YEARS TO PARENTAL SYMPTOM ONSET PREDICTS AMYLOID BURDEN IN HEALTHY ELDERLY WITH A PARENTAL HISTORY OF SPORADIC ALZHEIMER DISEASE

Abstract

In autosomal dominant genetic forms of Alzheimer's disease (AD), biomarker changes follow a predictable course, with mutation carriers showing progressive biomarker change as their age approaches their family's typical age of symptom onset. We sought to assess whether amyloid-beta (Aβ) burden, the main pathological hallmark of AD, appeared in a similarly predictable manner among cognitively normal persons with a parental history of “sporadic” AD. We analyzed cerebrospinal fluid (CSF) Aβ1–42 from 101 cognitively normal older adults from the PREVENT-AD cohort. We estimated each individual's proximity to their parent's symptom onset by subtracting their index relative's onset age from their current age [Estimated Years from Symptom Onset, Bateman NEJM;367: 795–804 2012]. We then assessed the relationship between proximity to parental symptom onset and Aβ levels, using APOE4 status and gender as interactive terms. These analyses were repeated in two independent cohorts using CSF and PIB-PET Aβ biomarkers. In the PREVENT-AD cohort, CSF Aβ1–42 values decreased (indicative of the presence of amyloid) as individuals approached their parent's age of symptom onset (Fig.1). Interaction analyses showed that this effect was stronger in both APOE4 carriers and women, even when controlling for age. The main findings were replicated in two independent cohorts using both CSF and PET data. Proximity to parent symptom onset might be used in clinical trials to help gauge the advancement of pre-clinical disease. “Estimated Years from Symptom Onset” and amyloid burden in sporadic AD. As individuals get closer to their parent age of onset (EYO) they show decreased concentrations of amyloid in the CSF and increased brain amyloid deposition as measured by PIB-PET. These relationships are stronger in women and in APOE4 carriers. Analyses were controlled for age, gender and education. t p<0.07 * p<0.05.