AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Association of Transthyretin pV142I Variant with Cognitive Function Among Black Individuals: Insights from the REGARDS Study
By Bal H, Chattopadhyay A, Pampana A et al.
Introduction: Hereditary Transthyretin (TTR) amyloidosis is generally caused by missense mutations that destabilize the TTR protein, resulting in its dissociation from the tetrameric to monomeric form, which may aggregate to form amyloid fibrils that deposit in various organs. Recent studies have highlighted the association of hereditary amyloidosis with cerebral amyloid angiopathies, cerebrovascular disease, and transient focal neurological episodes. Nearly 3-4% of Black individuals are carriers of the amyloidogenic rs76992529/pV142I variant of TTR. This study aimed to determine whether Black carriers had increased cognitive decline compared with non-carriers using the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods: Participants of this study underwent periodic cognitive tests using the Animal Fluency Test (AFT), the Six-Item Screener (SIS), Word List Learning (WLL), and the Word List Delayed Recall (WLD) test. Black individuals who were genotyped using Illumina Infinium Multi-Ethnic AMR/AFR BeadChip arrays (Illumina Inc) with available data for the pV142I variant were included, and those with cardiovascular diseases (CVD), stroke symptoms, atrial fibrillation, or cognitive impairment (SIS < 5) at baseline were excluded. Linear mixed effect models were used to estimate differences in cognitive decline for each test between pV142I carriers and non-carriers, with years since first test used as the time scale. Models included participant-specific random intercepts and random slopes to account for within-participant correlation and heterogeneity in cognitive trajectories. Interaction between carrier status and time was evaluated, which estimated the difference in cognitive change among carriers and non-carriers. Models were adjusted for the baseline features, the first 10 principal components of ancestry, and incident CVD events as time-varying covariates. All the analyses were performed in R 4.5.0. Results: Of 3,929 eligible Black individuals free of baseline CVD, 118 carried the pV142I variant. (Figure 1) The baseline features of carriers and non-carriers are shown in Figure 2 . Compared with non-carriers, pV142I carriers demonstrated a significantly faster decline in AFT (β = -0.125 points/year, p = 0.021), indicating reduced executive function over time. In contrast, there were no statistically significant differences in the rate of decline between carriers and non-carriers for SIS, WLL, or WLD. (Figure 3) Conclusion In this population sample of Black individuals, TTR pV142I carriers had an increased rate of decline in executive function compared with non-carriers. To our knowledge, this is the first study to evaluate longitudinal cognitive decline in TTR pV142I carriers, and our findings suggest an association with executive dysfunction over time, warranting further investigation and clinical monitoring.