Serum transthyretin and risk of cognitive decline and dementia: 22-year longitudinal study

Serum transthyretin (TTR) may be an early biomarker for Alzheimer's disease and related disorders (ADRD). We investigated associations of TTR measured at baseline with cognitive decline and incident ADRD and whether TTR trajectories differ between ADRD cases and non-cases, over 22 years before diagnosis. A total of 6024 adults aged 45-69 in 1997-1999 were followed up until 2019. TTR was assessed three times, and 297 cases of dementia were recorded. Higher TTR was associated with higher cognitive function at baseline; however, TTR was unrelated to subsequent change in cognitive function. TTR at baseline did not predict ADRD risk (hazard ratio per SD TTR (4.8 mg/dL) = 0.97; 95% confidence interval: 0.94-1.00). Among those later diagnosed with ADRD, there was a marginally steeper downward TTR trajectory than those free of ADRD over follow-up (P=0.050). Our findings suggest TTR is not neuroprotective. The relative decline in TTR level in the preclinical stage of ADRD is likely to be a consequence of disease processes.