The Aβ42:Aβ40 ratio modulates aggregation in beta-amyloid oligomers and drives metabolic changes and cellular dysfunction.

The pathophysiological role of Aβ₄₂ oligomers in the onset of Alzheimer's disease (AD) is heavily disputed, pivoting research toward investigating mixed oligomers composed of Aβ₄₂ and Aβ₄₀, which is more abundant but less aggregation-prone. This study investigates Aβ₄₂:Aβ₄₀ oligomers in different ratios, examining their adverse effects on endothelial cells, neurons, astroglia, and microglia, as well as in a human blood-brain barrier (BBB) model. Combining label-free Raman microscopy with complementary imaging techniques and biochemical assays, we show the prominent impact of Aβ₄₀ on Aβ₄₂ fibrillation, suggesting an inhibitory effect on aggregation. Mixed oligomers, especially with low proportions of Aβ₄₂, were equally detrimental as pure Aβ₄₂ oligomers regarding cell viability, functionality, and metabolism. They also differentially affected lipid droplet metabolism in BBB-associated microglia, indicating distinct pathophysiological responses. Our findings demonstrate the overarching significance of the Aβ₄₂:Aβ₄₀ ratio in Aβ oligomers, challenging the traditional focus on Aβ₄₂ in AD research.