Activation of PPARs also yielded conflicting data in rodent models of Alzheimer's disease and in human subjects. For example, in some, but not all studies, PPAR activation reduced amyloid deposition and reversed cognitive and memory decline (Yan et al., 2003; Pedersen and Flynn, 2004; Heneka et al., 2005; Nicolakakis et al., 2008; Escribano et al., 2010; Toledo and Inestrosa, 2010; Mandrekar-Colucci et al., 2012). The inconsistencies in the reported data may be due to use of different animal models of Alzheimer's disease, poor blood–brain barrier penetrance of PPAR agonists (i.e. inconsistent drug distribution) and widely variable dosing strategies (Maeshiba et al., 1997; Hemauer et al., 2010). Phase III clinical trials testing another PPARγ agonist, rosiglitazone, failed to show efficacy in patients with mild to moderate stages of Alzheimer's disease; however, the doses used in clinical trials were significantly lower than those shown to be beneficial in the rodent models (Gold et al., 2010).
