J Neurol Neurosurg Psychiatry. 2026 Aug 24:jnnp-2026-339037. doi: 10.1136/jnnp-2026-339037. Online ahead of print.
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 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 (amyloid-beta 42 (Aβ42), beta-secretase 1 (BACE1), glial fibrillary acidic protein (GFAP), pTau181, pTau231, pTau217, t0tal tau (MAPT), neurofilament light (NfL) and acetylcholinesterase (AChE)) robustly differed between carriers and non-carriers cross-sectionally. Longitudinal analyses showed elevated Aβ42 levels were statistically discernible in carriers approximately 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at approximately 21-24 years before expected symptom onset, 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 ADAD 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.
PMID:42637536 | DOI:10.1136/jnnp-2026-339037
