Frontal lobe microglia, neurodegenerative protein accumulation, and cognitive function in people with HIV

Microglia are implicated in Alzheimer’s Disease (AD) pathogenesis. In a middle-aged cohort enriched for neuroinflammation, we asked whether microgliosis was related to neocortical amyloid beta (Aβ) deposition and neuronal phosphorylated tau (p-tau), and whether microgliosis predicted cognition. Frontal lobe tissue from 191 individuals autopsied with detectable (HIV-D) and undetectable (HIV-U) HIV infection, and 63 age-matched controls were examined. Immunohistochemistry (IHC) was used to evaluate Aβ plaques and neuronal p-tau, and quantitate microgliosis with markers Iba1, CD163, and CD68 in large regions of cortex. Glia in the Aβ plaque microenvironment were quantitated by immunofluorescence (IF). The relationship of microgliosis to cognition was evaluated. No relationship between Aβ or p-tau accumulation and overall severity of microgliosis was discerned. Individuals with uncontrolled HIV had the greatest microgliosis, but fewer Aβ plaques; they also had higher prevalence of APOE ε 4 alleles, but died earlier than other groups. HIV group status was the only variable predicting microgliosis over large frontal regions. In contrast, in the Aβ plaque microenvironment, APOE ε 4 status and sex were dominant predictors of glial infiltrates, with smaller contributions of HIV status. Cognition correlated with large-scale microgliosis in HIV-D, but not HIV-U, individuals. In this autopsy cohort, over large regions of cortex, HIV status predicts microgliosis, whereas in the Aβ plaque microenvironment, traditional risk factors of AD (APOE ε 4 and sex) are stronger determinants. While microgliosis does not predict neurodegenerative protein deposition, it does predict cognition in HIV-D. Increased neuroinflammation does not initiate amyloid deposition in a younger group with enhanced genetic risk. However, once Aβ deposits are established, APOE ε 4 predicts increased plaque-associated inflammation.