Pathways underlying selective neuronal vulnerability in Alzheimer's disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra

Identifying factors underlying selective neuronal vulnerability is crucial for understanding Alzheimer's disease (AD) pathophysiology. The Neuromodulatory Subcortical System (NSS) includes nuclei that exhibit early, but varied vulnerability to tau accumulation and neuronal loss. This varied vulnerability represents a valuable opportunity to explore the underlying mechanisms of AD. In this study, we investigated factors contributing to selective neuronal vulnerability by comparing transcriptomic profiles of two similar NSS nuclei with differing vulnerabilities to AD, the locus coeruleus and substantia nigra. Using paired samples from well-characterized postmortem human tissue from individuals in early Braak stages and free of comorbid neuropathologic diagnoses, we identified pathways related to cholesterol homeostasis and antioxidant pathways response as key potential drivers of vulnerability., We leveraged transcriptomics and immunohistochemistry in paired samples from human postmortem tissue representing a vulnerable and resilient region – the locus coeruleus (LC) and substantia nigra (SN). These regions have comparable anatomical features but distinct vulnerability to AD. 
Participant selection and neuropathologic assessment
Cases were sourced from the Biobank for Aging Studies at the University of São Paulo  and the Neurodegenerative Disease Brain Bank at the University of California, San Francisco Memory and Aging Center which is an ADRC. Consent for brain donation was obtained from subjects or next of kin following the site-specific protocol approved by the relevant Institutional Review Board and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki. In both brain banks, brain tissue was sampled for neuropathological diagnosis following NACC guidelines. Basic histological and immunohistochemical stains..., , # Data from: Pathways underlying selective neuronal vulnerability in Alzheimer's disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra

**Immunohistochemistry data, supplementary data, and supplementary methods**

[https://doi.org/10.5061/dryad.sbcc2frgp](https://doi.org/10.5061/dryad.sbcc2frgp)

## Trancriptomic analysis

### Description of the data and file structure

The frozen half of the brainstem for selected cases was kept on dry ice during the dissection. A scalpel was used to shave down the midbrain until the pigmented SN was exposed. An additional 3-5mm of midbrain was shaved down around the rostral portion of the SN, with borders defined by the pigmented area. The protruding portion of the SN was sliced off of the shaved-down face of the midbrain and put into RNAlater (AM7020, Invitrogen) to protect RNA in case of thawing during transport for processing. The sample in RNAlater was frozen down at -80C and transported on dry ice.

The LC was isol..., This dataset is derived from human research subjects who enrolled in a research study approved by a site-specific IRB. Participants, or a next-of-kin, provided informed consent permitting the use of and sharing of de-identified data. All personally identifiable information are removed when data are shared using technical controls approved by the relevant IRB's.