Behavioral deficits and exacerbated neural and hemodynamic odor responses during lifespan of a mouse model of late onset Alzheimer's disease expressing humanized APOEε4 and Trem2*R47H.

Alzheimer's disease (AD) poses a significant global health challenge, being the most prominent cause of dementia with prevalence increasing as the population ages. While the majority of AD cases are late-onset (LOAD), current animal models predominantly represent the more aggressive, faster progressing early-onset AD (EOAD), limiting their ability in assessing early biomarkers and gaining deeper understanding of LOAD progression. This study explores a promising translatable model, the APOE4.TREM2 mouse, which combines the APOE4 allele and the Trem2 p.R47H mutation, both linked to increased AD risk in the human population. We performed behavioral phenotyping and measured hemodynamics and neurovascular coupling in dorsal olfactory bulbs (dOB) during odor stimulation of the APOE4.TREM2 mouse line. Experimental evidence of olfactory dysfunction prior to clinical symptoms suggests the opportunity of utilizing smell testing and fMRI as tools for screening of AD, both for preclinical and clinical studies. Here we assess and confirm the translatability of the APOE4.TREM2 mouse LOAD model, reporting exacerbated anxiety, deficits in odor-based foraging and spatial memory, and exacerbated odor-evoked dOB neural and intrinsic responses, but stable neurovascular coupling, in an age-dependent manner.