3rd Edition of Dementia World Conference 2026

Abstract

Alzheimer's disease (AD) is increasingly linked to metabolic failure and the depletion of Nicotinamide Adenine Dinucleotide (NAD), which is important for DNA repair and mitochondrial health. Current research explores two main NAD+ therapies, which are supplementing with precursors like Nicotinamide Riboside (NR) or directly restoring cellular homeostasis by activating salvage enzymes like NAMPT. This review compares these approaches' abilities to reverse advanced pathology and restore synaptic integrity. Methods: PubMed and ScienceDirect was searched for studies investigating NAD+ modulation in Alzheimer’s disease. Five recent primary studies (2018–2026), utilizing various mouse models of AD (such as APP/PS1, 5xFAD, and P301S) were selected. Results: Studies on NR supplementation consistently showed reduced neuroinflammation via the cGAS-STING pathway and decreased ABeta accumulation, leading to improved memory in early-to-mid stage AD models. In contrast, direct NAD+ homeostasis restoration via NAMPT activation (P7C3-A20) demonstrated a unique capacity to "reverse" advanced disease, including the normalization of p-tau217 levels and the repair of blood-brain barrier deterioration. Furthermore, targeting the NAMPT-NAD+-SIRT1/3 axis was found essential for restoring mitophagy, which is often impaired in AD. Evidence shows that successful metabolic restoration correlates with the physical recovery of "mushroom" spine density and synaptic strengthening. Conclusion: Both strategies provide significant neuroprotection, but direct restoration of NAD+ homeostasis through enzymatic activation may offer superior efficacy in reversing advanced, late-stage AD compared to precursor supplementation alone. While NR effectively reduces inflammatory markers and ABeta load, the restoration of internal NAD+ salvage mechanisms is important for reversing established tau pathology and restoring mitochondrial clearance. Future human trials should prioritize NAMPT activation as a potential reversal therapy for advanced dementia. Keywords: Alzheimer’s Disease, NAD+ homeostasis, Nicotinamide Riboside, NAMPT Activation