On 21 January, Dr Edward Wilson and colleagues published a paper in the Journal of Alzheimer’s Disease, showing that lithium microdosing can have functional benefits in Alzheimer’s disease (AD) rats with established amyloid pathology.
Lithium is often prescribed as a mood stabiliser for people with bipolar disorder, acting via multiple mechanisms that regulate neurotransmission. Interestingly, animal studies suggest that lithium may have additional neuroprotective benefits, decreasing amyloid deposition and improving cognition in mouse models of AD. However, clinical evidence supporting a therapeutic role for lithium in AD is more nuanced; while a 2017 Danish epidemiological study linked high lithium concentrations in drinking water with a reduced incidence of dementia, a 2018 US study suggested that this difference may be due to regional socioeconomic and healthcare disparities. A further issue to consider is the risk profile of Lithium: at sustained, high doses it can cause nausea, diarrhea and muscle weakness, which can lead to discontinuation of treatment.
Against this nuanced backdrop, Dr Wilson and colleagues aimed to investigate the effect of lithium microdosing on AD pathology in preclinical models of disease. Could microdoses of lithium be equally effective in mitigating cognitive decline, without the undesirable side-effects of conventional, high-dose lithium? To answer this question, the researchers tested the effects of NPO3 on cognition, amyloid plaque pathology and neuroinflammation in a rat model of AD. NPO3 is a new formulation of lithium that has much higher bioavailability than conventional lithium formulations, and has proved to be safe in a Phase I clinical trial for Huntington’s Disease.
First, Dr Wilson and colleagues administered NPO3 to transgenic AD rats and littermate controls for a period of 12 weeks, performing working memory tests to evaluate the effect of NPO3 on cognition. AD rats treated with NPO3 performed as well as their healthy counterparts, with diminished cholinergic bouton loss compared to AD rats that did not receive NPO3. In addition, NPO3 treatment reduced levels of soluble and aggregated amyloid beta in the brains and blood plasma of AD rats, also reducing markers of oxidative stress and neuroinflammation. Together, these results suggest that NPO3 effectively crosses the blood-brain barrier in rat models of AD, with therapeutic benefits in terms of cognition and markers of AD pathology.
Link to article: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad190862