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Principal Investigator: ANDERS M DALE
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $1,808,989
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is costly and burdensome. As the US population ages, AD’s public health impact
continues to grow. NIH and Alzheimer’s Association consensus statements indicate that understanding early
phases of disease progression—such as mild cognitive impairment (MCI)—beginning in middle age is key to
slowing dementia onset. Identifying at-risk individuals early is also estimated to result in massive savings.
Despite the protracted progression of AD brain pathology, little is known about its temporal course from middle
to older age, particularly for neuroimaging indices. The Vietnam Era Twin Study of Aging (VETSA) focuses on
early identification of risk for MCI/AD and AD-related brain changes beginning when subjects were in their 50s.
The proposed VETSA MRI wave 4 project, with a mean age of 74 (67-78), occurs during a time of increased
incident MCI/AD. That, in combination with our longitudinal data, allows for improved ability to determine
neuroimaging correlates, trajectories, and their predictors. Continued data collection will allow us to examine
the transition period from pre- to post-disease onset and expand on prediction from midlife for an increasing
number of individuals. This project is linked to the funded general VETSA 4 grant (AG050595) which collects
10-12 hours per subject of cognitive, health/medical, psychosocial and biomarker data. In addition, we can
elucidate genetic and environmental influences on these processes via combined twin and genome-wide
genotyping/polygenic score data. We also capitalize on early (age 20) cognitive data, a unique feature
enabling us to differentiate cognitive decline from longstanding differences. We request funds to cover MRI
acquisition, processing, and analysis (n=500), leveraging associated ongoing work in the general VETSA 4
grant. Aims are: 1) Develop, validate, and characterize novel early brain indicators of risk for MCI/AD. We will
develop and validate a novel AD brain signature based on diffusion MRI and show that this brain signature of
adults who are only in their 50s improves prediction of progression to MCI. We also hypothesize that integrity
of the locus coeruleus—the earliest brain site of tau deposition—will be another early, sensitive risk indicator.
2) Examine cerebrovascular risk factors and their relationship with cognition and AD biomarkers.
Cerebrovascular disease (CVD) is the most common pathology concomitant with AD and may contribute to
disease progression or be an independent source of brain and cognitive decline. We particularly focus on CVD
markers of white matter hyperintensities and arterial spin labeling (ASL) perfusion. 3) Quantify the magnitude
of neurodegeneration from midlife to early old age and its underlying genetic and environmental influences.
We will examine genetic influences on longitudinal change in macro- and micro-structural brain measures. Our
approach includes identifying mediating/moderating effects of risk factors across the lifespan and leveraging
our twin and genome-wide genotype data. Covering ~18 years, this project will be a resource for advancing
knowledge about early identification of risk for MCI/AD, with potential for a profound public health impact.
Terms: <21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD related dementia><ADRD><APOE e4><APOE-ε4><APOEε4><Adult><Adult Human><Age><Aged 65 and Over><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's and related dementias><Alzheimer's biomarker><Alzheimer's brain><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease biological marker><Alzheimer's disease brain><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 Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Aβ><Biological Markers><Blood Plasma><Brain><Brain Nervous System><Brain Pathology><Brain Vascular><Brain Vascular Disorders><Brain region><Causality><Cell Communication and Signaling><Cell Signaling><Cerebrovascular Circulation><Cerebrovascular Disease><Cerebrovascular Disorders><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Consensus><DWI (diffusion weighted imaging)><DWI-MRI><Data><Data Collection><Dementia><Deposit><Deposition><Development><Diabetes Mellitus><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease><Disease Marker><Disease Progression><Disorder><Disturbance in cognition><Early identification><Education><Educational aspects><Encephalon><Etiology><Funding><Genetic><Genetic Diversity><Genetic Variation><Genotype><Goals><Grant><Health><Hour><Hypertension><Impaired cognition><Individual><Intracellular Communication and Signaling><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Knowledge><Link><Locus Coeruleus><MR Imaging><MR Tomography><MRI><MRIs><MT-bound tau><Magnetic Resonance Imaging><Measures><Mediating><Medical><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Modality><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Nerve Degeneration><Neuron Degeneration><Nuclear Magnetic Resonance Imaging><Nucleus Pigmentosus Pontis><Onset of illness><Outcome><Participant><Pathologic><Pathology><Pattern><Perfusion><Phase><Plasma><Plasma Serum><Population><Position><Positioning Attribute><Predisposition><Primary Senile Degenerative Dementia><Process><Public Health><QOL><Quality Control><Quality of life><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Sampling><Savings><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smoking><Source><Structure><Susceptibility><Testing><Thick><Thickness><Time><Twin Multiple Birth><Twin Studies><Twins><United States National Institutes of Health><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viet Nam><Vietnam><White Matter Hyperintensity><Work><Zeugmatography><a beta peptide><abeta><above age 65><adulthood><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged brain><aged ≥65><ages><aging brain><alzheimer risk><amyloid beta><amyloid-b protein><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><arterial spin labeling><arterial spin tagging><beta amyloid fibril><bio-markers><biologic marker><biological signal transduction><biomarker><blood flow in brain><blue nucleus><brain blood circulation><brain blood flow><brain vascular disease><brain vascular dysfunction><brain vascular health><causation><cerebral blood flow><cerebral circulation><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular blood flow><cerebrovascular dysfunction><cerebrovascular health><cerebrovascular pathology><cognitive dysfunction><cognitive loss><cohort><cost><dMRI><data acquisition><data acquisitions><design><designing><developmental><diabetes><diffusion tensor imaging><disease causation><disease onset><disorder onset><genome scale><genome-wide><genomewide><high blood pressure><human old age (65+)><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><hypoperfusion><improved><in vivo><indexing><interest><intracranial vascular dysfunction><life span><lifespan><locus ceruleus structure><malleable risk><microtubule bound tau><microtubule-bound tau><mid life><mid-life><middle age><middle aged><midlife><mild cognitive disorder><mild cognitive impairment><modifiable risk><multi-modality><multimodality><neural degeneration><neural imaging><neuro-imaging><neurodegeneration><neurodegenerative><neuroimaging><neurological degeneration><neurological imaging><neuronal degeneration><novel><old age><older adult><older adulthood><over 65 years><p-tau><p-τ><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><posttranslational modification of tau><prevent><preventing><primary degenerative dementia><prodromal AD><prodromal Alzheimer's><prodromal Alzheimer's disease><protective factors><psychosocial><senile dementia of the Alzheimer type><soluble amyloid precursor protein><tau><tau Proteins><tau factor><tau phosphorylation><tau posttranslational modification><tau-1><vascular risk factor><virtual><τ Proteins><τ phosphorylation><≥65 years>