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UK Analysis Shows Low Transthyretin Levels Linked to Increased Risk of Multiple Diseases
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Key Takeaways
- Lower TTR levels are associated with increased risk of Alzheimer's, stroke, and other severe diseases, as shown in UK Biobank data.
- Mendelian randomization analysis suggests reduced TTR levels may contribute causally to increased disease risk, including Alzheimer's and rheumatoid arthritis.
A recently presented biobank data analysis showed associations between reduced transthyretin and higher incidence of conditions such as Alzheimer disease, cardiovascular disease, and rheumatoid arthritis.
Sami Khella, MD
(Credit: The College of Physicians of Philadelphia)
In a newly presented analysis of UK Biobank data, investigators reported that lower levels of transthyretin (TTR) were significantly associated with increased risk of several severe and fatal diseases, including Alzheimer disease (AD) and stroke. The study examined data from 447,497 UK Biobank participants, including 234 patients diagnosed with transthyretin amyloidosis (ATTR), a known progressive disease caused by destabilization of TTR and amyloid deposition.1
Investigators reported in the analysis that individuals with ATTR displayed lower levels of TTR and APOA1, and higher levels of NT-proBNP (P <.05). Authors noted that these patients also showed a significantly higher presence of comorbid diseases including AD, dementia, rheumatoid arthritis, chronic obstructive pulmonary disease, cerebrovascular disease, chronic kidney disease, hypothyroidism, hemorrhagic stroke, cataract, and peripheral artery disease (all, P <.05).
Among 24,296 unrelated Caucasian participants with TTR measurements, similarly reported findings revealed that decreased TTR levels were significantly associated with increased risk of AD, dementia, stroke, cerebrovascular disease, osteoporosis, peripheral artery disease, and chronic obstructive pulmonary disease (all, P <.05). To assess causality, investigators also conducted Mendelian randomization analysis, which demonstrated that reduced TTR levels preceded and may contribute to increased risk of AD, rheumatoid arthritis, chronic kidney disease, cataract, and osteoporosis (P <.05).
These findings were recently presented at the 2025 Peripheral Nerve Society (PNS) Annual Meeting, held May 17-20, in Edinburgh, Scotland, by lead author Sami Khella, MD, chief in the department of neurology at Penn Presbyterian Medical Center at the University of Pennsylvania School of Medicine. Authors noted that prior evidence has suggested a protective role of TTR in these diseases. Given these results, researchers noted that the long-term impact of ATTR therapies, particularly those targeting TTR stabilization versus suppression, may warrant further investigation.
A prior analysis of UK Biobank participants published in Nature Communications, led by Pankaj Arora, MD, and Naman Shetty, MD, demonstrated that reduced TTR levels were associated with increased risk of heart failure and death.2,3 These prior findings further reinforce the link between low TTR and adverse clinical outcomes as observed from the recent study presented at PNS 2025, highlighting the potential importance of TTR stability in disease prevention and progression.
In the previous study, researchers analyzed data from 35,206 UK Biobank participants who had undergone plasma profiling and were free of cardiovascular and chronic kidney disease at baseline. Findings showed that TTR levels were influenced by a range of clinical factors, including sex, inflammation, and metabolic measures. Notably, individuals carrying the pathogenic V142I TTR variant had significantly lower TTR levels than non-carriers (mean: -0.5 vs -0.1; P <.001).
Results revealed that TTR levels were reported lower in females and declined with higher levels of C-reactive protein. Conversely, higher TTR levels were associated with increasing body mass index, blood pressure, total cholesterol, albumin, triglycerides, and creatinine. Carriers of the V142I variant (n = 39) had significantly lower adjusted TTR levels than noncarriers (n = 35,167). Importantly, a standard deviation decrease in TTR levels was associated with a 17% increased risk of heart failure (HR, 1.17; 95% CI, 1.08–1.26) and an 18% increased risk of all-cause mortality (HR, 1.18; 95% CI, 1.14–1.24).
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