A research team from the Institut de Neurociències of the Universitat Autònoma de Barcelona (INc-UAB) has discovered that the two key pathological hallmarks of Alzheimer's—tau protein and beta-amyloid—affect brain circuits in distinct yet synergistic ways, particularly those linked to memory and emotions. The study was conducted in collaboration with the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) and the Universidad Pablo de Olavide (UPO).
Published in Molecular Psychiatry (Nature group), the findings reveal that tau accumulation in the hippocampus leads to memory deficits, while beta-amyloid buildup in the amygdala triggers emotional disturbances such as anxiety and fear—both early symptoms of the disease. Moreover, the combination of these two pathologies intensifies brain inflammation and dysfunction, amplifying their overall impact.
For decades, research into Alzheimer's disease has been shaped by two theories: one suggesting that the disease originates from tau buildup inside neurons, and another pointing to beta-amyloid accumulation as the primary trigger. These perspectives have largely dictated current therapeutic approaches, with treatments aiming to prevent the buildup of either tau or beta-amyloid in hopes of slowing disease progression. However, the research team led by researchers Carles Saura and Arnaldo Parra-Damas, from the UAB Department of Biochemistry and Molecular Biology and the INc-UAB, argues that a dual-targeted therapeutic strategy may be necessary to effectively combat this disease.
This breakthrough was made possible by the development of a novel transgenic mouse model that replicates both tau and beta-amyloid pathologies. "Although both proteins accumulate in the brains of Alzheimer's patients, most animal models used for studying the disease typically focus on only one of these factors", explains researcher Maria Dolores Capilla, lead author of the study. "In our research, we generated a transgenic mouse model exhibiting both tau and beta-amyloid accumulation, allowing us to analyze their individual and combined effects", adds the INc-UAB researcher.
These findings could reshape current treatment strategies, which often target only one of these toxic proteins. "Existing therapies have not achieved clear clinical benefits. Our study suggests that a therapeutic approach addressing multiple disease mechanisms—such as phosphorylated tau and beta-amyloid—could be more effective", concludes Carles Saura.
While further research is needed to confirm its applicability to humans, this study represents a significant step toward new investigative pathways for Alzheimer's treatment, the research team concludes.
