Effect of the Casein-Derived Peptide Met-Lys-Pro on Cognitive Function in Community-Dwelling Adults Without Dementia: A Randomized, Double-Blind, Placebo-Controlled Trial

Figures & data

Table 1 Baseline Characteristics of the Participants

Characteristics	MKP	Placebo
	(n = 134)	(n = 134)
Male/female, n	43/91	42/92
Age, years [range]	68.1 (8.4) [43–92]	68.5 (8.0) [46–88]
SBP, mmHg	126.1 (13.2)	127.2 (14.4)
DBP, mmHg	71.4 (9.4)	73.5 (10.5)
BMI, kg/m^2	23.0 (2.9)	22.5 (3.0)
Education, years	13.2 (1.7)	13.0 (1.8)
SF-8 (PCS)	61.7 (8.1)	62.3 (7.2)
SF-8 (MCS)	51.8 (5.5)	52.1 (4.7)
GDS	1.6 (1.6)	1.5 (1.5)
ADAS-cog [range]	4.1 (2.2) [0.3–12.3]	4.1 (2.1) [0.3–10.0]
MoCA-J [range]	25.8 (2.8) [18–30]	25.9 (2.9) [16–30]
HDS-R [range]	28.7 (1.5) [23–30]	28.6 (1.3) [23–30]

Note: Data represent numbers or means (with standard deviations).

Abbreviations: MKP, Met-Lys-Pro; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; SF-8, Short Form-8; PCS, Physical Component Summary; MCS, Mental Component Summary; GDS, Geriatric Depression Scale; ADAS-cog, cognitive subscale of the Alzheimer’s Disease Assessment Scale; MoCA-J, Japanese version of the Montreal Cognitive Assessment; HDS-R, Revised Hasegawa’s Dementia Scale.

Figure 1 Study flow diagram.

Abbreviation: MKP, Met-Lys-Pro.

Table 2 Summary of the Cognitive Tests in the Intention-to-Treat Population

	Group	Baseline	Week 12	Week 24	P value	ES (d)
Number of participants	M	134	129	128
	P	134	127	125
ADAS-cog total score	M	4.08 (2.17)	3.94 (2.14)	3.18 (1.88)	0.302	0.12
	P	4.10 (2.10)	4.21 (2.38)	3.43 (2.10)
Word recall	M	2.33 (1.17)	2.69 (1.27)	1.85 (1.16)	0.635	0.08
	P	2.40 (1.22)	2.87 (1.47)	1.93 (1.13)
Spoken language ability	M	0.01 (0.09)	0.00 (0.00)	0.00 (0.00)	NA	NA
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Comprehension of spoken language	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	NA	NA
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Word-finding difficulty	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	NA	NA
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Following commands	M	0.28 (0.48)	0.29 (0.52)	0.27 (0.46)	0.299	0.11
	P	0.31 (0.55)	0.23 (0.42)	0.22 (0.42)
Naming	M	0.00 (0.00)	0.01 (0.09)	0.00 (0.00)	NA	NA
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Constructions	M	0.09 (0.42)	0.02 (0.12)	0.01 (0.09)	0.054	0.24
	P	0.10 (0.30)	0.03 (0.18)	0.08 (0.41)
Ideational praxis	M	0.09 (0.42)	0.03 (0.28)	0.03 (0.28)	0.625	0.07
	P	0.04 (0.29)	0.09 (0.44)	0.02 (0.18)
Orientation	M	0.10 (0.32)	0.08 (0.32)	0.05 (0.26)	0.022*	0.30
	P	0.13 (0.38)	0.11 (0.34)	0.15 (0.38)
Word recognition	M	1.18 (1.06)	0.83 (0.88)	0.97 (0.94)	0.677	0.04
	P	1.13 (1.00)	0.88 (0.99)	1.01 (1.01)
Recall of test instructions	M	0.01 (0.09)	0.00 (0.00)	0.00 (0.00)	0.313	0.13
	P	0.01 (0.09)	0.00 (0.00)	0.01 (0.09)
MoCA-J	M	25.82 (2.83)	26.36 (2.61)	27.34 (2.24)	0.417	0.08
	P	25.87 (2.91)	26.18 (2.64)	27.14 (2.50)
HDS-R	M	28.67 (1.50)		28.18 (2.04)	0.885	0.05
	P	28.57 (1.34)		28.08 (1.99)

Notes: Data represent numbers or means (with standard deviations). *P < 0.05 (vs placebo). P values were derived by the analysis of covariance (the scores at week 24 were adjusted for the baseline score).

Abbreviations: M, Met-Lys-Pro; P, placebo; ADAS-cog, cognitive subscale of the Alzheimer’s Disease Assessment Scale; MoCA-J, Japanese version of the Montreal Cognitive Assessment; HDS-R, Revised Hasegawa’s Dementia Scale; ES, effect size; NA, not available because scores of both groups at week 24 were 0.

