In this proposal we explore the transition from preclinical to symptomatic Alzheimer disease (AD) by incorporating the novel tau imaging tracer ([18F]-AV-1451) within the biomarker-rich protocol of the Dominantly Inherited Alzheimer Network (DIAN). We leverage the existing infrastructure of DIAN and a collaboration with Avid Radiopharmaceuticals to initiate tau positron emission tomography (PET) imaging in this unique cohort. DIAN provides fundamental support to the hypothesis that AD consists of a preclinical stage in which accumulation of beta-amyloid (A?) plaques and tau neurofibrillary tangle (NFT) gradually lead to neuronal dysfunction and cognitive impairment. However, key gaps remain in our understanding of the temporal and spatial interactions that occur between A? and tau during the transition from preclinical to clinical symptoms. This proposal answers these fundamental questions through three aims.
Aim 1 studies the temporal dynamics of tau deposition (using AV-1451) in relation to estimated years to symptom onset (EYO) and existing biomarkers in DIAN (including cerebrospinal fluid, neuroimaging, and cognitive performance).
Aim 2 studies the spatial (both local and distributed) changes of tau deposition (using AV-1451).
Aim 3 studies the relationship between in vivo tau deposition (using AV-1451) and neuropathology. Unique to autosomal dominant AD (ADAD), the young age of the DIAN participants eliminates overlap with potential age-related neuropathology or tauopathy (PART). Our overall hypothesis is that conversion from cognitively normal to symptomatic AD can be accurately predicted by neuroimaging biomarkers, in particular by AV-1451 PET. Results from this proposal are fundamental for our understanding of PET tau as not only a diagnostic indicator of disease but also a therapeutic marker to evaluate the clinical efficacy of future interventions in ADAD.

Public Health Relevance

The Dominantly Inherited Alzheimer Network (DIAN) is an international study of autosomal dominant Alzheimer's disease (AD) which has provided critical information regarding our understanding of preclinical (asymptomatic) AD and to the development of clinical trials. This proposal examines a new tau positron emission tomography (PET) imaging biomarker ([18F]-AV-1451) in the context of DIAN. Results from this study will allow us to better understand the pathologic changes which occur during the transition from preclinical to symptomatic AD. We hypothesize that an interaction between amyloid and tau are required for conversion to symptomatic dementia in DIAN.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Hsiao, John
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Washington University
Schools of Medicine
Saint Louis
United States
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Chhatwal, Jasmeer P; Schultz, Aaron P; Johnson, Keith A et al. (2018) Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing. Brain 141:1486-1500
Gordon, Brian A; Blazey, Tyler M; Su, Yi et al. (2018) Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study. Lancet Neurol 17:241-250
Villeneuve, Sylvia; Vogel, Jacob W; Gonneaud, Julie et al. (2018) Proximity to Parental Symptom Onset and Amyloid-? Burden in Sporadic Alzheimer Disease. JAMA Neurol 75:608-619