ABSTRACT Mild traumatic brain injury (mTBI, concussion) has emerged as a risk factor for the development of neurodegenerative disorders such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy, which are characterized by the aberrant aggregation of tau within neural cells. However, the mechanisms linking mTBI to AD-related pathology later in life remain unknown. Disruption of the sleep-wake cycle (SWD) is a frequent chronic complaint after mTBI and also accompanies the development of AD. More recent clinical and translational research suggests that SWD may actually promote the development of Alzheimer’s-related pathology. Our preliminary data show that sleep disturbance is significantly associated with lower CSF Aβ42 levels (an AD-associated profile) in Veterans with mTBI >45 years of age. Based on these findings, we propose that post-TBI sleep disruption promotes the development of AD-related pathology following mTBI. This will be directly tested in Aim 1. The glymphatic system is a recently characterized brain-wide network of perivascular spaces that supports the clearance of both Aβ and tau. Glymphatic function is greatest during sleep and is impaired by TBI. Our published and preliminary data show that MRI-visible perivascular space burden (MV-PVS), a putative marker of glymphatic impairment, is increased among Veterans with blast mTBI and that these changes are associated with AD-related CSF biomarker profiles. In Aim 2, we will use novel MRI-based approaches to test whether glymphatic impairment predicts the development of AD-related pathology after blast mTBI. Sleep-wake behavior is regulated through central noradrenergic (NA) neurotransmission, with locus coeruleus (LC)-derived norepinephrine (NE) promoting arousal during waking. In our blast mTBI Veterans, CSF NE was elevated compared to controls and associated with poor sleep. However, the role that changes in central NA signaling play in promoting AD-related pathology following TBI is unknown. In Aim 3 we will test whether changes in measures of central NA tone predict the development of AD-related pathology after blast mTBI. Dr. Peskind’s 10-year longitudinal VA cohort will contribute 70 previously- and newly-enrolled Veterans >45 years of age with a history of repetitive blast mTBIs who will undergo assessment of: subjective and objective sleep; multi-domain clinical behavioral, neurological, and neurocognitive assessment; glymphatic function measured by MRI, and measurement of CSF/plasma AD/CTE-related biomarkers and NE. Aim 1. Define the role of sleep disruption in the development of post-TBI AD-related pathology. Aim 2. Define the role of glymphatic dysfunction in the development of post-TBI AD-related pathology. Aim 3. Define the role of alterations in central NA tone in the development of post-TBI AD-related pathology after TBI.

PROJECT NARRATIVE This study investigates – in Iraq/Afghanistan combat Veterans 45 years of age and older who have experienced multiple concussions from explosions – sleep disturbance, impairment of the brain’s own natural ability to clear waste products and toxic substances, and the brain adrenaline system. We are studying how these processes may combine to increase the risk of Alzheimer’s disease and other disorders that cause dementia. If we are successful, we will gain information that may help us prevent these devastating diseases.