Rapidly Progressive Alzheimer Disease and Related Dementias as a Phase Transition: Symptom Cascades and Survival Inflection.

Abstract (English)

BACKGROUND AND OBJECTIVES: Rapidly progressive Alzheimer disease and related dementias (rpADRD) is a clinically urgent syndrome characterized by accelerated deterioration. Because it is often confounded by acute etiologies, its definition remains poorly characterized. We aimed to evaluate rpADRD as a distinct clinical state, testing the hypothesis that it represents a clinical "phase transition" rather than a simple linear acceleration of typical neurodegenerative decline. Our objective was to define this transition threshold and quantify its impact on survival and disease trajectory. METHODS: We conducted a retrospective cohort study using longitudinal data from participants recruited across US Alzheimer's Disease Research Centers. We defined incident rpADRD as dementia development (global Clinical Dementia Rating [CDR] ≥1) within 1 year of symptom onset, or progression to moderate-to-severe impairment (global CDR ≥2) within 2 years. To isolate primary neurodegeneration, we excluded prion, infectious, metabolic, toxic, and autoimmune etiologies. We used time-dependent Cox regression, multistate modeling, and restricted cubic spline analyses to model nonlinear survival dynamics. RESULTS: The final analysis cohort included 2,307 participants (mean baseline age 78.9 years; 57.1% female). Over a mean follow-up of 7.3 years, 270 patients (11.7%) developed incident rpADRD. Patients transitioning to rpADRD were older than non-rpADRD patients (mean 80.0 vs 78.8 years). Crucially, the transition to rpADRD was strongly associated with increased subsequent mortality (hazard ratio = 4.03; 95% CI 3.53-4.61, <i>p</i> < 0.001). Multistate and spline modeling confirmed that this shift represents a distinct, nonlinear clinical phase transition rather than a linear exacerbation of functional decline. Furthermore, this critical tipping point was reliably preceded by an early cascade of neuropsychiatric symptoms. DISCUSSION: These findings validate a clinical "phase transition" model for rpADRD, demonstrating that survival decline is not merely a linear function of disease severity. Rather, rpADRD constitutes a distinct state of clinical homeostatic failure fundamentally shifting subsequent mortality risk, often predicted by early neuropsychiatric symptoms. Recognizing this nonlinear shift is vital for accurate prognostication and segregation of rapidly progressing phenotypes in trials. Major limitations include reliance on observational data, potential recall bias regarding symptom onset, and the exclusion of neuroimaging and fluid biomarkers because of high missingness.