Convergent Mechanisms and Novel Therapeutic Horizons in Neurodegenerative Diseases: A Comprehensive Review

Abstract

Neurodegenerative diseases (NDDs) represent one of the most pressing medical, social, and economic challenges of the twenty-first century. Characterized by the progressive structural and functional loss of neurons within the central and peripheral nervous systems, conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) share striking mechanistic overlaps despite their distinct clinical phenotypes. Historically categorized and managed as isolated clinical entities, recent breakthroughs in molecular biology, neuroimaging, and genetics have revealed a highly convergent pathophysiological landscape. Central to this shared pathogenesis are protein misfolding and aggregation, mitochondrial dysfunction, bioenergetic failure, chronic neuroinflammation, impairment of proteostatic networks, glutamate-mediated excitotoxicity, and non-cell-autonomous mechanisms involving glial interactions. This review provides a comprehensive synthesis of the shared molecular pathways driving neurodegeneration, contrasts these against disease-specific pathobiological profiles, evaluates the modern landscape of diagnostic fluid and imaging biomarkers, and critically analyzes the shift from symptomatic management to disease-modifying therapies. Specifically, we dissect emerging therapeutic modalities, including antisense oligonucleotides, adeno-associated virus-mediated gene therapies, monoclonal antibodies against pathological protein conformers, small-molecule modulators of neuroinflammation, and cellular reprogramming strategies. Finally, we discuss current translational hurdles—such as blood–brain barrier penetrance, patient stratification, and trial design—and propose an integrative framework for future therapeutic intervention.