The early months of the pandemic were fraught with anxiety, in no small part due to what felt like constant reports of new links between SARS-CoV-2 infection and ongoing medical events. Perhaps most concerning were the effects associated with “long” COVID. We’re used to headaches and coughs from a viral infection, but not brain fog and cognitive dysfunction.
As the pandemic has gone on these reports have, unfortunately, only gained more credibility. The links between COVID-19 and neurological issues now seem stronger than ever, but they raise two very important questions: how does SARS-CoV-2 induce cognitive dysfunction, and does it share these mechanisms with dementia?
For Alzheimer’s Awareness Month, we’re highlighting how a group of researchers from Gunma University, Japan has sought to answer these questions, and provide a deeper look at the possible connections between COVID-19 and Alzheimer’s disease (AD) risk (1).
Mapping the potential shared cellular basis of COVID-19 and Alzheimer’s disease
To examine possible transcriptional and cellular changes that are shared between COVID-19 and AD, Fu et al. took advantage of single nuclei RNA-seq (snRNA-seq) datasets generated with the Chromium Single Cell 3’ Gene Expression assay. Pooling nuclei from 10 AD patients, 8 COVID-19 patients, and 8 healthy controls, researchers characterized 141,633 nuclei and classified them into 34 distinct cell clusters.
Researchers next used prior studies to generate a list of AD-associated markers and identified 368 cell-type-specific genes. Of these, 323 were specific to neurons, 32 were identified as part of genome-wide association studies, and 14 were identified in both groups.
Using these AD markers, the group then examined individual cell types to determine whether specific subclusters were similarly impacted by COVID-19 and AD. Their first finding was an astrocytic cluster depleted in both AD and COVID-19 groups compared to controls. Intriguingly, a gene ontology analysis of this cluster revealed downregulation in genes related to synaptic function and signaling, a relevant finding given that synaptic loss is not only associated with AD but with reduced cognitive performance (2).
Moving into neurons, researchers further refined their analysis by developing an AD “risk score” and applying it across excitatory neuronal subpopulations. They identified not one but three clusters that were similarly impacted by COVID-19 and AD, all of which exhibited disruptions to pathways linked to synaptic morphology and function.
The group next looked at how affected cell types in AD and COVID-19 may communicate, using CellChat to predict ligand–receptor pairs. One impacted neuronal cluster exhibited strong interactions with other cells and, consistent with reports of increased glial communication in inflammation, AD and COVID-19 patients exhibited stronger interactions between microglial and astrocytic cell populations. Finally, when grouping all nuclei by patient condition, researchers showed high concordance between genes differentially expressed in COVID-19 and AD.
Charting the path ahead
While the data presented in the paper is preliminary, it paints an interesting picture where common mechanisms may underlie some facets of both SARS-CoV-2- and AD-induced cognitive dysfunction. While more work remains to be done, researchers are already calling for roadmaps to help determine the impact of COVID-19 on long-term dementia rates and demographics (3), highlighting how important these questions will be in the coming years.
Looking for more on how COVID impacts the CNS? Check out our previous blog, COVID and the CNS: Single cell tools shed light on the neurological consequences of COVID, to explore other ways that COVID may damage the brain.
- Fu Y, et al. Single-nucleus RNA sequencing reveals the shared mechanisms inducing cognitive impairment between COVID-19 and Alzheimer’s disease. Front Immunol 13: 967356 (2022). doi: 10.3389/fimmu.2022.967356
- Mecca AP, et al. Synaptic density and cognitive performance in Alzheimer's disease: A PET imagine study with [11 C]UCB-J. Alzheimers Dement (2022). doi: 10.1002/alz.12582
- Gordon MN, et al. Impact of COVID-19 on the Onset and Progression of Alzheimer's Disease and Related Dementias: A Roadmap for Future Research. Alzheimers Dement 18(5): 1038–1046 (2022). doi: 10.1002/alz.12488