| Abstrakt: |
Background: Autosomal dominant Alzheimer's disease (ADAD) is caused by known genetic mutations that start a cascade of events leading to Aβ deposition, tau pathology and neurodegeneration. Mutation carriers (MCs) are characterized by substantial amyloid accumulation, and dementia onset at or around the age of parental dementia onset. CSF, plasma Aβ, tau and ptau are well known biochemical biomarkers for AD. However, other proteomic changes associated with ADAD have not been explored in a systematic manner. Here, we generated high‐throughput CSF proteomic data from MCs and noncarriers (NCs), and identified proteins associated with mutation status and estimated years to symptom onset (EYO), in Dominantly Inherited Alzheimer Network (DIAN). Method: A total of 7,011 CSF proteins measured with the SomaScan 7k platform passed QC and Lumipulse assays from in 476 DIAN participants: 281 MCs, 185 NCs. We utilized linear models with participants' status, age, gender and surrogate variables to identify proteins associated with mutation status. Then, predictable trajectory intersection of EYO between MCs and NCs were identified. We applied enrichment analysis to evaluate biological functions of significant proteins. Result: We identified 243 significant proteins (FDR < 0.05) associated with status. The 'Established' AD biomarkers, phospho‐Tau181, Tau, neurofilament light polypeptide, Aβ42 were our top 5, 19, 25and 33 hits. The top 10 proteins included SMOC1, 14‐3‐3 proteins, SLIT2 or DNAJB9. Through the EYO trajectory intersection, we found several proteins with trajectory changes earlier than Aβ (‐11.0 years) or NEFL (‐11.6 years); these include SMOC1 and 14‐3‐3 proteins, with changes ‐30.7 and ‐13.5 years before the estimated symptomatic onset. Gene ontology analysis suggested that the identified proteins were enriched in axon development, axonogenesis and neuron projection morphogenesis. Alzheimer disease and pathways of neurodegeneration were identified by KEGG pathway gene set enrichment. The identified proteins were enriched in astrocytes, macrophages and neurons by cell marker analysis. Conclusion: Our analyses identified 243 proteins associated with ADAD mutation status. Of these 93% of them change before the estimated symptomatic onset and could be leveraged to better predict the year of symptom onset. The enrichment analysis revealed the identified proteins may closely associated with the development of Alzheimer disease. [ABSTRACT FROM AUTHOR] |
