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’s 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.
Forte et al. (Fri,) studied this question.