Post-Covid Alzheimer and Its Remediation via PROTACs Therapy: A Comprehensive Review.

BACKGROUND AND AIMS: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of aging characterized by memory loss and cognitive decline, associated with amyloid-β toxicity, tau hyperphosphorylation, and neurofibrillary tangle formation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the central nervous system and has been linked to neurological manifestations and accelerated neurodegeneration, including in individuals without pre-existing AD. Emerging evidence suggests COVID-19 may increase levels of hyperphosphorylated tau, potentially worsening AD severity. This review synthesizes current knowledge on COVID-19-AD interactions and evaluates proteolysis-targeting chimeras (PROTACs) as an emerging therapeutic strategy. METHODS: Narrative synthesis of recent literature on SARS-CoV-2-related neuropathology, tau pathology in AD, and the design and preclinical development of PROTACs targeting disease-relevant proteins via the ubiquitin-proteasome system. RESULTS: Reports indicate COVID-19 can precipitate or exacerbate neurodegenerative processes and is associated with increased tau phosphorylation and other biomarkers of neuronal injury. Conventional AD therapies remain limited in efficacy. PROTACs-heterobifunctional molecules that recruit target proteins to E3 ligases for proteasomal degradation-do not require classical active-site binding and have demonstrated preclinical potential for degrading pathogenic proteins, supporting their exploration against tau-driven pathology in AD. CONCLUSIONS: COVID-19 may intensify AD pathogenesis through mechanisms that include tau hyperphosphorylation, underscoring the need for targeted interventions. PROTACs offer a mechanistically distinct, protein-degradation-based approach with promise for modifying tau-mediated disease; rigorous preclinical and clinical studies are warranted to establish feasibility, safety, and therapeutic impact in AD.