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A perspective: PLA2G4A as drug target for vascular inflammation in Alzheimer's disease

Year: 2026
Type: article
Abstract: Anti-amyloid therapies for Alzheimer's disease (AD) modestly slow cognitive decline but carry significant risk of amyloid-related imaging abnormalities (ARIAs), brain swelling, and hemorrhage, particularly in apolipoprotein E ε4 carriers. Cerebral amyloid angiopathy (CAA) and vascular inflammation drive this vulnerability, highlighting the need for complementary strategies targeting upstream mechanisms of vascular injury. Cytosolic phospholipase A2 (cPLA2) regulates arachidonic acid and lysophosphatidylcholine-derived lipid signaling at the intersection of amyloid burden, oxylipin dysregulation, blood-brain barrier disruption, and neurovascular inflammation. By depleting protective membrane plasmalogens while amplifying inflammatory lipid mediators, cPLA2 creates a state of vascular vulnerability predisposing to ARIAs. This Perspective article synthesizes evidence from human, preclinical, and translational studies positioning cPLA2 as an upstream driver of CAA-related inflammation and vascular vulnerability in AD. We discuss biomarker and imaging approaches to assess cPLA2 activity in vivo and outline how targeting this pathway may enhance anti-amyloid therapy safety by mitigating ARIA risk.
DOI: 10.1002/alz.71320
Authors: Ambreen Kanwal, Bilal E. Kerman, Shaowei Wang, Kevin Camey, Boyang Li, Lisi Flores‐Aguilar, Nada Ali, Laura Beth McIntire, Chang April Shu, Stan G. Louie, Elizabeth Head, Zoe Arvanitakis, Hussein N. Yassine
Institutions: Washington University in St. Louis, University of Southern California, University of California, Irvine, Weill Cornell Medicine, Rush University Medical Center, Rush University
Language: English
Subfield: Physiology
Field: Medicine
Open Access status: hybrid
Estimated APC paid: $4,200
Awards: G1251185638, G127510776, G1282666458, G1593128567, G2178555009, G249615658, Brain cPLA2 as a mechanism for neuroinflammation in AD/ADRD with and without APOE4, G3488475769, G4436462243, Linking peripheral and brain insulin resistance to AD neuropathology and cognition, DHA brain delivery by APOE genotype, G5576348566, Alzheimer Disease Research Center, G9000015626, G9000059605, G9000099765, G9000122668, G9000128617, G9000155105, G9000195764, G9000343953, Elucidating endolysosomal trafficking dysregulation induced by APOE4 in human astrocytes, Drug Development for Alzheimer's neuroinflammation, G986202382
OpenAlex ID: W7152074830
FWCI: 3.926
Cites: 109
Cited by: 1
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