AbstractBackgroundDementias such as Alzheimer’s disease are characterized as neurodegenerative diseases. While researchers accept that the etiology of dementia involves multiple cell types, the use of “neuro” as a prefix to “degeneration” biases our mechanistic thinking towards the nerve cell. The cell type that has been most marginalized by this bias is the oligodendrocyte and its myelin ensheathment of the larger axons of the brain. As early as the 1960’s the involvement of myelin pathology had been recognized in the Alzheimer’s disease (AD) brain. Later, with advances in imaging technology, a strong argument was advanced for the mechanistic involvement of myelin, a cholesterol rich membrane, in the etiology of dementia.MethodFixed frozen human prefrontal cortex (BA9), hippocampus, and cerebellum were received from both the University of Pittsburgh ADRC and the NIH‐sponsored NeuroBioBank. Mouse brain from wild type and AD models (R1.40 and APP/PS1) were also obtained. Cryostat sections were immunostained for APP and various myelin‐related peptides.ResultThis myelin hypothesis will be reviewed and put in the AD context by summarizing recent results on the impact of APOE, a cholesterol carrier and a major risk factor gene for sporadic AD, on the cells of the oligodendrocyte lineage. Observations on the presence of APP and its processing secretases in oligodendrocytes will deepen the connection to the etiology of ADConclusionBoth past and present data support the assignment of an important role for oligodendrocytes in the initiation and progression of Alzheimer’s disease. Broadening our current “neurocentric” view will speed progress towards meaningful therapeutic approaches.