Applying high-resolution spatial transcriptomics to characterise the amyloid plaque cell niche in Alzheimer's Disease

The amyloid plaque cell niche is a pivotal hallmark of Alzheimer's disease (AD). Where early spatial transcriptomics (ST) technologies have provided valuable information on transcriptomic alterations in the small tissue domains overlaying with amyloid plaques, they lacked cellular resolution. Here we compare two novel high-resolution ST platforms, CosMx and Stereo-seq, in their ability to characterize the cellular response in the amyloid plaque niche in an AD mouse model. Combining the results from both techniques empowered us to survey the highly variable microglial-astrocytic response across the amyloid plaque micro-environment and provided a first insight into how these responses could relate to neuronal transcriptomic alterations. This pilot study demonstrates the great potential of high-resolution ST, while simultaneously highlighting limitations that, when addressed, will unleash the full power of these techniques to map the progression of molecular and cellular changes in the brains of AD patients. ### Competing Interest Statement B.D.S. has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies and is now consultant to Muna Therapeutics. B.D.S is a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics. M.F. is a consultant to Muna Therapeutics. Y.A. and J.H.K. are employees of BGI Research and M.V. and W.T.-C. are employed by Muna Therapeutics. W.T.-C. is also a stockholder of Muna Therapeutics.