For the first time since Alzheimer's disease (AD) was discovered, amyloid-modifying treatments are being evaluated in clinical trials, while other anti-tau antibodies and other disease-modifying treatments are in development. These treatment hold promise to modify the course of AD, and even prevent its clinical manifestation, if administered early enough. Three urgent needs now present themselves: 1) to improve our ability to detect preclinical AD and track is progression using biomarkers, 2) to understand the temporal relationships between amyloid aggregation, tau aggregation and cognitive decline, and 3) to leverage that information to increase the efficiency and probability of success of preclinical treatment trials. In this proposal, we work with an extraordinary kindred of approximately 5,000 individuals in Antioquia, Colombia, which contains roughly 1500 carriers of the autosomal-dominant Presenilin1 (PSEN1) E280A mutation. These carriers are virtually certain to develop early onset AD, and have a well-characterized disease course, with mild cognitive impairment (MCI) occurring at a mean age of 45, and dementia at a mean age of 51. Previously we used a cross-sectional approach to characterize biomarker changes as a function of age, and in relation to the kindred's mean age of clinical onset. We are currently performing the first cross-sectional tau PET imaging study with this kindred. The addition of the longitudinal data proposed here will greatly improve our understanding of the temporal and spatial trajectories of tau and amyloid in preclinical ADAD, and their relation to subsequent cognitive decline. These data will help inform the design and analysis of prevention trials, including the ongoing Alzheimer's Prevention Initiative (API) autosomal-dominant AD (ADAD) trial. We will acquire a comprehensive set of neuroimaging and neuropsychological data at baseline, 18- and 36-months in 30 cognitively unimpaired PSEN1 mutation carriers (ages 30-45 years), 30 age-matched non-carrier family members, and 20 cognitively impaired carriers (ages 40-55 years). The hypothesis that amyloid exerts harmful effects on the brain mainly by facilitating tau aggregation has been offered, but evidence for or against it in humans is limited. We hypothesize that in preclinical ADAD, cortical amyloid pathology precedes tau pathology in the medial temporal lobe (MTL). Further, tau should correlate more strongly than amyloid with memory network disruption and with cognitive impairment. All subjects will be evaluated to accomplish the following specific aims: 1) Examine the role of tau pathology in memory network dysfunction in preclinical ADAD; 2) Determine the extent to which PET measures of amyloid and tau pathology can be used as prognostic biomarker for subsequent cognitive decline and clinical progression; and 3) Provide a biomarker profile of preclinical ADAD that can inform AD trial design.

Public Health Relevance

This longitudinal study proposes the use of advanced neuroimaging techniques, including tau and amyloid PET imaging, to detect and track brain changes associated with preclinical Alzheimer?s disease (AD) in a unique kindred with autosomal dominant AD, the largest in the world. This effort will significantly improve our understanding of the evolution of AD pathology, temporal relationships between amyloid pathology, tau pathology and cognitive decline, and will help inform AD prevention trials, including the Alzheimer?s Prevention Initiative autosomal-dominant trial.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code