Rapid Decline displayed the most severe clinical and pathological profile, with early dementia onset and severe AD pathology—including β-amyloid, tau, TDP-43, CAA, atherosclerosis, hippocampal sclerosis, and Lewy bodies—alongside broad molecular disruption (e.g., epigenetic dysregulation, oxidative stress, glial activation, blood–brain barrier dysfunction, white matter degeneration), and multifactorial time-varying risk driven by APOEε4, frailty, and vascular factors. The gene discussed is TARDBP; the disease is Alzheimer disease.