PROPOSING THE NEUROGENESIS HYPOTHESIS FOR ALZHEIMER’S DISEASEWITH A CASE STUDY‐ PHASE 2 CLINICAL TRIALS OF NA‐831

Abstract

AbstractBackgroundIn the hippocampus, new neurons are generated throughout life via a process called adult hippocampal neurogenesis (AHN). In mild cognitive impairment (MCI) and mild to moderate AD (early AD), AHN is reduced suggesting that AHN impairment compromises hippocampal functions. Augmenting AHN could help prevent or slow cognitive decline in MCI and early AD. The neurogenesis hypothesis is supported by the results of a Phase 2 randomized, double‐blind, placebo controlled clinical trial of NA‐831.MethodNA‐831 is a small drug molecule, which activates synaptic AMPA receptors, and increases the expression of brain derived neurotrophic factor (BDNF), which is crucial in synaptic plasticity, learning and memory formation in the hippocampus. NA‐831 restores neurogenesis by increasing the number of DCX+PCNA+ neuroblast cells. The study was conducted in 56 patients with MCI, mild and moderate Alzheimer’s disease, who received 10mg to 30 mg of NA‐831 or placebo orally per day for 24 weeks.ResultNA‐831 provided a significant delay in cognitive decline in MCI as measured by ADAS‐Cog‐13, an average score difference of 3.4 compared to placebo (p = 0.01; ITT) after 24 weeks of treatment. Similarly, NA‐831 delayed cognitive decline in early AD, an average score difference of 4.1 com‐pared to placebo (p = 0.001; ITT). CIBIC‐Plus showed 78% of the study participants receiving NA‐831 improved (p = 0.01; ITT). NA‐831 was well‐tolerated at 30 mg/day for 24 weeks, and no serious adverse events were observed.ConclusionThe Neurogenesis Hypothesis, and details of the Phase 2 clinical trials will be presented and discussed.