Future directions in animal models of Alzheimer’s disease

The number of individuals affected with Alzheimer’s disease (AD) has increased substantially as the size and proportion of our population over 65 continues to increase. Approximately 6.08 million Americans had either clinical AD or mild cognitive impairment in 2017, and this number could grow to 15 million by 2060 (Alzheimer’s Association, 2017; Brookmeyer et al., 2018). Several promising drugs failed to show clinical benefit in completed trials, including recently solanezumab. Solanezumab showed potential results in transgenic mice but was unsuccessful in several clinical trials, including the new published double-blind placebo-controlled phase 3 trial (Honig et al., 2018). The failure of clinical trials for AD treatments also recently led Pfizer to announce the downsizing of its AD program (Anon, 2018).

These disappointments have resulted in a critical evaluation of the value of relying only on rodent models of AD before transitioning to human clinical trials that cost hundreds of millions of dollars. Transgenic mouse models are based largely on the expression of specific genes with identified mutations, including APP, PSEN1 or PSEN2. Mutations in these genes correlate with autosomal dominant mutations found in early onset AD, that account for less than 5% of the total AD cases. Although these models allow for testing of hypotheses linking genetic mutations and related molecular mechanisms to pathogenesis, the predictive validity of these models for treatments in human AD, where most cases do not arise from known genetic lesions, has been poor.

The cover image of this current issue shows a neurofibrillary tangle surrounded by neuropil threads stained with AT8 antibody in the human brain. AT8 recognizes phosphorylated paired helical filaments at both serine 202 and threonine 205. This full tau pathology profile is observed clearly in the human brain affected with AD, but it remains unclear whether other primates can naturally exhibit the same profile. Several groups have recently sought models of the sporadic form of AD. Macaque monkeys and great apes share 100% homology for the Aβ sequence with humans; great apes share 100% homology, and rhesus monkeys 98% homology, with humans for the sequence of the longest form of tau protein (Drummond and Wisniewski, 2017). Recently, Paspalas et al. reported that aged rhesus macaques manifest Braak stage III/IV AD-like pathology, including the presence of NFTs, as supported by electron microscopic visualization of paired helical filaments (Paspalas et al., 2017). Other groups have suggested the presence of AD-like NFTs, occurring naturally in aged African green monkeys (Cramer et al., 2018), or induced in adult rhesus macaques by the injection of Aβ oligomers (AβOs) in the brain (Forny-Germano et al., 2014). These Old World anthropoid species would be much more tractable than rodents for drug development research, and will increase the translational power of the studies with respect to preventing AD.