Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease

Abstract

Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia. This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant's proximity to his/her parent's symptom onset by subtracting the index relative's onset age from his/her current age. The association between proximity to parental symptom onset and Aβ levels was then assessed using apolipoprotein E ε4 (APOE4) status and sex as interactive terms. These analyses were performed again in 2 independent cohorts using CSF and Pittsburgh compound B carbon 11-labeled positron emission tomography (PIB-PET) Aβ biomarkers: the Adult Children Study (ACS) and the Wisconsin Registry for Alzheimer Prevention (WRAP) cohorts. The association between proximity to parental symptom onset and Aβ burden in asymptomatic individuals with a parental history of sporadic AD. The present analysis included a subset of 101 PREVENT-AD individuals (mean [SD] age, 61.8 [5.1] years; 30 [29.7%] male), 128 ACS participants (112 participants underwent CSF measurement: mean [SD] age, 63.4 [5.1] years; 31 [27.7%] male; and 107 underwent PIB-PET: mean [SD] age, 64.6 [5.3] years; 27 [25.2%] male), and 135 WRAP participants (85 participants underwent CSF measurement: mean [SD] age, 59.9 [6.0] years; 27 [31.8%] male; and 135 underwent PIB-PET: mean [SD] age, 59.6 [6.1] years; 43 [31.9%] male). In the PREVENT-AD cohort, individuals approaching their parent's onset age had lower CSF Aβ1-42 levels (range, 402-1597; B = -9.09, P = .04). This association was stronger in APOE4 carriers (B = -17.9, P = .03) and women (B = -19.8, P = .02). In the ACS cohort, the main association was replicated using PIB-PET data, and the sex interaction was replicated using CSF and PIB-PET data. In the WRAP cohort, the results were not replicated using cross-sectional data, but the main association and the APOE interaction were replicated using PIB-PET longitudinal data. These results suggest that proximity to parental symptom onset may help estimate Aβ biomarker changes in women or APOE4 carrier asymptomatic individuals with a parental history of sporadic AD.