Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment

Takeshi Ikeuchi; Mayuka Kanda; Hitomi Kitamura; Fumiyoshi Morikawa; Shuta Toru; Chika Nishimura; Kensaku Kasuga; Takayoshi Tokutake; Tetsuya Takahashi; Yasuko Kuroha; Nobuhiko Miyazawa; Shin Tanaka; Kumiko Utsumi; Kenjiro Ono; Satoshi Yano; Tadanori Hamano; Satoshi Naruse; Ryuji Yajima; Noriko Kawashima; Chikako Kaneko; Hisatsugu Tachibana; Yuki Yano; Yumiko Kato; Sakino Toue; Hiroko Jinzu; Akihiko Kitamura; Yuri Yokoyama; Eiji Kaneko; Minoru Yamakado; Kenji Nagao

doi:10.3389/fnut.2022.1040476

Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment

Front Nutr. 2022 Dec 14:9:1040476. doi: 10.3389/fnut.2022.1040476. eCollection 2022.

Authors

Takeshi Ikeuchi¹, Mayuka Kanda², Hitomi Kitamura², Fumiyoshi Morikawa³, Shuta Toru⁴, Chika Nishimura⁵, Kensaku Kasuga¹, Takayoshi Tokutake^{1

6}, Tetsuya Takahashi⁷, Yasuko Kuroha⁷, Nobuhiko Miyazawa⁸, Shin Tanaka⁹, Kumiko Utsumi¹⁰, Kenjiro Ono¹¹, Satoshi Yano¹¹, Tadanori Hamano¹², Satoshi Naruse¹³, Ryuji Yajima¹³, Noriko Kawashima¹⁴, Chikako Kaneko¹⁵, Hisatsugu Tachibana¹⁶, Yuki Yano², Yumiko Kato², Sakino Toue², Hiroko Jinzu¹⁷, Akihiko Kitamura¹⁸, Yuri Yokoyama¹⁸, Eiji Kaneko¹⁹, Minoru Yamakado²⁰, Kenji Nagao²

Affiliations

¹ Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
² Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co., Inc., Kawasaki, Japan.
³ Department of Psychiatry, Asahikawa Keisenkai Hospital, Asahikawa, Japan.
⁴ Department of Neurology, Nitobe Memorial Nakano General Hospital, Tokyo, Japan.
⁵ Kurumi Clinic, Tokyo, Japan.
⁶ Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
⁷ Department of Neurology, Nishiniigata Chuo Hospital, Niigata, Japan.
⁸ Department of Neurosurgery, Kofu Neurosurgical Hospital, Kofu, Japan.
⁹ Mishima Hospital, Niigata, Japan.
¹⁰ Department of Psychiatry, Sunagawa City Medical Center, Sunagawa, Japan.
¹¹ Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
¹² Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan.
¹³ Department of Neurology, Midori Hospital, Niigata, Japan.
¹⁴ Kawashima Neurology Clinic, Fujisawa, Japan.
¹⁵ Southern TOHOKU Medical Clinic, Koriyama, Japan.
¹⁶ Department of Neurology, Takatsuki General Hospital, Takatsuki, Japan.
¹⁷ Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Japan.
¹⁸ Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹⁹ Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan.
²⁰ Department of Nursing, Ashikaga University, Ashikaga, Japan.

Abstract

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants.

Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted.

Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group.

Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status.

Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

Keywords: APOE; MMSE–Mini-Mental State Examination; biomarker discovery; multicenter clinical study; protein malnutrition.

Copyright © 2022 Ikeuchi, Kanda, Kitamura, Morikawa, Toru, Nishimura, Kasuga, Tokutake, Takahashi, Kuroha, Miyazawa, Tanaka, Utsumi, Ono, Yano, Hamano, Naruse, Yajima, Kawashima, Kaneko, Tachibana, Yano, Kato, Toue, Jinzu, Kitamura, Yokoyama, Kaneko, Yamakado and Nagao.