Specific Lipid Abnormalities Are Inherently Associated with Late-Onset Alzheimer's Disease

INTRODUCTION Lipid abnormalities have been observed in brain, CSF, and blood in association with late-onset Alzheimer’s disease (LOAD). It is unknown which abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived neural lines.

iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Lipidomics analyses were performed on whole cell and mitochondrial extracts.

Large reductions in cholesterol esters (CE) and imbalances in fatty acids (FA) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids.

The findings identify abnormalities in CE and FA as likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by funds from the Program for Neuropsychiatric Research, McLean Hospital (BMC) and NIGMS: R35GM134949 (IL). 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: IRB of Mass General Brigham gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 Data Availability All data produced in the present study are available upon reasonable request to the authors