Core Viewpoint - The study published by the team from the University of Chicago identifies a specific mutation in the PICALM gene that leads to the accumulation of harmful lipid droplets in microglia, resulting in impaired phagocytic function and increased risk of late-onset Alzheimer's disease (LOAD) [2][3][7]. Group 1: Research Findings - The research utilized a functional genome-wide association study (GWAS) approach to identify potential LOAD risk mutations in neurons, astrocytes, and microglia derived from human induced pluripotent stem cells (iPSCs) [5]. - The study revealed 26 functional risk mutations specific to LOAD, most of which are present in microglia [5]. - The LOAD risk allele rs10792832 in the PICALM gene reduces the binding of the transcription factor PU.1 and the expression of PICALM, impairing the uptake of β-amyloid (Aβ) and neurofibrillary debris [5]. Group 2: Mechanism of Action - The research elucidates that the selective susceptibility of microglia to LOAD is mediated through the accumulation of harmful lipid droplets at the PICALM gene locus [7]. - Microglia carrying the PICALM risk allele show enrichment in transcriptional pathways related to cholesterol synthesis and lipid droplet formation [5]. - Genetic and pharmacological interventions in microglia confirmed the causal relationship between reduced PICALM expression, lipid droplet accumulation, and impaired phagocytic function [5]. Group 3: Implications for Clinical Interventions - This study provides a critical neurobiological basis for developing new clinical intervention strategies for Alzheimer's disease [7].