Sex-specific APOE4-dependent innate immunity regulates meningeal lymphatics, brain lipids, neuroinflammation, and cognition
Publication date: 26/03/2026
Authors: Delivanoglou N, Todd KT, Almeida F, Rego S, Changavi A, Spajer M, Ayuso VE, Pinho-Correia LM, Sanchez G, das Neves SP, Barber MJ, Schrader R, Sacilotto P, Martens YA, Heckman MG, Bu G, Tanzi RE, Thoma
Journal: Neuron
Commentary: The study provides a compelling investigation into the mechanisms underlying the sex-specific effects of the APOE4 allele on Alzheimer’s disease risk. The authors show that APOE4 drives sexually dimorphic innate immune and lymphatic responses, identifying the meningeal lymphatic system as a critical, sex-dependent hub in disease pathogenesis.
To address this question, the authors used humanized male and female mice expressing APOE4 (E4/E4) and combined longitudinal in vivo imaging of cerebrospinal fluid drainage with flow cytometry and dural single-cell RNA sequencing to characterize the immunological profile and lymphatic changes over time.
Their findings reveal marked sex-specific differences in immune activation and meningeal lymphatic function. While young E4/E4 mice (2-4 months old) maintain a homeostatic state, middle-aged mice (11-13 months old) develop progressive dysfunction characterized by altered CSF clearance and chronic dural immune activation. Specifically, the pharmacological inhibition of the innate immunity through CSF1R inhibition produced different outcomes between both sexes: E4/E4 females showed neuroprotection and improved cognitive performance, whereas E4/E4 males experienced accelerated cognitive decline. APOE4 expression also induced distinct patterns of immune activation in the brain-draining cervical lymph nodes, further highlighting sex-dependent differences in the peripheral immune response. These findings were validated through the integration of human brain snRNA-seq data from six independent cohorts, confirming that the sexually dimorphic leukocyte activation patterns observed in murine models are conserved in patients with AD.
Collectively, the data highlight the need to consider the meningeal dura as a critical, sex-specific hub for APOE4-related disease and underscore the importance of incorporating biological sex into the development of therapeutic strategies. These findings provide a strong rationale for future studies aimed at designing sex-tailored immunotherapies to mitigate APOE4-driven cognitive decline.
Commented by: Ester Licastro
DOI: https://doi.org/10.1016/j.neuron.2026.02.030
