Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4‐Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR‐Linked Pro‐Clearance State

ABSTRACT The mouse gene Lilrb4a , an ortholog of human leukocyte immunoglobulin‐like receptor B4 ( LILRB4 ), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)‐related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4‐associated cerebral amyloid angiopathy without altering amyloid‐β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator‐activated receptor (PPAR)‐related and broader metabolic pathways in Lilrb4a ‐deficient mice. Consistently, biochemical analyses showed reduced p‐SHP‐2, NF‐κB‐p65, and p‐STAT1, increased p‐STAT3, and induction of anti‐inflammatory and clearance‐associated effectors, including Arg‐1, TGF‐β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR‐γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR‐γ agonism recapitulated key pro‐clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4‐associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR‐linked pro‐clearance program as a potential downstream component of this response.