Structural and Functional Connectivity Across Age in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia. Most AD patients, however, have a sporadic form of AD, making it challenging to understand the early pathological development of the disease before cognitive impairment. To address this, a combination of in vivo magnetic resonance imaging (MRI), computational neuroimaging, and molecular biology was performed in the App NL-G-F/NL-G-F knock-in (APPKI) mouse model of AD, which harbors three familial AD mutations in the amyloid precursor protein (App) gene. The structural and functional connectivity of the brain was measured in early, middle, and late age using diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI), respectively. First, using DTI, APPKI had reduced fractional anisotropy, a proxy of microstructural integrity, between middle and late age compared to wild-type (WT) mice. In middle age, before changes in DTI, APPKI mice showed increased number of oligodendrocytes, but reduced lipid content, suggesting that there may be an impairment in myelin homeostasis and repair mechanisms. Second, the functional connectivity (FC) of the hippocampus was analyzed using rs-fMRI. While interhemispheric FC generally increased with age, in APPKI mice, interhemispheric FC was higher in early age, but lower after middle age, compared to WT mice. Conversely, intrahemispheric FC generally decreased across age, but with reduced laterality in APPKI mice compared to WT mice, where WT mice showed increased FC in the right hemisphere relative to the left. Finally, the FC gradient of the hippocampus was analyzed using the rest2vec graph embedding method. In early and middle age, the left–right gradient was dominant, suggesting that the hemispheres were more functionally segregated. However, in late age, the gradient shifted from left–right to anterior–posterior, suggesting that the anterior and posterior aspects of the hippocampus were more functionally segregated. These results suggest that AD pathology alters both brain structural integrity, oligodendrocyte populations, and myelin, as well as functional connectivity in the hippocampus. Taken together, these findings help to give better insight into the basic progression of AD pathology, as well as provide potential biomarkers for the development of therapeutic strategies.