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Abstract
Objective To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.
Methods We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.
Results Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7–10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.
Conclusion These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.
Glossary
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- ADAD=
- autosomal dominant Alzheimer disease;
- aMC=
- asymptomatic mutation carriers;
- CDR=
- Clinical Dementia Rating scale;
- DIAN=
- Dominantly Inherited Alzheimer Network;
- EYO=
- estimated years to symptom onset;
- FDG=
- fluorodeoxyglucose;
- LME=
- linear mixed effects model;
- LOAD=
- late-onset Alzheimer disease;
- MC=
- mutation carriers;
- NC=
- noncarriers;
- NFT=
- neurofibrillary tangle;
- p-tau=
- phosphorylated tau;
- PiB=
- Pittsburgh compound B
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Coinvestigators are listed at links.lww.com/WNL/A698.
CME Course: NPub.org/cmelist
- Received August 22, 2017.
- Accepted in final form July 5, 2018.
- © 2018 American Academy of Neurology
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