ABSTRACT
Objective Compare cognitive and hippocampal volume (HCV) trajectories in asymptomatic middle-aged and older adults with positive cerebrospinal fluid (CSF) markers of β-amyloid (Aβ) or tau to adults without an AD-associated biomarker profile.
Method 392 adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer’s Prevention or Wisconsin Alzheimer’s Disease Research Center) completed a lumbar puncture and at least two biennial or annual neuropsychological evaluations. Cutoffs for Aβ42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5) and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group × age at each visit on cognitive and HCV outcomes.
Results 215 participants (69%) were biomarker negative (preclinical AD Stage 0), 46 (15%) were Aβ+ only (preclinical AD Stage 1), 25 (8%) were Aβ+ and tau+ (preclinical AD Stage 2), and 28 (9%) were tau+ only. Both Stage 1 and Stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and non-linear decline on list-learning and set-shifting measures compared to Stage 0. The tau+ only group did not significantly differ from Stage 0 in rates of cognitive decline.
Conclusion In an asymptomatic at-risk cohort, elevated CSF Aβ (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.
Footnotes
lrclark{at}medicine.wisc.edu, seberman{at}medicine.wisc.edu, dlnorton2{at}wisc.edu, rekoscik{at}wisc.edu, jonaitis{at}wisc.edu, Kaj.Blennow{at}neuro.gu.se, bbb{at}medicine.wisc.edu, sa{at}medicine.wisc.edu, scj{at}medicine.wisc.edu, henrik.zetterberg{at}clinchem.gu.se, cmc{at}medicine.wisc.edu
AUTHOR CONTRIBUTIONS: Lindsay Clark: Drafting/revising the manuscript, study concept or design, analysis or interpretation of data, statistical analysis. Sara Berman: Drafting/revising the manuscript, study concept or design, analysis or interpretation of data, statistical analysis. Derek Norton: Analysis or interpretation of data, statistical analysis. Rebecca Koscik: Drafting/revising the manuscript, Analysis or interpretation of data, statistical analysis. Erin Jonaitis: Drafting/revising the manuscript, Analysis or interpretation of data, statistical analysis. Kaj Blennow: Analysis or interpretation of data, Contribution of vital reagents/tools/patents. Barbara Bendlin: Analysis or interpretation of data, obtaining funding. Sanjay Asthana: Study concept or design, study supervision or coordination, obtaining funding. Dr. Asthana reports no disclosures. Sterling Johnson: Drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision or coordination, obtaining funding. Henrik Zetterberg: Analysis or interpretation of data, contribution of vital reagents/tools/patents. Cynthia Carlsson: Study concept or design, analysis or interpretation of data, acquisition of data, study supervision or coordination.
AUTHOR DISCLOSURES:
Dr. Clark reports no disclosures.
Ms. Berman reports no disclosures.
Mr. Norton reports no disclosures.
Dr. Koscik reports no disclosures.
Dr. Jonaitis reports no disclosures.
Dr. Blennow holds the Torsten Söderberg professorship in Medicine.
Dr. Bendlin reports no disclosures.
Dr. Johnson reports no disclosures.
Dr. Zetterberg is a Wallenberg Academy Fellow.
Dr. Carlsson is a site principal investigator for a project jointly funded by the NIH and Lilly (A4 study).
STUDY FUNDING: The project described was supported by NIH grants UL1TR00427, ADRC P50 AG033514 (SA), R01 AG027161 (SCJ), R01 AG021155 (SCJ), R01AG037639 (BBB), F30 AG054115 (SEB), T32 GM007507 (SEB) and T32 GM008692 (SEB).