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Biphasic Changes in CSF Biomarkers in AD
Data from clinicopathological and biomarker studies of Alzheimer’s disease (AD) have converged to support the existence of a long “preclinical” (asymptomatic) stage during which pathologies develop before the appearance of cognitive symptoms. Substantiating the longitudinal change in biomarkers over time will advance our basic understanding of the disease and provide information critical for the design and interpretation of disease-modifying clinical trials that use biomarkers for subject enrollment, for proof of target engagement, or as outcome measures. Biomarkers are required to identify individuals in the preclinical stage to target them for secondary prevention trials designed to preserve normal cognitive function. Study of families with autosomal-dominant AD (ADAD) mutations permits characterization of biomarker changes during the full range of the disease process because of the certainty of eventual dementia in mutation carriers and the relatively predictable ages at symptom onset within families. Analysis of cerebrospinal fluid (CSF) collected longitudinally in research participants in the Dominantly Inherited Alzheimer Network (DIAN), a multicenter, international biomarker study of ADAD, revealed reductions in amyloid-β1–42 (indicating the presence of amyloid plaques) and increases in markers of neuronal injury (tau, ptau181, and VILIP-1) in mutation carriers during the early presymptomatic stage. However, concentrations of injury-related markers in carriers at later stages of the disease decreased over time, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. If corroborated, this longitudinal pattern of neurodegeneration-related biomarker change will likely influence the definition and interpretation of a positive versus negative effect of a therapy on disease progression.
- Copyright © 2014, American Association for the Advancement of Science
