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Principal Investigator: Sterling C Johnson
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $2,617,616
Funding agency: National Institute on Aging
PROJECT SUMMARY / ABSTRACT
This project conducts longitudinal Alzheimer’s Disease (AD) biomarker imaging on participants in the Wisconsin
Registry for Alzheimer’s Prevention, a midlife observational cohort that is risk-enriched for AD due to parental
history of AD dementia. We have been conducting longitudinal amyloid positron emission tomography (PET)
with [11C]PiB since 2009 and tau PET with [18F]MK-6240 since 2017 together with advanced MRI, CSF and now
longitudinal plasma biomarkers. In the prior funding period we demonstrated that non-demented persons who
are Amyloid positive (A+), and tau+ (T+) have been exhibiting cognitive decline since midlife; we developed
computational methods to construe amyloid from a temporal standpoint, including individual estimates of A+
onset age and its duration; we found that A+ chronicity predicts cognitive decline and time to dementia—which
is ~23 years, giving empirical support to an oft-cited heuristic; we were an early adopter of [18F]MK-6240 for tau
PET imaging and delineated its imaging characteristics; we developed and applied cutting edge measures of
vascular compromise in the brain with dynamic 4D flow imaging including novel ways for assessing vessel
stiffness that is associated with amyloid. The overarching hypothesis of this renewal is that recontextualizing
PET amyloid burden along its temporal dimension and anchoring our analyses to A+ onset age and/or its duration
will explain heterogeneity in the expression of other biomarkers and cognitive decline. A secondary goal is to
determine what can be learned from serial plasma markers of A and T and N (relative to A+ chronology). In Aim
1, anchored to amyloid onset age we will examine factors related to progression of other biomarkers including
tau, and examine cognitive decline over a 15 yr period of observation. We will determine the characteristics
associated with T+ onset and rate of change (using MK6240 PET) relative to A+ chronicity; we will identify those
who are exhibiting disease resistance (i.e., T- in the presence of more chronic A+) and identify the modifiable
and genetic factors associated with this biomarker pattern; we will also examine plasma and CSF markers of AD
and related disorders. In Aim 2: We will examine conditional processes regarding the added influence of vascular
MRI measures on cognitive decline in the presence of progressing AD proteinopathy and patterns of
neurodegeneration. Finally, Aim 3 employs computational algorithms to create a joint spatiotemporal profile of
amyloid tau and neurodegeneration enabling a joint estimate of disease burden and progression. Significance:
This work will fill in the biomarker timeline from late-middle age, providing clarity on the temporal span of
preclinical AD proteinopathy anchored to amyloid onset. This project has the potential to greatly improve
individualized prognostic precision in view of overall known disease burden, to shed insight on characteristics of
disease resistance, and inform prevention strategies.
Terms: <(4D) flow MRI><4-D MR imaging><4-D MRI><4-D flow MR imaging><4-D flow MRI><4-D flow imaging><4-D flow magnetic resonance imaging><4-D magnetic resonance imaging><4D MR imaging><4D MRI><4D flow MR imaging><4D flow MRI><4D flow imaging><4D flow magnetic resonance imaging><4D magnetic resonance imaging><AD dementia><AD prevention><AD related dementia><ADRD><Active Follow-up><Address><Age of Onset><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer disease prevention><Alzheimer prevention><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's biomarker><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease biological marker><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimers Dementia><Alzheimer’s biological marker><Alzheimer’s disease biomarker><Amentia><Amyloid><Amyloid Substance><Amyloidosis><Astroprotein><Atlases><Aβ burden><Biological Markers><Blood Plasma><Blood Vessels><Brain><Brain Nervous System><Characteristics><Chronic><Chronology><Clinical Trials><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collection><Computational algorithm><Computing Methodologies><Data><Data Sources><Dementia><Dimensions><Disease><Disease Progression><Disease Resistance><Disorder><Disturbance in cognition><Encephalon><Exhibits><Funding><GFA-Protein><GFAP><Genetic><Genotype><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Goals><Groups at risk><Health><Heterogeneity><History><Image><Impaired cognition><Individual><Investigators><Isoforms><Joints><Knowledge><Liquid substance><Longitudinal observation study><Longitudinal, observational study><MR Imaging><MR Tomography><MRI><MRIs><MT-bound tau><Magnetic Resonance Imaging><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><NAC precursor><NMR Imaging><NMR Tomography><Nerve Degeneration><Neuron Degeneration><Nuclear Magnetic Resonance Imaging><Outcome><PARK1 protein><PARK4 protein><PET><PET Scan><PET imaging><PETSCAN><PETT><Participant><Pathology><Pattern><People at risk><Persons><Persons at risk><Phenotype><Plasma><Plasma Serum><Populations at Risk><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Preventative strategy><Prevention Research><Prevention strategy><Preventive strategy><Primary Senile Degenerative Dementia><Process><Protein Isoforms><RC3 protein><Rad.-PET><Recording of previous events><Registries><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Risk><SNCA><SNCA protein><Secondary Prevention><Serial Learning><Standardization><Symptoms><Time><Vascular Diseases><Vascular Disorder><Wisconsin><Work><Zeugmatography><a-beta burden><a-syn><a-synuclein><abeta burden><abnormally aggregated tau protein><active followup><alpha synuclein><alpha synuclein gene><alphaSP22><alzheimer risk><amyloid burden><amyloid disease><asyn><beta amyloid burden><bio-markers><biologic marker><biomarker><blood vessel disorder><burden of disease><burden of illness><cognitive dysfunction><cognitive loss><cohort><computational methodology><computational methods><computer algorithm><computer based method><computer methods><computing method><disease burden><dynamic system><dynamical system><filamentous tau inclusion><fluid><follow up><follow-up><followed up><followup><four dimensional MR imaging><four dimensional MRI><four dimensional flow><four dimensional magnetic resonance imaging><genome scale><genome-wide><genomewide><glial activation><glial cell activation><heuristics><histories><imaging><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><improved><insight><learning activity><learning method><learning strategies><learning strategy><liquid><longitudinal course><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mid life><mid-life><middle age><middle aged><midlife><neural degeneration><neurodegeneration><neurodegenerative><neurogranin><neurological degeneration><neuronal degeneration><neuronal pentraxin><non A-beta component of AD amyloid><non A4 component of amyloid precursor><non-demented><nondemented><novel><p17 protein kinase C substrate><paired helical filament of tau><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical><preclinical><primary degenerative dementia><prognostic><progression biomarker><progression marker><rate of change><resistance to disease><resistant disease><resistant to disease><self-aggregate tau><senile dementia of the Alzheimer type><spatiotemporal><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau factor><tau fibrillization><tau filament><tau neurofibrillary tangle><tau oligomer><tau paired helical filament><tau polymerization><tau-tau interaction><timeline><tool><vascular><vascular dysfunction><vasculopathy><willingness><α synuclein gene><α-syn><α-synuclein><β-amyloid burden><βamyloid burden><τ Proteins><τ aggregation>