The THBS4 gene encodes a glycoprotein involved in inflammatory responses and synaptogenesis. THBS4 is expressed at higher levels in the brain of humans compared with nonhuman primates, and the protein accumulates in β-amyloid plaques. We analyzed THBS4 genetic variability in humans and show that two haplotypes (hap1 and hap2) are maintained by balancing selection and modulate THBS4 expression in lymphocytes. Indeed, the balancing selection region covers a predicted transcriptional enhancer. In humans, but not in macaques and chimpanzees, THBS4 brain expression increases with age, and variants in the balancing selection region interact with sex in influencing THBS4 expression (pinteraction = 0.038), with hap1 homozygous females showing lowest expression. In Alzheimer disease (AD) patients, significant interactions between sex and THBS4 genotype were detected for peripheral gray matter (pinteraction = 0.014) and total gray matter (pinteraction = 0.012) volumes. Similarly to the gene expression results, the interaction is mainly mediated by hap1 homozygous AD females, who show reduced volumes. Thus, the balancing selection target in THBS4 is likely represented by one or more variants that regulate tissue-specific and sex-specific gene expression. The selection signature associated with THBS4 might not be related to AD pathogenesis, but rather to inflammatory responses.