Rapidly Progressive Alzheimer’s Disease: Candidate Mechanisms and Diagnostic Challenges

Meiling Cao, Lumin Leng, Ping Liu, Ziqi Fan, Guoping PengDepartment of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoping Peng, Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, 1367 Wenyi West Rd, Yuhang District, Hangzhou, Zhejiang, 311121, People’s Republic of China, Email guopingpeng@zju.edu.cnAbstract: Alzheimer’s disease (AD) usually follows a slowly progressive course, but some patients experience unusually rapid cognitive and functional decline. This clinical phenotype, commonly termed rapidly progressive Alzheimer’s disease (rpAD), has no consensus definition; its status as a distinct biological entity remains unresolved, and its reported frequency depends strongly on operational criteria and referral settings. To synthesize current evidence, we conducted targeted literature searches (up to August 31, 2026) of clinical, neuropathological, and biomarker studies. This narrative review extends earlier overviews by integrating newer genetic, tau-seeding, and blood-biomarker findings with conflicting clinical evidence, while distinguishing candidate mechanisms from established diagnostic tools. Selected autopsy and biomarker studies suggest differences in amyloid-β and tau conformations, synaptic and mitochondrial proteins, neuroinflammatory responses, and concomitant pathologies; however, most data are associative, derive from small or selected cohorts, and do not establish rpAD as a discrete disease subtype. In practice, evaluation should confirm AD pathology while promptly excluding treatable causes and rapidly progressive mimics, particularly Creutzfeldt-Jakob disease (CJD), using established tools such as cerebrospinal fluid biomarkers, MRI, and PrP RT-QuIC. Cerebrospinal fluid, molecular imaging, structural MRI, and emerging blood biomarkers can provide supportive evidence, but no biomarker profile has been prospectively validated as an rpAD-specific diagnostic rule. Harmonized definitions and prospective, biomarker-stratified multicenter validation are required before candidate mechanisms or biomarkers can guide rpAD-specific interventions.Keywords: rapidly progressive alzheimer’s disease, rapidly progressive dementia, prion-like mechanisms, tau conformers, Aβ seeding