Abstract
Alzheimer’s disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, functional ability and behavior, but its underlying causes are to date unclear and a disease-modifying cure is still unavailable
According with its potential favorable effects, we recently demonstrated that homotaurine supplementation has a positive consequence on hippocampus atrophy and short-term episodic memory loss in individuals at the earliest clinical state of AD, namely subjects suffering from amnestic mild cognitive impairment
Patients not carrying the apolipoprotein E (APOE) ε4 allele exhibited a slight increase of the IL-18 inhibitor following the homotaurine supplementation (Figure 1, lower right panel), with values approaching the statistical significance
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, functional ability and behavior, but its underlying causes are to date unclear and a disease-modifying cure is still unavailable. As a possible therapeutic agent for AD treatment, homotaurine reduces Aβ levels in CSF of patients with mild to-moderate disease (Aisen et al, 2006), slows brain atrophy (Gauthier et al, 2009) and exerts positive effect on cognitive impairment (Saumier et al, 2009). In a phase III AD clinical trial, homotaurine does not satisfy pre-fixed primary outcomes failing to demonstrate changes in cognitive function compared to placebo, but this result is possibly confounded by high statistical variability of data and is paralleled by post hoc analyses in a subgroup of patients, revealing some protective effects on hippocampal volume loss (Aisen et al, 2011). According with its potential favorable effects, we recently demonstrated that homotaurine supplementation has a positive consequence on hippocampus atrophy and short-term episodic memory loss in individuals at the earliest clinical state of AD, namely subjects suffering from amnestic mild cognitive impairment (aMCI; Spalletta et al, 2016). Regardless the favorable disease-modifying activities of homotaurine, its therapeutic efficacy and mechanism of action have yet to be fully elucidated
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