Gateway: patient olfactory neurons for large-scale discovery in neurodegenerative disease.

An estimated 42% of Americans over age 55 will develop dementia, but the molecular understanding of dementia and neurodegenerative disease is constrained because the living human brain cannot be routinely sampled during disease progression. Olfactory sensory neurons provide a clinically accessible neuronal tissue source with developmental, transcriptional, and disease-relevant links to the central nervous system. Here we describe Gateway, a platform that combines device guided olfactory epithelium biopsy, onsite fixation, and 10x Genomics FLEX RNA profiling to generate single-cell transcriptomic data from living patient neurons. We present a 4-million-cell atlas representing 202 human donors, including healthy controls and individuals with neurodegenerative diseases, and release it as an open resource through CELLxGENE. We define the cellular composition of the human olfactory epithelium and show that Gateway captures neuronal functional and compartmental programs and detects more brain-enriched genes than other clinically accessible transcriptomic sample types. In exploratory analyses of Alzheimer's Disease and Parkinson's Disease, we identify dysregulation of pathways and GWAS-implicated genes related to key neurodegenerative mechanisms such as neuroinflammation, endolysosomal biology, proteostasis, and synaptic maintenance. Together, this atlas and clinical workflow establish living patient olfactory neurons as a scalable complementary modality for neuroscience research, target discovery, and biomarker development in neurodegenerative disease.