Thyroid Function and the Risk of Alzheimer's Disease: A Mendelian Randomization Study

Area of Science:

• Neuroscience
• Endocrinology
• Genetics

Background:

• Observational studies suggest a link between thyroid function and dementia risk, but causality remains unclear.
• Investigating the causal relationship between thyroid function within the normal range and Alzheimer's disease (AD) risk is crucial.
• Understanding the role of hypothyroidism in AD pathogenesis requires further investigation.

Purpose of the Study:

• To determine if genetically predicted normal range thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels causally influence Alzheimer's disease (AD) risk.
• To examine the potential causal effect of hypothyroidism on AD risk.
• To investigate potential reverse causation between AD and thyroid function.

Main Methods:

• Mendelian randomization (MR) analyses utilized genetic variants associated with normal range TSH and fT4 levels.
• Secondary analyses focused on hypothyroidism and employed bidirectional MR to assess reverse causality.
• Large-scale summary statistics from the ThyroidOmics Consortium and AD genome-wide association studies were used.

Main Results:

• Increased genetically predicted normal range TSH levels were associated with a decreased risk of AD (p=0.02).
• This association was more pronounced in individuals younger than 50 years (p=0.04).
• No significant causal associations were found for fT4, hypothyroidism, or reverse causation from AD to thyroid function.

Conclusions:

• Genetically predicted TSH levels within the normal range, especially in younger individuals, may be protective against AD.
• Thyroid-stimulating hormone (TSH) shows a potential protective role against Alzheimer's disease (AD) in specific populations.
• Further research is needed to elucidate the pathophysiological mechanisms underlying the observed TSH-AD association.