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Original Investigation
May 2018

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

Author Affiliations
  • 1Department of Psychiatry, McGill University, Montreal, Quebec, Canada
  • 2Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
  • 3Douglas Mental Health University Institute, Studies on Prevention of Alzheimer's Disease (StOP-AD) Centre, Montreal, Quebec, Canada
  • 4McGill Centre for Integrative Neuroscience, McGill University, Montreal, Quebec, Canada
  • 5Department of Neurology, Washington University School of Medicine, St Louis, Missouri
  • 6Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri
  • 7Department of Radiology, Washington University School of Medicine, St Louis, Missouri
  • 8Wisconsin Alzheimer's Institute, University of Wisconsin–Madison School of Medicine and Public Health, Madison
  • 9Alzheimer's Disease Research Center, University of Wisconsin–Madison School of Medicine and Public Health, Madison
JAMA Neurol. 2018;75(5):608-619. doi:10.1001/jamaneurol.2017.5135
Key Points

Question  Can proximity to parental symptom onset be used to help estimate amyloid-β burden in preclinical sporadic Alzheimer disease?

Findings  In this study of 101 cognitively normal individuals with a parental history of sporadic Alzheimer disease, amyloid-β burden increased as individuals approached their parent’s age at symptom onset.

Meaning  This study indicates that, as in autosomal dominant Alzheimer disease, an individual’s proximity to parent’s age at symptom onset may help estimate the advancement of preclinical disease.

Abstract

Importance  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.

Objective  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  The association between proximity to parental symptom onset and Aβ burden in asymptomatic individuals with a parental history of sporadic AD.

Results  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.

Conclusions and Relevance  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.

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