We humans are very unusual in being capable of a prolonged post-reproductive life span, a life period associated with susceptibility to late-onset Alzheimer’s disease. Human brains are rich in molecules called sialic acids, which are recognized by certain receptors (called “Siglecs”) on brain immune cells (microglia). Such recognition by a Siglec called CD33 already is known to regulate immune reactions that are important in disease risk and progression, and we have shown that humans have newly evolved a protective form of this receptor. The same receptor also is exploited by important human pathogens that affect younger humans and may have resulted in wide variations in human CD33 function. This, in turn, could have affected changes in neuroinflammation in late-onset AD. We are working on a detailed structural and functional exploration of the many human variations in CD33, which may reveal other protective forms––perhaps suggesting novel therapeutic approaches.