What distinguishes persons with Alzheimer’s disease (AD) or other age-related cognitive impairments from age- and sex-matched cognitively healthy individuals, and what distinguishes these two populations from those who are of very advanced age with preserved cognition (e.g., Super Agers), has been intensely investigated for decades. A multitude of techniques and approaches has provided key insights, but the consensus is that some still-unknown combination of parameters is the most likely explanation. Recent systems biology studies have identified genetic networks that are linked to AD risk, resilience, severity, or pathology, which can be consid- ered “interactomes” that promote or protect against AD progression and pathogenesis, referred to here as the m109 and the BIN1 interactomes. Recent studies examining these interactomes with targeted proteomics in the human dorsolateral prefrontal cortex (dlPFC) have expanded this tight linkage to the proteomic level. As the genomic landscape conferring either risk of, or resilience to, AD continues to be established, determining the neuroanatomical expression patterns of the proteins encoded by these genes is critical. Moreover, how their expression patterns relate to each other and to individual cell-types is crucial for understanding why these net- works are implicated in AD. Furthermore, expression patterns of these interactomes may differ substantially in regions with AD-linked pathology as compared to adjacent, pathology-lacking microregions. This application is relevant to NOT-AG-19-033 and proposes three Aims that build upon recent RNAseq/genomic/proteomic studies using a combination of high-resolution immunolocalization techniques that will uniquely generate neu- roanatomical expression patterns with multiplexed detail using both immunofluorescence array tomography and immunogold electron microscopy in AD, asymptomatic AD, non-cognitively impaired, and Super Ager dlPFC. The overarching hypothesis is that proteins encoded by the genetic risk/resilience interactomes are mis- localized or aberrantly expressed in AD brain and cortical white matter with MRI abnormalities. Aim 1 will de- termine the expression patterns of proteins encoded by the m109 and BIN1 interactomes in relation to synaptic markers in the dlPFC neuropil. Aim 2 determine the expression patterns of proteins encoded by the m109 and BIN1 protein clusters in relation to AD pathology in both the dlPFC gray matter and white matter. Aims 1 and 2 will also include examination of protein expression patterns in behaviorally characterized rodent models of AD to establish cross-species validation of distributional motifs in human dlPFC and rodent prelimbic cortex. Aim 3 will determine the expression patterns of proteins encoded by the m109 and BIN1 protein clusters in relation to the MRI abnormalities in human frontal and temporal cortex white matter. The main deliverable is to use distributional motifs of risk and resilience factors, consider...