Why clinical studies of Alzheimer’s fail

Amyloid-β pathology is believed to be a key component underlying Alzheimer’s Disease. However, most treatments that target amyloid-β have failed clinical trials. To systematically evaluate these treatments and possible reasons for failure, Adriano Aguzzi (USZ), Jin Hyung Lee (Stanford University), and their teams developed a technology for imaging a whole brain and quantifying the full three-dimensional extent of pathology.

Why do most clinical trials targeting Alzheimer’s Disease fail? Jin and Adriano wanted to find out. They developed a novel technology for rapid tissue clearing and imaging  to quantify the full spatial distribution of amyloid-β plaques in an intact mouse brain. This technology could resolve plaques at micron-level resolution while providing a whole-brain, three-dimensional readout. This was crucial for accurately localizing changes in pathology caused by the various treatments against Alzheimer’s Disease they tested.

Their main finding was that two specific treatments (BACE1 inhibitors and polythiophene) showed almost completely complementary efficacies. The BACE1 inhibitor was most effective at 5 months along the progression of Alzheimer’s Disease, whereas the polythiophene was most effective at 14 months. More interestingly, when these two drug effects were aligned, the scientists found they impacted distinct brain regions.

These findings help them understand that when testing drugs for Alzheimer’s Disease in preclinical and clinical trials, great care must be taken to evaluate the impact on specific brain regions and disease stages.

Reference: Kirschenbaum, D., Dadgar‐Kiani, E., Catto, F., Voigt, F. F., Trevisan, C., Bichsel, O., … & Aguzzi, A. (2023). Whole‐brain microscopy reveals distinct temporal and spatial efficacy of anti‐Aβ therapies. EMBO Molecular Medicine, 15(1), e16789.

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Image: Whole-mount Thy1-YFP mouse brain cleared with technology described in article. The image was recorded with a mesoSPIM (Voigt et al 2019). Provided by Daniel Kirschenbaum (USZ, Institute of Neuropathology).