Not all regions are created equal: identifying regions and cell types associated with cognitive resilience in the AD‐BXD model population

Background The relationship between regional cell composition, brain pathology, and memory impairment in Alzheimer’s disease (AD) remains incompletely understood. The specific brain regions and tracts (and their interactions) that explain the heterogeneity of cognitive decline with AD are not clear. By integrating brain‐wide immunohistochemistry and cognitive outcomes we can achieve unbiased detection of regions of interest (ROIs) and identify cellular correlates of cognitive resilience for causal testing. Method Immunohistochemistry(IHC) was completed to evaluate neurodegeneration (NeuN), gliosis (Iba1&GFAP), amyloid beta(Aβ) pathology(AB1‐42), and cell bodies(Thionine) in adult (6 months(m)) and middle‐aged (14m) mice of the AD‐BXD genetic reference panel (n = 227). Using the QUINT workflow, hemibrain slices were systematically segmented and registered to the Allen Brain Atlas to gain a global perspective of percent cell and pathology coverage. IHC traits were correlated with contextual fear conditioning outcomes to identify regions whose stain composition is associated with memory performance. Results Contrary to our prior work using ELISA‐based Aβ measurement, we find that Aβ quantified via IHC at the presymptomatic time point (6m) is strongly correlated with differences in short‐ and long‐term memory in 14m female 5XFAD carriers. Furthermore, the degree of astrogliosis at 6m in cortical, striatal, and thalamic regions acts as a predictor of cognitive outcomes at 14m. While age‐related decreases in NeuN load were not observed, wide variation in neurodegeneration levels could be attributed to strain differences and 14m NeuN load was positively correlated with 14m long‐term memory among this female 5XFAD population. Highlighting the importance of genetic background on AD progression, we were able to categorize strains as resilient or susceptible to pathological and cognitive decline and evaluate the overlap of these traits. Strains that exhibit the unique identity of being pathologically susceptible but cognitively resilient offer a novel opportunity to investigate the underlying mechanisms of protection from cognitive decline with AD. Conclusion Integrating brain‐wide IHC and behavioral data, we were able to identify regional and cellular correlates that may predict downstream cognitive outcomes. Detection of these biomarkers may prove a valuable resource to disseminate the insidious prodromal stages of AD in which biochemical changes precede apparent c