{"doi":"10.3389/fmolb.2025.1727385","title":"Editorial: Estrogens and neurodegeneration: a link between menopause and Alzheimer’s disease in women","abstract":"Alzheimer's disease (AD) remains one of the most pressing public health challenges of our time.One of its most striking, yet historically underexplored, features is its disproportionate impact on women. Nearly two-thirds of all AD cases occur in women. While women do live longer on average, longevity alone does not explain this gap. Increasing evidence support that the biological changes during the menopause transition represents a neurological turning point that may accelerate the trajectory of brain aging in women. Understanding why women are disproportionately affected by AD has therefore become a critical challenge in neuroscience and aging research. This Research Topic explores menopause, and the hormonal upheaval that accompanies it, as a critical inflection point in neurodegeneration and highlights emerging mechanisms and therapeutic strategies that reflect the complexity of the female brain across the lifespan. For decades, estrogen has been recognized as a key neuroprotective hormone. It maintains synaptic integrity, supports mitochondrial function, regulates cerebral blood flow, and modulates neuroinflammation (Galea, Frick et al. 2017). However, the field has often viewed menopause through the narrow lens of \"estrogen loss,\" as if it were a single hormonal event. In reality, menopause triggers a cascade of hormonal shifts -including endocrine, metabolic, vascular, and neurological changes -and only now are we beginning to understand how these changes might interact to influence neurodegenerative processes. The articles in this collection move the field beyond estrogen alone and toward a more integrated understanding of endocrine aging in women. Mervosh and Devi (Mervosh and Devi 2025)revisit the role of hormonal changes at menopause with renewed depth. They emphasize both classical genomic estrogen receptor signalling and rapid, nongenomic actions that influence cognitive resilience. Importantly, they situate estrogen within a network of interacting risk factors-including APOE genotype and cardiovascular healthhighlighting why hormone therapy (HT) has shown heterogeneous results across studies. Rather than asking \"Does HT work?\", their review reframes the conversation: When, how, and for whom does HT provide benefit? This perspective reinforces the \"critical window hypothesis,\" which proposes that HT is most effective when initiated near the onset of menopause, before extensive neural aging or pathology occur (Maki 2013). However, estrogen is only one part of the overall picture. Xue and colleagues draw attention to follicle-stimulating hormone (FSH), which rises dramatically during menopause, and may itself have direct pathological effects on the brain (Xue, Zuo et al. 2025). Their review links elevated FSH levels to key AD-related pathological mechanisms, including neuroinflammation, metabolic dysfunction, vascular changes, and amyloid pathology. By proposing FSH as an active driver of neurodegeneration and a potential therapeutic target, they expand the field's view of menopause from simple estrogen deficiency to the broader endocrine shifts that characterize midlife in women.Building on this expanded endocrine perspective, Lizcano and colleagues introduce an innovative therapeutic concept: combining estrogens with GLP-1 receptor agonists (Lizcano, Sanabria et al. 2025). Traditionally used in metabolic disorders like type 2 diabetes, GLP-1 agonists are now emerging as neuroprotective agents for neurodegenerative disorders like AD and Parkinson's disease (Hölscher 2024). The authors argue that combined use of GLP-1 agonists with estrogenic compounds may offer a dual-action benefit, simultaneously targeting mitochondrial dysfunction, oxidative stress, and insulin signalling deficits. This synergy is particularly relevant in postmenopausal women, who often experience simultaneous endocrine and metabolic shifts that contribute to neurodegenerative risk.Complementing these conceptual advances are a series of empirical","journal":"Frontiers in Molecular Biosciences","year":2025,"id":580356,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1491182,"name":"Andrea Bertolini","orcid":"0000-0001-7020-4824","position":1,"is_corresponding":false},{"id":1491183,"name":"Mario Dı́az","orcid":"0000-0001-5692-8906","position":2,"is_corresponding":false},{"id":871322,"name":"Roberta Marongiu","orcid":"0000-0002-7609-7000","position":3,"is_corresponding":false},{"id":262779,"name":"Manuela Leri","orcid":"0000-0002-3785-0805","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:58:38.868285Z","pmid":"41280324","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}