Project Summary
Growing clinical evidence suggests that traumatic brain injury (TBI) is a major risk-factor over an
individual’s lifetime, and results in symptoms and pathophysiology consistent with Alzheimer’s disease (AD)
and related dementias (ADRD). Rodent models recapitulate early pathological clinical features of TBI, but it
is unknown if these models manifest long-term ADRD features such as cognitive decline, neurodegenerative
brain atrophy, chronic inflammation, vascular disturbances, and accumulation of amyloid-β (Aβ) and altered
fluid biomarker levels. Well-known risk factors for TBI-induced ADRD (i.e. APOE, sex etc.) influence
susceptibility for lifespan progression, but the role of TBI pathophysiology has not been well characterized.
This proposal will fill these knowledge gaps using a closed head injury (CHI) TBI model over the animal’s
lifespan that exhibits ADRD-like features. Using the CHI TBI model, we will examine how AD risk alleles (i.e.
humanized amyloid-β (hAβ), APOEε4, and hAβ.APOEε4) accelerate ADRD progression. Importantly, cognitive
behavioral outcomes, clinically relevant neuroimaging (PET, MRI) using established protocols (ADNI3)
combined with fluid biomarkers will be used to assess disease advancement. Construct and face validity
measures (within and between performance sites will be demonstrated using multi-modal data modeling to
confirm replicability and to differentiate between TBI+ADRD from TBI or ADRD trajectories alone.
Using our CHI TBI mouse model, which replicates human mild/moderate TBI, and exhibits altered blood
brain barrier (BBB), progressive cognitive decline, late Aβ deposition, chronic neuroinflammation, and
progressive vascular perturbations, we will establish in sex and age-specific manner the conditions for TBI
evolution to ADRD. We also will leverage NIA-funded MODEL-AD platform mice expressing hAβ and APOEε4
on a C57BL/6J (B6) background, as significant risk factors for ADRD progression. Using these models
exposed to TBI, we will investigate how injury exposure at 3 epochs (juvenile 17D; middle 8M, old 12M) across
lifespan (24M of age) influences progression to ADRD (Aim 1). A repeated CHI TBI will be identically tested
to demonstrate a further increased vulnerability to ADRD (Aim 2). Finally, we will leverage these multi-modal
data in an unbiased manner to establish internal/external consistency and reproducibility (construct validity)
as well as modeling how this maps to human progressive trajectories to dissociate TBI+ADRD from TBI or
ADRD alone (Aim 3). These Aims will demonstrate, validate, and replicate our hypothesis that TBI throughout
the lifespan continuum leads to age-specific trajectories towards ADRD symptomology. The proposed
research will result in a deeply phenotyped TBI model as it progresses to ADRD, and the role of sex and age
of injury. The derived data will serve as a significant resource to accelerate future research into the
mechanisms of TBI ADRD.
