Advance-CTR Pilot Projects Program (2019)
"Using an Alzheimer's Disease Blood Test to Predict Amyloid PET in APOE ɛ4 Non-Carriers"
Co-PI: Jessica Alber, PhD
Preclinical Alzheimer’s disease (AD) (Sperling et al., 2011; Jack et al., 2018) is defined as the presence of AD biomarkers, such as beta-amyloid plaques (Aβ) on positron emission tomography brain imaging (Aβ PET), in the absence of clinical AD symptoms, and represents an ideal window for administration of potential secondary prevention therapeutics via AD prevention clinical trials. High screen fail rate on amyloid PET in AD prevention trials is cost prohibitive and delays the discovery of effective disease modifying therapeutics. The proposed study will examine the utility of combining apolipoprotein Ɛ (APOE; a genetic risk marker for AD) and novel blood-based biomarkers to predict Aβ PET results among cognitively normal older adults. The goal is to develop an economical and robust algorithm to identify at-risk individuals for AD prevention research and accelerate the discovery of effective secondary prevention therapeutics.
The proposed study has two specific aims: 1) Apply and validate novel blood-based biomarkers to predict Aβ PET positivity in cognitively normal older adults screening for AD prevention trials; 2) Demonstrate the incremental utility of blood-based biomarkers over APOE ɛ4 in predicting Aβ PET positivity, especially among APOE ɛ4 non-carriers. One hundred and fifty five participants will be recruited from the Butler Alzheimer’s Prevention Registry. All participants will complete APOE genotyping and blood draw, within 18 months of Aβ PET as part of a clinical trial screen at the Butler Hospital Memory & Aging Program. An AD blood proteomic assay (O’Bryant et al., 2016) will be tested in this study. Blood samples will be processed on a multiplex platform using electrochemiluminescence (ECL) and proteomic scores based on the 21- protein assay will be generated. Additionally, plasma Aβ42 and Aβ40 will be measured via single molecular array technology (SIMOA) and the Aβ42/40 ratio will be computed. Extra blood samples will be archived to validate future novel AD blood biomarkers. The receiver operating characteristic (ROC) approach will be used to determine the accuracy of APOE and blood biomarkers in predicting Aβ PET positivity. Logistic regression will be used to test the incremental utility of APOE (ɛ4 carrier vs. non-carrier), blood biomarkers (AD proteomic scores, Aβ42/40 ratio), and their interaction in predicting Aβ PET positivity. Positive results will support development of a widely accessible and cost-effective AD risk algorithm involving a blood test and APOE genotyping, to identify people most likely to be Aβ PET positive for more invasive and expensive PET imaging, in AD clinical research and practice.