{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:00:13Z","timestamp":1791342013238,"version":"4.3.1"},"reference-count":65,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN 2022\u2014CUP","award":["B53D23014710006."],"award-info":[{"award-number":["B53D23014710006."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NeuroSci"],"abstract":"<jats:p>Recent advances in neurodegenerative disease research increasingly support the existence of multiple trajectory signatures underlying the heterogeneity of cognitive decline syndromes. Originally proposed in Parkinson\u2019s disease, the brain-first and body-first models have emerged as conceptual frameworks to explain variability in disease onset, prodromal features, and progression across dementia-related disorders. Brain-first phenotypes are defined by the early emergence of central nervous system pathology and cognitive symptoms, whereas body-first phenotypes are characterized by prominent peripheral or autonomic dysfunctions that precede central involvement. Within this perspective, neurodegeneration is not viewed as a uniform, brain-restricted process, but a dynamic interaction between central, peripheral, and network-level mechanisms. Integrating central and peripheral biomarkers, autonomic physiology, and alterations in functional connectivity provides a coherent framework for interpreting phenotypic heterogeneity and prodromal dysregulation across dementia syndromes. Current evidence supporting brain-first and body-first trajectories is largely associative, and their clinical translation requires rigorous validation. Accordingly, this narrative perspective review aims to provide a critical and integrative conceptual framework that synthesizes existing evidence, identifies unresolved questions, and outlines research priorities for trajectory-based stratification, rather than offering a definitive diagnostic classification or pharmacological evaluation. The present work adopts a conceptual and mechanistic perspective rather than a clinically prescriptive or trial-oriented one. Its aim is to articulate a generative framework capable of producing testable hypotheses about disease trajectories and biomarker constellations across neurodegenerative syndromes.<\/jats:p>","DOI":"10.3390\/neurosci7030057","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:11:13Z","timestamp":1778271073000},"page":"57","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Brain-First vs. Body-First Models in Neurodegenerative Disease: A Perspective Review"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5223-041X","authenticated-orcid":false,"given":"Giuseppe","family":"Forte","sequence":"first","affiliation":[{"name":"Department of Dynamic, Clinical Psychology and Health Studies, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4430-3367","authenticated-orcid":false,"given":"Maria","family":"Casagrande","sequence":"additional","affiliation":[{"name":"Department of Dynamic, Clinical Psychology and Health Studies, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13195-020-00612-7","article-title":"Imaging biomarkers in neurodegeneration: Current and future practices","volume":"12","author":"Young","year":"2020","journal-title":"Alzheimer\u2019s Res. 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