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AD/PD 2023 | Underlying mechanisms of vulnerability in early Alzheimer’s disease

There are over a dozen neuromodulatory subcortical structures of the brain that are affected very early on in Alzheimer’s disease (AD), and the locus coeruleus is one of the more vulnerable nuclei. Alexander J. Ehrenberg, PhD candidate, University of California, Berkeley, CA, explains his work assessing the mechanisms underlying vulnerability in patients with AD and their potential as therapeutic targets. This study was conducted using brainstem tissue samples from a wide age range of patients. The more vulnerable locus coeruleus and the less vulnerable substantia nigra were dissected in order to identify differences that may underly selective vulnerability. Using differential gene expression analysis and gene ontology, the study found significant differences in pathways related to oxidative stress, lipid metabolism, and neuroinflammation. Targeting mechanisms related to early vulnerability is a promising strategy in AD, as it addresses the underlying biology of the disease rather than consequential pathology. Currently, Dr Ehrenberg and his team are developing hypotheses based on the transcriptomic data and hoping to test them in vitro and in vivo to answer what specific oxidative stress pathways are involved, how specific organelles are affected, and where along these pathways vulnerability can be modified. This interview took place at the AD/PD™ 2023 congress in Gothenburg, Sweden.

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AJE has received support for travel from the Rainwater Charitable Foundation and Deutsches Zentrum für Neurodegenerative Erkrankungen, has received consulting fees from Epiodyne Inc., holds stock in Eiger Biopharmecuticals, is a Science Editor for “Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association”, and serves on the executive committee for the Neuromodulatory Subcortical Systems PIA of ISTAART.