Systemic lipid and glucose modulation differentially affects cognitive function and neuroinflammation in a mouse model of Alzheimer's disease

Demos Kynigopoulos¹Eleni Fella¹Lucy Shahabian¹Christiana Christodoulou¹Revekka Papacharalambous¹Konstantinos Diskos^2,3Lida Evmorfia Vagiaki^2,3Kyriaki Sidiropoulou^2,3Menelaos Pipis¹Kleopas A Kleopa¹Elena Panayiotou^1*

• ¹The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
• ²Idruma Tekhnologias kai Ereunas, Heraklion, Greece
• ³Panepistemio Kretes Panepistemioupole Bouton, Heraklion, Greece

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and cognitive decline. Increasing evidence implicates systemic metabolic dysregulation in AD pathogenesis, but whether modulating peripheral lipid and glucose metabolism can alter disease progression remains unclear. In this study, we investigated the effects of two FDA-approved metabolic agents-Alirocumab, a PCSK9 inhibitor that lowers LDL cholesterol, and Gliclazide, a sulfonylurea that enhances insulin secretion-on neuropathology, synaptic function, and cognition in male 5xFAD mice, a transgenic model of AD. Animals received chronic treatment for five months, and assessments included behavioral testing, electrophysiology, ELISA, lipidomics, and adipokine profiling. Alirocumab significantly improved spatial working memory, restored hippocampal long-term potentiation, and normalized synaptophysin expression.Gliclazide reduced neuroinflammation and partially preserved glial and neuronal markers. Both treatments lowered brain amyloid burden and modulated adipokine levels, with Alirocumab elevating leptin and omentin in both brain and serum. Lipidomic analysis of visceral adipose tissue revealed distinct lipid remodeling and identified candidate pathways linking systemic metabolism to central nervous system outcomes. These findings demonstrate that systemic modulation of lipid and glucose metabolism can influence key neurodegenerative and synaptic processes in AD, supporting the view that metabolic interventions may provide a viable strategy to modify disease progression.