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Hypothetical Preclinical Alzheimer Disease Groups and Longitudinal Cognitive Change

TitleHypothetical Preclinical Alzheimer Disease Groups and Longitudinal Cognitive Change
Publication TypeJournal Article
Year of Publication2016
AuthorsSoldan, A, Pettigrew, C, Cai, Q, Wang, MC, Moghekar, AR, O'Brien, RJ, Selnes, OA, Albert, MS
JournalJAMA Neurol
Date PublishedJun 01
ISBN Number2168-6149
Accession Number27064267
KeywordsAdult, Aged, Aged, 80 and over, Alzheimer Disease/cerebrospinal fluid/*complications/genetics, Amyloid beta-Peptides/cerebrospinal fluid, Apolipoproteins E/genetics, Cognition Disorders/cerebrospinal fluid/*etiology/genetics, Cohort Studies, Disease Progression, Female, Humans, Male, Mental Status Schedule, Middle Aged, Neuropsychological Tests, Peptide Fragments/cerebrospinal fluid, tau Proteins/cerebrospinal fluid, Young Adult

IMPORTANCE: Clinical trials testing treatments for Alzheimer disease (AD) are increasingly focused on cognitively normal individuals in the preclinical phase of the disease. To optimize observing a treatment effect, such trials need to enroll cognitively normal individuals likely to show cognitive decline over the duration of the trial. OBJECTIVE: To identify which group of cognitively normal individuals shows the greatest cognitive decline over time based on their cerebrospinal fluid biomarker profile. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, cognitively normal participants were classified into 1 of the following 4 hypothetical preclinical AD groups using baseline cerebrospinal fluid levels of Abeta and tau or Abeta and phosphorylated tau (p-tau): stage 0 (high Abeta and low tau), stage 1 (low Abeta and low tau), stage 2 (low Abeta and high tau), and suspected non-AD pathology (SNAP) (high Abeta and high tau). The data presented herein were collected between August 1995 and August 2014. MAIN OUTCOMES AND MEASURES: An a priori cognitive composite score based on the following 4 tests previously shown to predict progression from normal cognition to symptom onset of mild cognitive impairment or dementia: Paired Associates immediate recall, Logical Memory delayed recall, Boston Naming, and Digit-Symbol Substitution. Linear mixed-effects models were used to compare the cognitive composite scores across the 4 groups over time, adjusting for baseline age, sex, education, and their interactions with time. RESULTS: Two hundred twenty-two cognitively normal participants were included in the analyses (mean follow-up, 11.0 years [range, 0-18.3 years] and mean baseline age, 56.9 years [range, 22.1-85.8 years]). Of these, 102 were stage 0, 46 were stage 1, 28 were stage 2, and 46 were SNAP. Individuals in stage 2 (low Abeta and high tau [or p-tau]) had lower baseline cognitive scores and a greater decline in the cognitive composite score relative to the other 3 groups (beta