Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• Alzheimer's disease (AD) presents with diverse clinical syndromes, indicating region-specific neuronal vulnerability to tau pathology.
• Distinct AD variants like amnestic AD, logopenic variant primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA) show tau accumulation in specific brain areas (CA1, STG, occipital cortex, respectively).
• Understanding selective neuronal vulnerability is key to elucidating AD pathogenesis.

Purpose of the Study:

• To investigate the molecular mechanisms underlying region-specific neuronal vulnerability in Alzheimer's disease.
• To identify vulnerable neuronal subpopulations by contrasting AD variants with distinct pathological hotspots.
• To utilize single-nucleus RNA sequencing (snRNA-seq) to explore molecular drivers of neuronal susceptibility.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was performed on postmortem brain tissue from 68 individuals (24 amnestic AD, 11 lvPPA, 6 PCA, 27 controls).
• Nuclei were extracted from CA1 hippocampal sector, posterior superior temporal gyrus (STG), and occipital cortex.
• Bioinformatics analysis using Seurat in R identified neuronal subpopulations and assessed region-specific vulnerability using the Wald statistical test.

Main Results:

• Over 1.58 million nuclei were analyzed, revealing 17 inhibitory and 16 excitatory neuronal subpopulations.
• Six excitatory subpopulations (Exc-subs) demonstrated region-specific vulnerability.
• A specific subpopulation, Ex L2/3 IT RORB GRIN1, showed significant vulnerability in CA1 (amnestic AD) and STG (amnestic and lvPPA cases), with a trend in the occipital cortex (PCA cases).

Conclusions:

• A particular excitatory neuron subpopulation exhibits heightened susceptibility in tau-affected regions across amnestic and atypical AD syndromes.
• These findings highlight a common vulnerable neuronal subtype contributing to diverse AD clinical presentations.
• Further quantitative pathology and case analyses are planned to validate findings and refine understanding of AD's molecular drivers.