Navigating the Molecular Maze of Alzheimer’s Disease: Developing A Human Hippocampal Atlas to Bridge Discovery and Clinical Practice

Alzheimer’s disease (AD), the primary cause of dementia worldwide, persists as an enigma, with the specific molecular and cellular mechanisms driving cognitive decline still eluding understanding. To aid in unraveling this enigma, we generated a spatial transcriptomic atlas of the human hippocampus with single-cell resolution, leveraging integration of spatial mapping with single-cell transcriptomic profiles from six individuals with or without AD. Utilizing this complex and multi-dimensional data, the atlas pinpoints AD-associated transcriptomic changes with spatial specificity, such as a pronounced elevation of inflammatory responses and energy metabolism in fimbria and CA4, respectively. AD also caused alterations of the cellular composition in hippocampal subregions, even around the amyloid-beta (Aβ) plaques. Finally, our investigation uncovered pathways intricately linked to synthesis and secretion of extracellular vesicles (EVs). Within these altered pathways, we identified several corresponding proteins, including CCK and PMP2, that are readily detectable in human blood, holding promise for aiding AD diagnosis in clinical settings. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement National Natural Science Foundation of China under Grant 82020108012, Leading Innovation and Entrepreneurship Team of Zhejiang Province under Grant 2020R01001, and Innovative Institute of Basic Medical Science of Zhejiang University and the National Science and Technology Innovation 2030 Major Program (2021ZD0204401). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All experiments related human brain tissues in this study were reviewed and approved by the Human Ethics Committee of the School of Medicine, Zhejiang University (approval no . 2022 012) and the Institutional Review Board on Ethics Committee of Beijing Genomics Institute (BGI, approval no. BGI IRB 22080). Human plasma and CSF sample studies were approved by the clinical research ethics committees of the First Affiliated Hospital, College of Medicine, Zhejiang University (approval no. 2022 043). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors