Reddi_2025_ACS.Omega_10_5148

Alzheimer's disease (AD) is an aging-related irreversible neurodegenerative disease affecting mostly the elderly population. The main pathological features of AD are the extracellular Abeta plaques generated by APP cleavage through the amyloidogenic pathway, the intracellular neurofibrillary tangles (NFT) resulting from the hyperphosphorylated tau proteins, and cholinergic neurodegeneration. However, the actual causes of AD are unknown, but several studies suggest hereditary mutations in PSEN1 and -2, APOE4, APP, and the TAU genes are the major perpetrators. In order to understand the etiology and pathogenesis of AD, various hypotheses are proposed. These include the following hypotheses: amyloid accumulation, tauopathy, inflammation, oxidative stress, mitochondrial dysfunction, glutamate/excitotoxicity, cholinergic deficiency, and gut dysbiosis. Currently approved therapeutic interventions are donepezil, galantamine, and rivastigmine, which are cholinesterase inhibitors (ChEIs), and memantine, which is an N-methyl-d-aspartate (NMDA) antagonist. These treatment strategies focus on only symptomatic management of AD by attenuating symptoms but not regeneration of neurons or clearance of Abeta plaques and hyperphosphorylated Tau. This review focuses on the pathophysiology, novel therapeutic targets, and disease-altering treatments such as alpha-secretase modulators, active immunotherapy, passive immunotherapy, natural antioxidant products, nanomaterials, antiamyloid therapy, tau aggregation inhibitors, transplantation of fecal microbiota or stem cells, and microtubule stabilizers that are in clinical trials or still under investigation.