MMFS TREATMENT AMELIORATES FRONTAL CORTEX DYSFUNCTION IN MILD-MODERATE ALZHEIMER’S DISEASE PATIENTS

Alzheimer's Disease (AD) is a synaptic dysfunction disease; synaptic loss is the best predictor of cognitive decline. Therefore, a compound that can increase synaptic density, plasticity, and function could have potential for treating AD. L-Threonic acid Magnesium salt (L-TAMS) is a compound that increases intraneuronal Mg2+at the synaptic terminal leading to improved energy supply, thereby enhancing synaptic density, plasticity, and function, particularly in the frontal cortex and hippocampus. These regions are associated with cognitive function, memory, and neuropsychiatric disorders. A previous study in human showed that oral administration of L-TAMS (clinical code: MMFS) can increase global cognitive ability in older adults with mild cognitive impairment (MCI), with large improvements in executive function. In the current study, 15 subjects with mild-moderate AD were orally administered MMFS for 2 months, and effects on cognitive abilities and neuropsychiatric symptoms were evaluated. Consistent with previous findings, MMFS treatment significantly improved global cognitive ability, evaluated by MMSE (change: +1.73 ± 2.49 SD), with most of the improvement in the executive function domain. Improvements in memory and language functions, evaluated by ADAScog and R-BANS, did not reach significance. MMFS treatment also significantly improved neuropsychiatric symptoms of depression and anxiety, measured by the Geriatric Depression Scale and Hamilton Anxiety Rating scale, respectively. Notably, improvement in MMSE significantly correlated with baseline depression (r=0.826, p<0.001) and baseline anxiety (r=0.642; p=0.018); subjects who had neuropsychiatric symptoms above the diagnostic cutoff at baseline demonstrated a greater improvement in global cognitive ability (MMSE change: +3.29 ± 1.60 SD). MMFS treatment-induced improvements in overall cognitive ability and neuropsychiatric symptoms were strongly positively correlated with change in intracellular Mg2+, supporting MMFS’ mechanism of action and indicating target engagement. Taken together, these findings suggest that 2-months MMFS treatment ameliorates frontal cortex dysfunction in mild-moderate AD, and thus provide compelling support for further clinical development of MMFS for AD treatment. In particular, AD patients with frontal dysfunction are most likely to respond to MMFS treatment.