Lost in translation: Inconvenient truths on the utility of mouse models in Alzheimer's disease research

Abstract

The recent, controversial approval of antibody-based treatments for Alzheimer's disease (AD) is fueling a heated debate on the molecular determinants of this condition. The discussion should also incorporate a critical revision of the limitations of preclinical mouse models in advancing our understanding of AD. We critically discuss the limitations of animal models, stressing the need for careful consideration of how experiments are designed and results interpreted. We identify the shortcomings of AD models to recapitulate the complexity of the human disease. We dissect these issues at the quantitative, qualitative, temporal, and context-dependent levels. We argue that these models are based on the oversimplistic assumptions proposed by the amyloid cascade hypothesis (ACH) of AD and fail to account for the multifactorial nature of the condition. By shedding light on the constraints of current experimental tools, this review aims to foster the development and implementation of more clinically relevant tools. While we do not rule out a role for preclinical models, we call for alternative approaches to be explored and, most importantly, for a re-evaluation of the ACH.

Keywords: APOE; Amyloid; Tau; aging; medicine; neurodegeneration; neuroinflammation; neuroscience.

Figure 1.. Limitations of the preclinical mouse models of Alzheimer’s disease (AD).

The scheme reports the pillars of the amyloid cascade hypothesis (ACH) left; modified from Karran et al., 2011. For each step, we aimed at identifying key limitations in the preclinical modeling of the cascade. We envision that these pitfalls, along with discrepancies of the amyloid construct cascade itself, critically dampen the potential translational value of these models.

Figure 2.. Inconsistencies in the trajectories of Alzheimer’s disease (AD) pathology between humans and preclinical models.

(A) The pictogram illustrates the dynamics of β-amyloid (Aβ) (red) and tau (blue) pathology as well as the trajectory of cognitive symptoms (green) in the sporadic forms of AD (modified from Frisoni et al., 2022). Please note that, in the case of familial form of AD (fAD) or APOEε4-related AD, the pathology follows a similar sequence of events but with early and steeper trajectories (Frisoni et al., 2022). (B) The pictogram estimates the dynamics of key AD features as observed in the most widely used AD mouse models. Unlike what is observed in humans, in these preclinical settings, cognitive deficits usually anticipate the appearance of Aβ pathology. Tau inclusions and signs of overt neurodegeneration are absent. (C) The pictogram estimates the dynamics of key AD features as observed in second-generation knock-in mouse models of AD. In this experimental setting, Aβ pathology anticipates the development of subtle cognitive decline (Sakakibara et al., 2018). Like first-generation overexpressing models, tau tangles and brain atrophy are absent. The trajectories in B and C have been estimated by employing data extracted from publications using the mouse models listed in Table 1 and normalized for each pathological feature. Time courses of the original reports were used whenever possible, alternatively, early studies investigating the time-dependent changes in the phenotype of these models were interrogated.