Hypothetical preclinical Alzheimer disease groups and longitudinal cognitive change

Anja Soldan, Corinne Pettigrew, Qing Cai, Mei Cheng Wang, Abhay R. Moghekar, Richard J. O'Brien, Ola A. Selnes, Marilyn S. Albert, Barbara Rodzon, Rebecca F Gottesman, Ned Sacktor, Guy McKhann, Scott Turner, Leonie Farrington, Maura Grega, Gay Rudow, Daniel D'Agostino, Scott Rudow, Michael Miller, Susumu MoriTilak Ratnanather, Timothy Brown, Hayan Chi, Anthony Kolasny, Kenichi Oishi, Thomas Reigel, Laurent Younes, Abby Spangler, Roberta Scherer, David Shade, Ann Ervin, Jennifer Jones, Matt Toepfner, Lauren Parlett, April Patterson, Aisha Mohammed, Daisy Lu, Juan Troncoso, Barbara Crain, Olga Pletnikova, Karentmr Fisher

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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 Aβ and tau or Aβ and phosphorylated tau (p-tau): stage 0 (high Aβ and low tau), stage 1 (low Aβ and low tau), stage 2 (low Aβ and high tau), and suspected non-AD pathology (SNAP) (high Aβ 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 Aβ 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 (β ≤ -0.06 for all and P ≤ .001 for the rate of decline for all). Individuals in stage 0, stage 1, and SNAP did not differ from one another in cognitive performance at baseline or over time (11.0 years) and showed practice-related improvement in performance. The APOE ϵ4 genotype was not associated with baseline cognitive composite score or the rate of change in the cognitive composite score. CONCLUSIONS AND RELEVANCE These results suggest that, to optimize observing a treatment effect, clinical trials enrolling cognitively normal individuals should selectively recruit participants with abnormal levels of both amyloid and tau (ie, stage 2) because this group would be expected to show the greatest cognitive decline over time if untreated.

Original languageEnglish (US)
Pages (from-to)698-705
Number of pages8
JournalJAMA Neurology
Issue number6
StatePublished - Jun 2016

ASJC Scopus subject areas

  • Clinical Neurology


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