Moderation of thyroid hormones for the relationship between amyloid and tau pathology
Authors: Byeon Jeong Hyeon , Byun Min Soo , Yi Dahyun , Jung Joon Hyung , Sohn Bo Kyung , Chang Yoon Young , Kong Nayeong , Jung Gijung , Ahn Hyejin , Lee Jun-Young , Lee Yun-Sang , Kim Yu Kyeong , Lee Dong Young , Sohn Chul-Ho , Jung Inhee Mook- , Choi Murim , Lee Yu Jin , Hahn Seokyung , Kim Hyun Jung , Chang Mun Young , Lee Seung Hoon , Han Na Young , Pae Jisoo , Park Hansoo , Kim Jee Wook , Lee Jong-Min , Lee Dong Woo , Moon Seok Woo , Baek Hyewon , Kim Yoon-Keun , Kim Jong-Won , Ryu Seung-Ho , Kim Shin Gyeom , Woo Jong Inn , Kim Sang Eun , Cheon Gi Jeong , Kang Koung Mi , Park Jee-Eun , Yu Hyeong Gon , Choi Hyo Jung , Choe Young Min , Kim Kwangsoo , Jeon So Yeon , Kim Woo Jin , Ko Kang , Lee Jun Ho , Park Sung Wook , Joung Haejung , Lee Han Na , Byeon Gihwan , Sung Kiyoung , Han Dong Kyun , Han Seung Min , Kim Min Jung , Kim Min Jae , Park Seo Hee , Kim Mimi , Cha Woojin , Yeom Hyeryeon , Keum Musung , Kim Min Jeong , Kim Donghee , Kim Kyungtae , Choi Jeongmin , Choi Hye Ji , Sol Bae Han , Woo Dohyun , Ha Seunghyuk ,   for the KBASE Research Group
Published: July 2024

Abstract
Background
Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition.

Methods
This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET.

Results
No associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition.

Conclusion
Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.