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Original Investigation |

Hypothetical Preclinical Alzheimer Disease Groups and Longitudinal Cognitive Change

Anja Soldan, PhD1; Corinne Pettigrew, PhD1; Qing Cai, MS2; Mei-Cheng Wang, PhD2; Abhay R. Moghekar, MBBS1; Richard J. O’Brien, MD, PhD3; Ola A. Selnes, PhD1; Marilyn S. Albert, PhD1 ; for the BIOCARD Research Team
[+] Author Affiliations
1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
3Department of Neurology, Duke University School of Medicine, Durham, North Carolina
JAMA Neurol. 2016;73(6):698-705. doi:10.1001/jamaneurol.2016.0194.
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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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Figure 1.
Timeline Showing the Design of the BIOCARD Study

Shown are types of data collected each year for BIOCARD between 1995 and 2014. CSF indicates cerebrospinal fluid; JHU, The Johns Hopkins University; MRI, magnetic resonance imaging; and NIH, National Institutes of Health.

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Figure 2.
Estimates of Longitudinal Cognitive Change for the 4 Hypothetical Preclinical Alzheimer Disease (AD) Groups

Shown are estimates from linear mixed-effects models predicting longitudinal cognitive composite scores over time among individuals classified into the 4 preclinical AD groups (stage 0, stage 1, stage 2, and suspected non–Alzheimer disease pathology [SNAP]) using baseline cerebrospinal fluid Aβ1-42 and phosphorylated tau (p-tau) (A) or Aβ1-42 and total tau (B) for classification. The estimates are adjusted for baseline age, sex, education, and their interactions with time. Stage 2 had a greater decline and lower baseline cognitive composite scores than the other groups, which did not differ from one another (Table 3).

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