The first kinase inhibitors tested in clinical trials targeted GSK3β, a serine/threonine kinase involved in a wide range of cellular processes including differentiation, growth, motility, and apoptosis, [44] known to be dysregulated in Alzheimer’s disease [45]. Lithium, a small molecule that is FDA-approved as a mood stabilizer, was found to reduce tau hyperphosphorylation and aggregation in P301L transgenic mice via a mechanism that was dependent on GSK3β inhibition [46]. These data led to national and international Phase 2 trials in AD, but after 10 weeks of treatment with lithium, no effect was found on cognition, mood, or CSF biomarkers (pTau or Aβ) [47]. In a later trial in patients with PSP or CBS, lithium was poorly tolerated, and only one patient was able to complete 28 weeks of treatment (NCT00703677).
