Sex- and region-dependent neuroinflammation in Alzheimer's disease

INTRODUCTION: Despite known sex differences in immune function and Alzheimer's disease (AD), most studies of neuroinflammation in AD have not been analyzed by sex. METHODS: We performed quantitative in vitro autoradiography of hippocampus, entorhinal cortex, and parietal cortex using [³H]-PK1195 and [¹⁸F]-T807. Proinflammatory microRNA (miRNA) expression in parietal cortex was measured by quantitative polymerase chain reaction (qPCR). RESULTS: We found significant, region-dependent elevations of translocator protein (TSPO) density in AD relative to cognitively normal (CN) and mild cognitive impairment (MCI) in women but not men. Density of tau was increased in AD relative to CN and MCI in both sexes, but only women showed a significant positive correlation between tau and TSPO density. The expression of proinflammatory miRNAs was also significantly increased in AD versus CN or MCI women but not men. DISCUSSION: Women are more susceptible than men to AD/tau-related neuroinflammation, supporting a sex-specific re-examination of the effects of neuroinflammation-targeting interventions in AD. Highlights: We show that neuroinflammation in Alzheimer's disease (AD) is modulated by sex in a region-specific manner. Neuroinflammation was highest in the subiculum and significant only in women. Inflammatory microRNAs (miRNAs) increased in the parietal cortex of women, but not men, with AD. Deposition of tau was highest in the entorhinal cortex and significant in both sexes. Density of tau and TSPO was positively and significantly correlated only in AD women.