SORL1‐retromer regulates endosomal recycling and helps explain Alzheimer’s regional vulnerability

The importance of the endosomal recycling pathway for cellular health was recognized ever since its reverse trafficking itinerary, clathrin‐dependent endocytosis, was described. Vital for synaptic function, a recent study found that neurons are endowed with a distinct unit dedicated to the recycling pathway. Akin to how endocytosis is regulated by a functional unit formed by the clathrin coat interacting with low‐density lipoprotein‐related receptors (LDLRs), recent studies will be reviewed suggesting that endosomal recycling in neurons is regulated by a functional unit comprised of a neuronal‐enriched retromer coat that interacts with the sortilin‐related receptor SORL1. Genetic studies suggest that rare truncating mutations in SORL1, inducing SORL1 haploinsuffiency, acts a causal event in triggering Alzheimer’s disease (AD). In agreement with this interpretation, recent studies will be reviewed showing that SORL1 haploinsufficiency can trigger AD’s cardinal pathologies, including showing in mice that it leads to selective atrophy in the trans‐entorhinal cortex. These studies suggest that SORL1‐retromer recycling is a causal pathway in AD that when disrupted can trigger AD’s molecular, cellular, and anatomical pathologies. When interpreted together with a collection of other studies this recent insight suggests why the trans‐entohrinal cortex is so dependent on SORL1‐retromer recycling, why the trans‐entorhinal cortex is differentially vulnerable even to ‘sporadic’ AD, and why AD anatomically ‘spreads’ over time.