Putting together our latest findings with those published earlier by our group and others, we propose a model where accelerated ApoE-mediated sulfatide transport in AD, a process mediated by multiple factors including Aβ, ApoE4, increased cellular debris, and/or aging, leads to early sulfatide deficiency, which in turn triggers a neuroinflammatory response that is driven by the loss of myelin sulfatide but not through classic demyelination. Here, APOE is linked to Alzheimer disease.