In summary, we present evidence that mild forms of HAND are associated with decreased CSF EV Aβ42 levels and an increased CSF EV Tau/Aβ42 ratio and may relate to the risk of an aMCI/AD-related biotype of “HAND” that is not caused directly by HIV infection but is potentially impacted by HIV-associated factors such as chronic immune activation, neuroinflammation, oxidative stress, vascular disease, and ART exposure. Here, MAPT is linked to Alzheimer disease.