Synergy between amyloid-β and tau in Alzheimer’s disease

Abstract

Patients with Alzheimer’s disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this ‘triggering’ function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ–tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.

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Fig. 1: Aβ plaques accelerate tau spreading and cognitive decline in human AD.
Fig. 2: The interaction between Aβ and tau enhances neural circuit impairment.
Fig. 3: Microglia may be critical intermediaries of Aβ–tau synergy.
Fig. 4: Aβ and tau pathways may converge at the level of gene expression.

Data availability statement

Data sharing not applicable to this review article as no data sets were generated.

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Acknowledgements

We are grateful to S. S. Harris for his support preparing this manuscript, and we thank B. I. Lee for help with the figures. We acknowledge the donors of Alzheimer’s Disease Research (ADR), a program of BrightFocus Foundation, for the generous support of this research (grant number: A2019112S). M.A.B. is further supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the Medical Research Council, Alzheimer’s Society and Alzheimer Research UK and by a UKRI Future Leaders Fellowship (grant number: MR/S017003/1). B.T.H. is supported by the Massachusetts Alzheimer’s Disease Research Center (P30AG062421), the JPB foundation, the National Institutes of Health (R01AG058674) and the Tau Consortium.

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M.A.B. and B.T.H. conceived the original idea and wrote the paper.

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Correspondence to Marc Aurel Busche.

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Busche, M.A., Hyman, B.T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-0687-6

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