TY - JOUR
T1 - Hypothetical preclinical Alzheimer disease groups and longitudinal cognitive change
AU - Soldan, Anja
AU - Pettigrew, Corinne
AU - Cai, Qing
AU - Wang, Mei Cheng
AU - Moghekar, Abhay R.
AU - O'Brien, Richard J.
AU - Selnes, Ola A.
AU - Albert, Marilyn S.
AU - Rodzon, Barbara
AU - Gottesman, Rebecca F
AU - Sacktor, Ned
AU - McKhann, Guy
AU - Turner, Scott
AU - Farrington, Leonie
AU - Grega, Maura
AU - Rudow, Gay
AU - D'Agostino, Daniel
AU - Rudow, Scott
AU - Miller, Michael
AU - Mori, Susumu
AU - Ratnanather, Tilak
AU - Brown, Timothy
AU - Chi, Hayan
AU - Kolasny, Anthony
AU - Oishi, Kenichi
AU - Reigel, Thomas
AU - Younes, Laurent
AU - Spangler, Abby
AU - Scherer, Roberta
AU - Shade, David
AU - Ervin, Ann
AU - Jones, Jennifer
AU - Toepfner, Matt
AU - Parlett, Lauren
AU - Patterson, April
AU - Mohammed, Aisha
AU - Lu, Daisy
AU - Troncoso, Juan
AU - Crain, Barbara
AU - Pletnikova, Olga
AU - Fisher, Karentmr
N1 - Publisher Copyright:
Copyright 2016 American Medical Association. All rights reserved.
PY - 2016/6
Y1 - 2016/6
N2 - 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.
AB - 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.
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U2 - 10.1001/jamaneurol.2016.0194
DO - 10.1001/jamaneurol.2016.0194
M3 - Article
C2 - 27064267
AN - SCOPUS:84974602452
SN - 2168-6149
VL - 73
SP - 698
EP - 705
JO - JAMA Neurology
JF - JAMA Neurology
IS - 6
ER -