These data will hopefully stimulate further discussions

These data will hopefully stimulate further discussions in research circles and among stakeholder groups. Future research should involve a larger number of people after they have been informed of their amyloid PET status to provide additional insight on the effects of such knowledge on actual behaviors and decisions. Long-term studies on behavioral and psychological outcomes should be done to complement cross-sectional studies such as this one. There is also a need to better understand the long term and the immediate ethical issues surrounding AD risk disclosure.

Acknowledgments
The Rhode Island Alzheimer Prevention Registry was supported by funds initially from an infrastructure grant to the Alzheimer\’s Disease Cooperative Study, under 5U01 #AG10483-21, and it leucine enkephalin manufacturer is currently supported by funds from Long Term Care Group who had no role in any aspect of the study or the article. The authors received no direct funds from any source for their participation in this study.

Introduction
To date, cerebrospinal fluid (CSF, amyloid-beta [Aβ]1–42, total tau [t-tau], and phosphorylated tau [p-tau]) and neuroimaging biomarkers (structural/functional magnetic resonance imaging [fMRI] and amyloid-imaging) have been among the most studied biomarkers in individuals with prodromal AD symptoms (mild cognitive impairment [MCI]) or full AD dementia. These biomarker methods are currently the “gold standard” for biomarker-based risk prediction and their clinical utility is described in opinions of the International Working Group (IWG), National Institute of Aging-Alzheimer\’s Association (NIA-AA), European Medicines Agency (EMA), and Food and Drug Administration (FDA) [1–4]. However, CSF biomarkers suffer from the invasive nature of a lumbar puncture, issues with laboratory-to-laboratory variability and reproducibility, and a lack of globally recognized reference standards and cutoff values. In addition, neuroimaging methods require (1) specialized, expensive magnetic resonance imaging (MRI) and/or positron emission tomography (PET) scanning equipment that are only available at specific medical centers; (2) use of labile reagents; (3) specially trained medical personnel to administer the tests and interpret the results [5]; and (4) establishment of threshold/cutoff values meaningful for clinical observations.
A simple, genetics-based biomarker risk algorithm (GBRA) using a combination of apolipoprotein E (APOE, ε2,ε3,ε4), translocase of outer mitochondrial membrane 40 homolog (TOMM40) rs10524523 variable length poly-T repeat polymorphism (TOMM40′523) genotypes, and age has been developed as a prognostic tool for assessing AD age-of-onset (AOO) in asymptomatic people [6]. In this study, we present data on the predictive characteristics of the GBRA to identify people at risk for MCI due to AD [7], and comparative data for CSF and neuroimaging (fMRI) based biomarkers, and neurocognitive testing. The overall hypothesis to be tested is that the combination of age, APOE genotype, and TOMM40′523 genotype, used in an algorithm based on historical MCI/AD AOO data, will outperform algorithms based on age alone or APOE genotype in predicting conversion from normal cognition to dementia (phenoconversion) when assessed by receiver operating curves (ROC) analysis or other well-defined statistical methods to compare biomarkers. Also compared are the categories for risk of phenoconversion with widely used biomarkers for AD including CSF-based biomarkers, Pittsburgh Compound B (PIB)-PET imaging of amyloid burden, and neurocognitive tests.

Methods

Results
The Bryan-ADRC cohort was used to develop the GBRA; the ADNI cohort was used to assess the performance of the GBRA in an independent data set. Presented here are preliminary data on the predictive value of a GBRA based on age and two genetic variants: APOE genotype and TOMM40′523 genotype. The performance characteristics for the GBRA are compared with the performance characteristics of a CSF biomarker based on the combination of Aβ1–42 and t-tau, which provided a PPV of 65% (53–77%, 95% CI) in a recent meta-analysis [2]. These CSF markers were recently qualified by the EMA for selecting patients for clinical trials of AD therapeutics [2].