Aims

In the hippocampus, new neurons are generated throughout life via a process called adult hippocampal neurogenesis (AHN). In mild cognitive impairment and Alzheimer's disease, AHN is reduced suggesting that augmenting AHN could help prevent or slow cognitive decline. We will discuss the neurogenesis hypothesis and highlight its application as a potential treatment for AD.

Methods

We have developed a small molecule drug NA-831, which activates synaptic AMPA receptors, and increases the expression of BDNF. BDNF 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.

A randomized clinical trial of NA-831 was conducted in 32 patients with MCI, who received 10 mg of NA-831 or placebo orally per day for 24 weeks, and in 24 patients with early AD, who received 30 mg of NA-831 or placebo orally per day for 24 weeks.

Results

After 24 weeks of treatment, NA-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). Similarly, NA-831 delayed cognitive decline in early AD, an average score difference of 4.1 compared 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.

Conclusions

With the clinical trial results, we will discuss the neurogenesis hypothesis and highlight its application as a potential treatment for AD.