Untangling Alzheimer's disease with spatial multi-omics: a brief review

Abstract

Alzheimer's disease (AD) is the most common form of neurological dementia, specified by extracellular β-amyloid plaque deposition, neurofibrillary tangles, and cognitive impairment. AD-associated pathologies like cerebral amyloid angiopathy (CAA) are also affiliated with cognitive impairment and have overlapping molecular drivers, including amyloid buildup. Discerning the complexity of these neurological disorders remains a significant challenge, and the spatiomolecular relationships between pathogenic features of AD and AD-associated pathologies remain poorly understood. This review highlights recent developments in spatial omics, including profiling and molecular imaging methods, and how they are applied to AD. These emerging technologies aim to characterize the relationship between how specific cell types and tissue features are organized in combination with mapping molecular distributions to provide a systems biology view of the tissue microenvironment around these neuropathologies. As spatial omics methods achieve greater resolution and improved molecular coverage, they are enabling deeper characterization of the molecular drivers of AD, leading to new possibilities for the prediction, diagnosis, and mitigation of this debilitating disease.

Keywords: Alzheimer’s disease; imaging mass spectrometry (IMS); immunoflorescence; mass spectrometry; microscopy; neuroscience; spatial multi-omics; spatial transcriptomics (ST).

FIGURE 1

Spatial profiling and imaging technologies used in brain studies. (A,B) The GeoMx platform allows for highly multiplexed analysis of gene and protein expression [modified from Walker et al. (2022)]. (A) The Hippocampal CA1 subregion labeled with morphology markers (AT8, green; β-amyloid, aqua; IBA-1, red; nuclear marker SYTO13, blue) to highlight targeted NFTs and surrounding areas. (B) Heatmap of differentially expressed proteins when comparing NFTs to normal neurons (p < 0.01). (C) Representative highly multiplexed CycIF images of astroscytes from a AD donor highlighting ALDH1L1, EAAT2, GFAP, and Aβ [modified from Muñoz-Castro et al. (2022)]. (D) MALDI imaging mass spectrometry lipid data from murine brain collected at 10 μm spatial resolution. Selected images include m/z 834.5437 ([PS(40:6)-H]^–, –0.12 ppm error), m/z 883.5683 ([PI(38:5)-H]^–, –0.45 ppm error), m/z 885.5498 ([PI(38:4)-H]^–, –0.23 ppm error), and m/z 906.6431 ([SHexCer(t42:1)-H]^–, –1.9 ppm error) [modified from Spraggins et al. (2019)].