connectome hypothesis, which invokes degenerative mechanisms selective for brain synapses. This hypothesis has itself been challenged by findings showing selective default mode network (DMN) vulnerability in AD, seen in altered functional connectivity metrics obtained years and even decades before the appearance of clinical symptoms. More recent proposals have sought to introduce functional notions that are closely aligned with clinical symptoms and are based on the known homeostatic tendency to preserve brain functional integrity. Homeostatic mechanisms are known to involve a plethora of processes that are operative at multiple levels, from molecular and cellular domains to circuit and network operation. Among these, DMN homeostasis is notable for contributing to global functional representations and sustaining autopoiesis (self-maintenance), which promotes dynamic interactions with a variable world. Emerging findings from AD pathophysiology, seen in sleep disturbances and memory related dysfunctions, suggest that higher order, DMN homeostasis may be affected in AD, which could offer a broader causal framework illuminating the interdependence of varied molecular instigators, cellular and circuit disruptors, and systemic failures.