Assessing Co‐Localization of <scp>ITM2B</scp> With Alzheimer's Disease and Limbic‐Predominant Age‐Related <scp>TDP</scp>‐43 Encephalopathy Neuropathologic Changes

Mutations in the Integral membrane protein 2B (ITM2B) gene are linked to the development of familial British and Danish dementias, two relatively early-onset dementia disorders known also to be associated with Tau neurofibrillary tangles (NFTs). However, to date, the involvement of ITM2B in limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) remains unclear. To address this question, we used brain samples from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. We investigated the patterns and co-localizations of ITM2B immunohistochemistry in subiculum, CA1, CA2, CA3 and dentate gyrus of the hippocampus from brains with Alzheimer's disease neuropathologic changes (ADNC), LATE-NC, and comorbid ADNC+LATE-NC, as well as low-pathology controls (n = 4 per disease state). There was frequent co-localization between ITM2B protein and intracellular Tau pathology in ADNC; however, there was a far weaker rate of co-localization between ITM2B and TDP-43 pathology. There also was, as previously described, an association between ITM2B immunostaining and neuritic-appearing amyloid plaques. Additionally, co-localization of intracellular ITM2B pathology with Thioflavin-S in NFTs suggested a potential role for ITM2B in marking neurons undergoing transition from relatively healthy (early NFT-bearing cells) to more severely affected (later NFT-bearing) cellular disease states. This study indicates that ITM2B has a relatively specific pattern of involvement in Tau-related neurodegeneration and in neuritic amyloid plaques, while implying minimal, if any, role for ITM2B in the synergistic relationship between Tau and TDP-43 pathologies.