History of Traumatic Brain Injury with Loss of Consciousness and APOE ε4 Carriers Synergistically Increase Late-Life Amyloid PET Burden

Background Traumatic brain injury with loss of consciousness (TBI-LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimer’s disease (AD) biology remain incompletely defined. APOE ε4 is the strongest genetic predictor of amyloid accumulation in late-onset AD, it may moderate the long-term consequences of head injury. This study investigates whether history TBI-LOC independently contributes or synergistically interacts with APOE ε4 to amplify late-life amyloid and tau burden. Methods 429 participants completed the Ohio State University TBI screening tool and an amyloid PET scan (centiloids). A subcohort (n=352) also underwent tau PET. TBI history was classified by recency (10 years) and severity (no TBI, dazing/confusion [TBI-DZ], TBI-LOC). Analyses were stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR=0 vs CDR>0). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE ε4, including an APOE*TBI-LOC status interaction term, while Fisher’s exact tests evaluated TBI recency and biomarker positivity. Results In CDR=0 participants (n=365), 119 reported a history of TBI, comprising 56 TBI-DZ and 63 TBI-LOC. TBI-LOC but not TBI-DZ, correlated with elevated amyloid PET levels (p<0.001; [4.6-17]). Furthermore, an interaction between APOE ε4 and TBI-LOC indicated that TBI-LOC augmented the amyloid-related risk associated with the APOE ε4 allele (p=0.003; [4.3-21]). The interaction persisted when stratified by TBI recency with only remote TBI-LOC (occurring more than 10 years prior) associated with increased amyloid PET (p=0.003 [5.2-25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI-amyloid correlations were observed among symptomatic participants (CDR>0; n=64) suggesting a ceiling effect of pathology once clinical dementia is present. Conclusions History of remote TBI-LOC is linked to elevated amyloid PET levels in later life, particularly among APOE ε4 carriers with a CDR=0. The robust findings for amyloid, contrasted with null tau results and the reduced association in symptomatic cases underscore the importance of considering TBI history when screening for preclinical AD and assessing early-stage risk.