Weight trajectories in aging humanized APOE mice with translational validity to human Alzheimer's risk population: A...

Translational validity of mouse models of Alzheimer's disease (AD) is variable. Because change in weight is a well-documented precursor of AD, we investigated whether diversity of human AD risk weight phenotypes was evident in a longitudinally characterized cohort of 1,196 female and male humanized APOE (hAPOE) mice, monitored up to 28 months of age which is equivalent to 81 human years. Autoregressive Hidden Markov Model (AHMM) incorporating age, sex, and APOE genotype was employed to identify emergent weight trajectories and phenotypes. In the hAPOE-AD mouse cohort, five distinct weight trajectories emerged: three trajectories were associated with a weight loss phenotype (36% of mice, n = 426), one with weight gain (13% of mice, n = 152), and one trajectory of no change in weight (34% of mice, n = 403). The AHMM model findings were validated with post-hoc survival analyses, revealing differences in survival rates across the five identified phenotypes. Further validation was performed using body composition and plasma β-amyloid data from mice within the identified gain, loss and stable weight trajectories. Weight gain trajectory was associated with elevated plasma β-amyloid levels, higher body fat composition, lower survival rates and a greater proportion of APOE4/4 carriers. In contrast, weight loss was associated with greater proportion of hAPOE3/4 carriers, better survival rates and was predominantly male. The association between weight change and AD risk observed in humans was mirrored in the hAPOE-AD mouse model. Weight trajectories of APOE3/3 mice were equally distributed across weight gain, loss and stability. Surprisingly, despite genetic uniformity, comparable housing, diet and handling, distinct weight trajectories and divergence points emerged for subpopulations. These data are consistent with the heterogeneity observed in the human population for change in body weight during aging and highlight the importance of longitudinal phenotypic characterization of mouse aging to advance the translational validity of preclinical AD mouse models.