Unbiased Classification of the Human Brain Proteome Resolves Distinct Clinical and Pathophysiological Subtypes of Cognitive Impairment

The hallmark amyloid-β and tau deposition of Alzheimer's disease (AD) represents only a fraction of its diverse pathophysiology. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured ~8,000 protei...

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Published inbioRxiv
Main Authors Higginbotham, Lenora A, Carter, E Kathleen, Dammer, Eric B, Haque, Rafi U, Johnson, Erik Cb, Duong, Duc, Yin, Luming, De Jager, Phillip L, Bennett, David A, Lah, James J, Levey, Allan I, Seyfried, Nicholas T
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 25.07.2022
Cold Spring Harbor Laboratory
Edition1.1
Subjects
Aging
Alzheimer's disease
Cognitive ability
Dementia disorders
Geriatrics
Inflammation
Mass spectroscopy
Neurodegeneration
Neurodegenerative diseases
Neuroscience
Pathophysiology
Prefrontal cortex
Proteomes
Proteomics
Tau protein
β-Amyloid
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ISSN2692-8205
2692-8205
DOI10.1101/2022.07.22.501017

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Summary:The hallmark amyloid-β and tau deposition of Alzheimer's disease (AD) represents only a fraction of its diverse pathophysiology. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured ~8,000 proteins across >600 dorsolateral prefrontal cortex tissues from Religious Orders Study and Rush Memory and Aging Project participants with clinical diagnoses of no cognitive impairment, mild cognitive impairment (MCI), and AD dementia. Unbiased classification of MCI and AD cases based on individual proteomic profiles resolved three classes whose expression differed across numerous cell types and biological ontologies. Two of these classes displayed molecular signatures atypical of those previously observed in AD neurodegeneration, such as elevated synaptic and decreased inflammatory markers. In one class, these atypical proteomic features were associated with clinical and pathological hallmarks of disease resilience. These results promise to better define disease heterogeneity within the cognitively impaired elderly and meaningfully impact diagnostic, prognostic, and therapeutic precision. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://www.synapse.org/ADsubtype
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Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2022.07.22.501017