Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

Harnessing diversity to study Alzheimer's disease: A new iPSC resource from the NIH CARD and ADNI.

The iDA Project (iPSCs to Study Diversity in Alzheimer's and Alzheimer's Disease-related Dementias) is generating 200 induced pluripotent stem cell lines from Alzheimer's Disease Neuroimaging Initiative participants. These lines are sex balanced, include common APOE genotypes, span disease stages, and are ancestrally diverse. Cell lines and characterization data will be shared openly.

Apolipoprotein E in lipid metabolism and neurodegenerative disease.

Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.