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

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

Takeshi Ikeuchi  1 , Mayuka Kanda  2 , Hitomi Kitamura  2 , Fumiyoshi Morikawa  3 , Shuta Toru  4 , Chika Nishimura  5 , Kensaku Kasuga  1 , Takayoshi Tokutake  1   6 , Tetsuya Takahashi  7 , Yasuko Kuroha  7 , Nobuhiko Miyazawa  8 , Shin Tanaka  9 , Kumiko Utsumi  10 , Kenjiro Ono  11 , Satoshi Yano  11 , Tadanori Hamano  12 , Satoshi Naruse  13 , Ryuji Yajima  13 , Noriko Kawashima  14 , Chikako Kaneko  15 , Hisatsugu Tachibana  16 , Yuki Yano  2 , Yumiko Kato  2 , Sakino Toue  2 , Hiroko Jinzu  17 , Akihiko Kitamura  18 , Yuri Yokoyama  18 , Eiji Kaneko  19 , Minoru Yamakado  20 , Kenji Nagao  2
Affiliations

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

Takeshi Ikeuchi et al. Front Nutr. .

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.

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Conflict of interest statement

TI, FM, STor, CN, TTa, NM, STan, KU, KO, TH, SN, NK, CK, HT, AK, EK, and MY’s respective institutions or research organizations were paid for joint research or case incorporation by Ajinomoto Co., Inc. MK, HK, YYa, STou, YKa, HJ, and KN are full-time employees of Ajinomoto Co., Inc. Ajinomoto Co., Inc. funded the study and participated in the study design, implementation, analysis, and interpretation of the data. This does not alter the authors’ adherence to all of the journal policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Summary of study design. MCI, mild cognitive impairment; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; CN, cognitively normal; PFAA, plasma free amino acid.
FIGURE 2
FIGURE 2
Comparison of plasma free amino acid (PFAA) concentrations among mild cognitive impairment (MCI)-stable, Alzheimer’s disease (AD)-convert, and cognitively normal (CN) individuals. Differences in PFAA concentrations between groups are described by the receiver operating characteristic (ROC) of an area under the curve (AUC). (A) The MCI-stable group was set as the control. (B) The CN group was set as the control. In the CN group, taurine data were partially missing (N = 48 were missing).
FIGURE 3
FIGURE 3
Stratified analysis of plasma branched-chain amino acid (BCAA) concentrations in mild cognitive impairment (MCI) individuals by apolipoprotein E ε4 (APOEε4) positive/negative status. Red and blue dots represent females and males, respectively. Crude p: p-value calculated based on the logistic regression model with no covariates. Adjusted p: p-value calculated based on the logistic regression model adjusted for age, sex, and BMI. Bold text indicates statistical significance according to a p-value less than 0.05.
See this image and copyright information in PMC

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