- March 31, 2026
- Nick Fox, et al., University College London
Topic/Product:
CNS Disease Panel 120
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma
Abstract
Background Autosomal dominant Alzheimer’s disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation.
Methods We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers.
Results Nine proteins (Aβ42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed Aβ42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use.
Conclusion Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD.
Authors & Affiliations
Christopher R. S. Belder¹²³, Amanda J. Heslegrave⁴, Owen Swann⁴, Emily Abel³⁴, Millie Beament³, Moneeb Nasir³, Helen Rice³, Philip S. J. Weston³⁴, Natalie S. Ryan³⁴, Lyle J. Palmer⁵, Amy Brodtmann# ⁶⁷⁸⁹, Timothy Kleinig¹², Henrik Zetterberg⁴¹⁰¹¹¹²¹³¹⁴, and Nick C. Fox³⁴
¹ School of Medicine, Adelaide University, Adelaide, SA, Australia
² Department of Neurology, Royal Adelaide Hospital and Queen Elizabeth Hospital, Adelaide, SA, Australia
³ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK
⁴ UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
⁵ Australian Institute of Machine Learning, Adelaide University, Adelaide, SA, Australia
⁶ School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
⁷ Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
⁸ Alfred Health, Monash University, Melbourne, Victoria, Australia
⁹ Melbourne Health Cognitive Neurology Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
¹¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
¹² Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
¹³ Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
¹⁴ Centre for Brain Research, Indian Institute of Science, Bangalore, India