Endocytic scaffolds at the crossroads of Alzheimer’s disease and neuronal aging

More than a century after Alois Alzheimer's neuropathological description, the mechanisms driving Alzheimer's disease (AD) remain only partially understood, and the failure of most clinical trials underscores the need to identify and target alternative pathogenic pathways. Recent genetic, biochemical, and cellular studies support the view that AD is characterized by early alterations in the endolysosomal system and implicate multiple endocytic scaffold proteins as key drivers of AD progression. In this review, we summarize the current knowledge of five endocytic scaffold proteins, CALM, AP-2, BIN1, CD2AP, and ITSN1, which have been identified as AD risk factors by genome-wide association studies. We describe how, under physiological conditions, they couple membrane remodeling to intracellular signaling, whereas in AD they influence amyloid precursor protein trafficking, amyloid-β (Aβ) generation, tau pathology, and synaptic integrity. Finally, we propose a model in which cell type-specific and age-dependent dysfunction of endocytic scaffolds defines a pathogenic hotspot of proteostasis failure and offers new entry points for therapeutic intervention.