Targeting Neuroinflammation in Alzheimer's Disease: Repurposed Nucleoside Reverse Transcriptase Inhibitors and the Therapeutic Potential of Kamuvudine-9

Abstract

Alzheimer's disease (AD) is a progressive neurological illness that causes cognitive deterioration. Current medications only help with the symptoms to a limited extent. Over the past decade, nucleoside reverse transcriptase inhibitors (NRTIs), historically used as antiretrovirals, have appeared as surprising contenders for modifying AD. Aside from their antiviral activity, NRTIs have immunomodulatory actions, such as inhibiting the NLRP3 inflammasome, lowering amyloid and tau pathology and modulating neuroinflammation. A second-generation analogue, Kamuvudine-9, has been designed to balance these neuroprotective advantages with reduced mitochondrial toxicity and off-target antiviral effects, offering a safer long-term solution for chronic neurodegenerative disorders. This review synthesises mechanistic data, preclinical data, observational studies and new clinical findings to make a unified case for NRTIs and K-9 as multitarget therapeutic compounds in AD. By emphasising their dual mechanism, retroelement inhibition and inflammasome blockade coupled with innovation in drug delivery and pharmacogenomics, we highlight how repurposing this class would remake the therapeutic landscape. In contrast to amyloid-directed interventions, NRTIs and K-9 act on converging inflammatory and genetic mechanisms that mediate both amyloid and tau pathology, making them universal modulators of disease course. Prospects for future advances in precision medicine, nanocarrier delivery and large-scale validation of interventions may reveal a new generation of accessible, disease-modifying treatments for AD.