Humans are 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 called microglia. Such recognition by a Siglec called “CD33” already is known to regulate immune reactions that are important in late-onset AD risk and progression; 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 forms of Alzheimer’s. We propose a detailed structural and functional exploration of the many human variations in CD33, which may reveal other protective forms that may identify novel therapeutic approaches.