PICALM allele linked to microglial lipid changes

A study maps functional LOAD risk variants in iPSC-derived brain cells and links a PICALM allele to lipid droplet accumulation and impaired microglial clearance.

PICALM Alzheimer’s risk allele drives lipid droplet buildup in microglia

Researchers mapped functional LOAD risk variants by examining allele specific open chromatin across iPS cell derived neurons, astrocytes and microglia. They identified functional variants at 26 LOAD risk loci, with many effects confined to microglia. At the microglia specific PICALM locus, the risk allele rs10792832 reduced PU.1 binding and PICALM expression, impairing uptake of amyloid beta and myelin debris.

Microglia carrying the PICALM risk allele showed transcriptional enrichment of cholesterol synthesis and lipid droplet formation. Genetic and pharmacological perturbations established a causal link between reduced PICALM expression, lipid droplet accumulation and phagocytosis deficits, suggesting lipid droplet buildup as a mechanism of LOAD vulnerability at this locus.

This study highlights cell type context as a key dimension in genetic risk. Many LOAD signals may act primarily in microglia rather than neurons, which could reshape how researchers target the disease.

Using iPSC models helps isolate mechanisms but raises questions about how well these cells mirror aging brains. Translating cellular findings into therapies will require careful work to avoid unintended effects on microglial function and brain lipid balance.

Highlights

The study opens a path toward targeting microglial lipids in Alzheimer's, but much work lies ahead.