Alzheimer's polygenic risk in predicting longitudinal decline in non-demented
individuals with history of traumatic brain injury 
   Lead Investigator:    William Mantyh
   Institution      :    UCSF
   E-Mail           :    william.mantyh@ucsf.edu
   Proposal ID      :    1377



   Proposal Description:
   The relationship and underlying mechanism between traumatic brain injury (TBI) and TBI-related dementia is poorly understood. Well established evidence exists linking TBI with increased risk for numerous neurodegenerative brain diseases, such as Alzheimer?s disease (AD), Chronic Traumatic Encephalopathy (CTE), and Parkinson?s disease. However, TBI survivors do not invariably develop a neurodegenerative disease later in life and patients with dementia usually do not have a history of head injury, indicating that more work is needed to understand the relationship between TBI and TBI-associated dementia.     The polygenic hazard score (PHS) (Desikan, 2017), which identified genetic risk factors that account for the variability in the age of onset of late onset Alzheimer's disease (LOAD), may also have promise in predicting the variation in age of onset of dementia in patients with a history of TBI. There are numerous reasons to believe that this LOAD-derived PHS is worth exploring as a predictive measure in patients with a history of TBI. Firstly, epidemiologic studies have suggested a link between TBI and AD (Sivanandam, 2012), and past TBI exposure has been suggested to drive onset of AD to an earlier age (Schaffert, 2018 Mendez, 2015). Secondly, strikingly similar to the early stages of AD, early neuropathology studies in TBI have found that diffuse amyloid plaques appear rapidly in the acute phase of patients following head injury (Roberts, 1991 and 1994 Ikonomovic, 2004). More recent literature suggests that amyloid-beta within the axon may serve as a reservoir for plaque formation (Johnson, 2010). Thirdly, Chronic Traumatic Encephalopathy (CTE) is strongly linked to repetitive but also single head trauma (Mez, 2017), and is a disease that shares numerous features with AD (Mez, 2017 McKee 2016).     Although there are considerable and important differences in the neurofibrillary tangles in CTE vs. AD, including ultrastructural differences in tau filament tertiar