Traumatic brain injury is widely viewed as a risk factor for dementia, but the biological mechanisms underlying this association are still unclear. In previous studies, traumatic brain injury has been associated with the hallmark pathologies of Alzheimer's disease, i.e. amyloid-β plaques and neurofibrillary tangles comprised of hyperphosphorylated tau. Depending on the type and location of trauma, traumatic brain injury can induce spatially heterogeneous brain lesions that may pre-dispose for the development of Alzheimer's disease pathology in aging. Therefore, we hypothesized that a history of traumatic brain injury may be related to spatially heterogeneous amyloid-β and tau pathology patterns that deviate from the stereotypical temporo-parietal patterns in Alzheimer's disease. To test this, we included 103 Vietnam War veterans of whom 65 had experienced traumatic brain injury ( n = 40, 38.8% mild; n = 25, 24.3% moderate/severe). Most individuals had a history of 1 ( n = 35, 53.8%) or 2 ( n = 15, 23.1%) traumatic brain injury events. We included the group without a history of traumatic brain injury ( n = 38, 36.9%) as controls. The majority was cognitively normal ( n = 80, 77.7%), while a subset had mild cognitive impairment ( n = 23, 22.3%). All participants underwent [ 18 F]florbetapir/Amyvid amyloid-β PET and [ 18 F]flortaucipir/Tauvid tau-PET 39.63 ± 18.39 years after their last traumatic brain injury event. We found no differences in global amyloid-β and tau-PET levels between groups, suggesting that a history of traumatic brain injury does not pre-dispose to accumulate amyloid-β or tau pathology in general. However, we found that traumatic brain injury was associated with altered spatial patterns of amyloid-β and tau, with relatively greater deposition in fronto-parietal brain regions. These regions are prone to damage in traumatic brain injury, while they are typically only affected in later stages of Alzheimer's disease. Moreover, in our traumatic brain injury groups, the association between amyloid-β and tau was reduced in Alzheimer-typical temporal regions but increased in frontal regions that are commonly associated with traumatic brain injury. Altogether, while acknowledging the relatively small sample size and generally low levels of Alzheimer's disease pathology in this sample, our findings suggest that traumatic brain injury induces spatial patterns of amyloid-β and tau that differ from patterns observed in typical Alzheimer's disease. Furthermore, traumatic brain injury may be associated with a de-coupling of amyloid-β and tau in regions vulnerable in Alzheimer's disease. These findings indicate that focal brain damage in early/mid-life may change neurodegenerative trajectories in late-life., Competing Interests: C.G. is supported by a Dementia Fellowship grant from ZonMW (10510022110010). E.G.B.V. is PI for DIAN trials, WashU, ACI, Alnylam, CogRX therapeutics, New Amsterdam Pharma, Janssen, Roche, Vivoryon, ImmunoBrain, Alector, Biogen, BMS, Prothena, GSK, Aviadobio, Treeway. E.G.B.V. is consulent for New Amsterdam Pharma, Treeway, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, Roche, Eli Lilly en Esai. Y.A.L.P. has received funding from the Dutch Brain Foundation, ZonMW, NWO and the Mooiste Contact Fonds (both paid to her institution). Projects of R.O. received support of the European Research Council, ZonMw, NWO, National Institute of Health, Alzheimer Association, Alzheimer Nederland, Stichting Dioraphte, Cure Alzheimer’s fund, Health Holland, ERA PerMed, Alzheimerfonden, Hjarnfonden, Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. R.O. was speaker at symposia organized by GE healthcare. R.O. is an advisory board member for Asceneuron, Bristol Myers Squibb and Biogen. All the aforementioned has been paid to the institutions. R.O. is part of the editorial board of Alzheimer’s Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. N.F. received research support from the Alzheimer Forschung Initiative, the Hertie Network of Excellence in Neuroscience, the German Parkinson Foundation (DPG), the Legerlotz Foundation, the Gerhard and Ilse Schick Foundation, the Alzheimer’s Association, the Bright Focus Foundation, LMU excellence and the DFG excellence initiative, as well as speaker honoraria from Eisai, GE Healthcare, Life Molecular Imaging and Consulting Honoraria from MSD., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)