Belder_2026_medRxiv__

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 (Abeta42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed Abeta42 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. WHAT IS ALREADY KNOWN ON THIS TOPIC: The molecular pathology of Alzheimer's disease develops many years before the onset of symptoms, and multiple plasma biomarkers of Alzheimer's pathology have been identified. Understanding the timing of biomarker abnormality is important to guide trial design for the timing of interventions to prevent the onset of dementia. WHAT THIS STUDY ADDS: Using an autosomal dominant Alzheimer's disease cohort, we identify multiple plasma biomarkers that distinguish mutation carriers from non-carrier familial controls and characterise the timing of these changes relative to symptom onset. We demonstrate that biomarkers show change many years before symptom onset: markers of abnormal tau phosphorylation more than 20 years prior, followed by markers of reactive astrocytosis and synaptic dysfunction approximately 15 years prior, and neurodegenerative markers within 10 years of symptoms. HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY: Plasma biomarkers could be used in pre-clinical autosomal dominant Alzheimer's disease to chart disease trajectories and predict symptom onset, allowing targeted disease-modifying therapy implementation and optimised clinical trial design.