title: Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease.
abstract: Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post-traumatic stress disorder diagnoses. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance in individuals at genetic risk for Alzheimer's disease, with the caveat that the order of causal effects cannot be inferred from cross-sectional studies. These results underscore the importance of documenting head injuries even within the mild range as they may interact with genetic risk to produce negative long-term health consequences such as neurodegenerative disease.
authors.affiliation: National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.|Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Jasmeet P
authors.initials: JP
authors.lastname: Hayes
authors.affiliation: National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.|Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Logue
authors.affiliation: National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sadeh
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.|Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Spielberg
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.|Memory Disorders Research Center, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Mieke
authors.initials: M
authors.lastname: Verfaellie
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.|Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.|Memory Disorders Research Center, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hayes
authors.affiliation: National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Reagan
authors.affiliation: Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.|Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard University, Boston, MA, USA.|Harvard Medical School, Harvard University, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Salat
authors.affiliation: National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Wolf
authors.affiliation: Geriatric Research, Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Regina E
authors.initials: RE
authors.lastname: McGlinchey
authors.affiliation: Geriatric Research, Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Milberg
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Annjanette
authors.initials: A
authors.lastname: Stone
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Schichman
authors.affiliation: National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Miller
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D012044:Regression Analysis; D012307:Risk Factors; D014728:Veterans; D055815:Young Adult
chemical_list: D001057:Apolipoproteins E
keywords: MRI; episodic memory; neurodegenerative; neuroimaging genetics; polygenic risk score