Sex-Specific Vulnerability in Neurodegenerative Disorders: Molecular Mechanisms, Biomarkers, and Preclinical Targets

Sex is one of the strongest and most consistent risk factors in neurodegenerative disease, yet the biological mechanisms behind it remain poorly understood. Women bear a disproportionate burden of Alzheimer’s disease, while other disorders such as Parkinson’s disease and amyotrophic lateral sclerosis show a male bias. These differences are not explained by lifespan alone. They point to sex-specific molecular and cellular programs — shaped by sex chromosomes, gonadal hormones, and their interaction with age and genetic risk — that influence how the brain accumulates pathology, mounts neuroinflammatory responses, and loses synaptic and neuronal integrity.

Despite growing recognition of this problem, most mechanistic studies remain underpowered to detect sex effects, and preclinical work has historically favored single-sex designs. As a result, we still lack a clear picture of how sex modulates amyloid-beta and tau pathology, microglial and astrocytic function, endolysosomal trafficking, lipid metabolism, and the genetic and epigenetic risk architecture of neurodegeneration. Closing this gap is essential for developing biomarkers and therapies that work for all patients.

This Research Topic aims to bring together original research and reviews that dissect the molecular, cellular, and systems-level basis of sex-specific vulnerability across neurodegenerative disorders. We particularly welcome studies that use in vivo preclinical models, patient-derived cell systems, and post-mortem human tissue to move beyond describing sex differences toward explaining the mechanisms that drive them.

We invite submissions addressing, but not limited to:

o Sex differences in genetic, epigenetic, and protein-level changes, including candidate biomarkers

o Hormonal and sex-chromosome contributions to disease mechanisms and progression

o Sex-specific roles of neuroinflammation, microglial function, and neuro-immune interactions

o Mechanisms of synaptic dysfunction, endolysosomal trafficking, and lipid metabolism analyzed by sex

o Identification of new targets and sex-informed preclinical therapeutic approaches

o Novel methods and models that enhance understanding of the pathways underlying sex-specific risk

o Studies using transgenic animal models or patient-derived cell-based systems that incorporate sex as a biological variable

In line with the scope of the Neurodegeneration section, contributions should provide detailed, in-depth insight into the molecular and cellular aspects of neurodegenerative disease, ideally including in vivo preclinical models. Studies limited to general cell death in cell models, stroke, purely clinical reports, or interventions that do not clarify the underlying neurodegenerative mechanisms of action fall outside the scope of this collection.

By assembling mechanistic work across disorders and model systems, this Research Topic will help establish sex as a core biological variable in neurodegeneration research and accelerate the development of biomarkers and therapies tailored to the distinct vulnerabilities of women and men.