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

APOE4 Status is Related to Differences in Memory-Related Brain Function in Asymptomatic Older Adults with Family History of Alzheimer’s Disease: Baseline Analysis of the PREVENT-AD Task Functional MRI Dataset

“…Participant demographics and mean motion during fMRI are shown in Table 2 . Evidence suggests that proximity to the age of AD diagnosis in a parent or sibling may predict the onset of dementia symptomatology [ 32 ]. We therefore included estimated years to AD symptom onset (EYO), calculated as the age of AD onset in the earliest affected family member subtracted from the participant’s current age, as part of these baseline analyses.…”

Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well‐characterized cohorts

“…It is also possible that, despite similar levels of Aβ burden at baseline, females may accumulate Aβ at a faster rate, however, the literature has not comprehensively investigated this supposition. In one recent study, proximity to parental estimated year of onset for sporadic AD corresponded with higher Aβ burden cross-sectionally in females relative to males, but no evidence was found of sex differences in Aβ accumulation longitudinally [37].…”

Brain properties predict proximity to symptom onset in sporadic Alzheimer’s disease

“…Our work builds on a growing body of literature suggesting that, despite its simplicity, the years to estimated symptom onset measure may contain important information with respect to preclinical trajectories. Accumulation of amyloid-β in the cerebral cortex is an early and specific marker of Alzheimer’s disease, and years to estimated symptom onset has been associated with abnormality in amyloid biomarkers across three cohorts of individuals with a family history of Alzheimer’s disease, including the present sample ( Villeneuve et al , 2018 ). Similarly, years to estimated symptom onset has been associated with decline in cognition in another, similar cohort ( Ritchie et al , 2017 ).…”