AUTHOR=Consens Micaela E. , Chen Yuxiao , Menon Vilas , Wang Yanling , Schneider Julie A. , De Jager Philip L. , Bennett David A. , Tripathy Shreejoy J. , Felsky Daniel 

TITLE=Bulk and Single-Nucleus Transcriptomics Highlight Intra-Telencephalic and Somatostatin Neurons in Alzheimer’s Disease

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=15

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.903175

DOI=10.3389/fnmol.2022.903175

ISSN=1662-5099

ABSTRACT=<p>Cortical neuron loss is a pathological hallmark of late-onset Alzheimer’s disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β = −0.48, <italic>p</italic><sub><italic>bonf</italic></sub> = 8.98 × 10<sup>–9</sup>) and intra-telencephalic (IT) excitatory neurons (β = -0.45, <italic>p</italic><sub><italic>bonf</italic></sub> = 4.32 × 10<sup>–7</sup>). Replication in three AD case-control single-nucleus RNAseq datasets most strongly supported the bulk tissue association of fewer SST neurons in AD. In depth analyses of cell type proportions with specific AD-related neuropathological and cognitive phenotypes revealed fewer SST neurons with greater brain-wide post-mortem tau and beta amyloid, as well as a faster rate of antemortem cognitive decline. In contrast, greater IT neuron proportions were associated with a slower rate of cognitive decline as well as greater residual cognition–a measure of cognitive resilience–but not canonical AD neuropathology. Our findings implicate somatostatin inhibitory and intra-telencephalic excitatory neuron subclasses in the pathogenesis of AD and in cognitive resilience to AD pathology, respectively.</p>