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Most prevalent neurodegenerative disorders take decades to develop and their early detection is challenged by confounding non-pathological ageing processes. For all neurodegenerative conditions, we continue to lack longitudinal gene expression data covering their large temporal evolution, which hinders the understanding of the underlying dynamic molecular mechanisms. Here, we overcome this key limitation by introducing a novel gene expression contrastive trajectory inference (GE-cTI) method that reveals enriched temporal patterns in a diseased population. Evaluated on 1969 subjects in the spectrum of late-onset Alzheimer's and Huntington's diseases (from ROSMAP, HBTRC and ADNI datasets), this unsupervised machine learning algorithm strongly predicts neuropathological severity (e.g. Braak, amyloid and Vonsattel stages). Furthermore, when applied to in vivo blood samples at baseline (ADNI), it significantly predicts clinical deterioration and conversion to advanced disease stages, supporting the identification of a minimally invasive (blood-based) tool for early clinical screening. This technique also allows the discovery of genes and molecular pathways, in both peripheral and brain tissues, that are highly predictive of disease evolution. Eighty-five to ninety per cent of the most predictive molecular pathways identified in the brain are also top predictors in the blood. These pathways support the importance of studying the peripheral-brain axis, providing further evidence for a key role of vascular structure/functioning and immune system response. The GE-cTI is a promising tool for revealing complex neuropathological mechanisms, with direct implications for implementing personalized dynamic treatments in neurology., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Most prevalent neurodegenerative disorders take decades to develop and their early detection is challenged by confounding non-pathological ageing processes. For all neurodegenerative conditions, we continue to lack longitudinal gene expression data covering their large temporal evolution, which hinders the understanding of the underlying dynamic molecular mechanisms. Here, we overcome this key limitation by introducing a novel gene expression contrastive trajectory inference (GE-cTI) method that reveals enriched temporal patterns in a diseased population. Evaluated on 1969 subjects in the spectrum of late-onset Alzheimer's and Huntington's diseases (from ROSMAP, HBTRC and ADNI datasets), this unsupervised machine learning algorithm strongly predicts neuropathological severity (e.g. Braak, amyloid and Vonsattel stages). Furthermore, when applied to in vivo blood samples at baseline (ADNI), it significantly predicts clinical deterioration and conversion to advanced disease stages, supporting the identification of a minimally invasive (blood-based) tool for early clinical screening. This technique also allows the discovery of genes and molecular pathways, in both peripheral and brain tissues, that are highly predictive of disease evolution. Eighty-five to ninety per cent of the most predictive molecular pathways identified in the brain are also top predictors in the blood. These pathways support the importance of studying the peripheral-brain axis, providing further evidence for a key role of vascular structure/functioning and immune system response. The GE-cTI is a promising tool for revealing complex neuropathological mechanisms, with direct implications for implementing personalized dynamic treatments in neurology. [ABSTRACT FROM AUTHOR]