Table 3 Subgroup Analysis of the Cognitive Tests by Age

	Group	Age < 65 Years		Age ≥ 65 Years
		Baseline	Week 24	Baseline	Week 24
Number of participants	M	33	32	101	96
	P	35	32	99	93
ADAS-cog total score	M	3.35 (2.25)	2.88 (1.80)	4.32 (2.10)	3.28 (1.91)
	P	3.09 (1.67)	2.68 (1.33)	4.45 (2.12)	3.69 (2.25)
Word recall	M	1.81 (1.12)	1.75 (1.19)	2.50 (1.14)	1.88 (1.15)
	P	1.97 (0.96)	1.86 (0.91)	2.54 (1.27)	1.96 (1.20)
Spoken language ability	M	0.00 (0.00)	0.00 (0.00)	0.01 (0.10)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Comprehension of spoken language	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Word-finding difficulty	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Following commands	M	0.30 (0.47)	0.31 (0.47)	0.28 (0.49)	0.26 (0.46)
	P	0.29 (0.57)	0.16 (0.37)	0.31 (0.55)	0.25 (0.43)
Naming	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Constructions	M	0.00 (0.00)	0.00 (0.00)	0.12 (0.48)	0.01 (0.10)*
	P	0.03 (0.17)	0.00 (0.00)	0.12 (0.33)	0.11 (0.48)
Ideational praxis	M	0.03 (0.17)	0.00 (0.00)	0.11 (0.47)	0.04 (0.32)
	P	0.00 (0.00)	0.00 (0.00)	0.05 (0.33)	0.02 (0.21)
Orientation	M	0.18 (0.46)	0.03 (0.18)	0.07 (0.26)	0.06 (0.28)*
	P	0.09 (0.37)	0.06 (0.25)	0.14 (0.38)	0.18 (0.42)
Word recognition	M	1.02 (1.20)	0.79 (1.03)	1.23 (1.00)	1.03 (0.90)
	P	0.69 (0.62)	0.60 (0.60)	1.28 (1.07)	1.16 (1.09)
Recall of test instructions	M	0.00 (0.00)	0.00 (0.00)	0.01 (0.10)	0.00 (0.00)
	P	0.03 (0.17)	0.00 (0.00)	0.00 (0.00)	0.01 (0.10)
MoCA-J	M	26.79 (2.13)	27.66 (1.94)	25.50 (2.97)	27.24 (2.33)
	P	27.09 (2.63)	28.25 (1.34)	25.44 (2.89)	26.76 (2.70)
HDS-R	M	28.79 (1.14)	29.28 (0.96)	28.63 (1.60)	27.81 (2.18)
	P	28.74 (1.07)	29.41 (1.07)	28.51 (1.42)	27.62 (2.03)

Notes: Data represent numbers or means (with standard deviations). *P < 0.05 (vs placebo). Data were analyzed by the analysis of covariance (the scores at week 24 were adjusted for the baseline score).

Abbreviations: M, Met-Lys-Pro; P, placebo; ADAS-cog, cognitive subscale of the Alzheimer’s Disease Assessment Scale; MoCA-J, Japanese version of the Montreal Cognitive Assessment; HDS-R, Revised Hasegawa’s Dementia Scale.

Table 4 Subgroup Analysis of the Cognitive Tests by MoCA-J Score

	Group	MoCA-J < 26		MoCA-J ≥ 26
		Baseline	Week 24	Baseline	Week 24
Number of participants	M	57	54	77	74
	P	55	52	79	73
ADAS-cog total score	M	5.25 (2.10)	4.15 (2.10)	3.22 (1.79)	2.48 (1.34)
	P	5.19 (1.96)	4.17 (2.09)	3.34 (1.85)	2.90 (1.95)
Word recall	M	2.93 (1.09)	2.44 (1.20)	1.89 (1.02)	1.41 (0.91)
	P	2.95 (1.13)	2.31 (1.15)	2.01 (1.13)	1.66 (1.04)
Spoken language ability	M	0.02 (0.13)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Comprehension of spoken language	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Word-finding difficulty	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Following commands	M	0.39 (0.53)	0.30 (0.50)	0.21 (0.44)	0.26 (0.44)
	P	0.33 (0.55)	0.31 (0.47)	0.29 (0.56)	0.16 (0.37)
Naming	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Constructions	M	0.14 (0.35)	0.00 (0.00)	0.05 (0.46)	0.01 (0.12)
	P	0.15 (0.36)	0.13 (0.60)	0.06 (0.25)	0.04 (0.20)
Ideational praxis	M	0.14 (0.58)	0.02 (0.14)	0.05 (0.22)	0.04 (0.35)
	P	0.02 (0.13)	0.04 (0.28)	0.05 (0.35)	0.00 (0.00)
Orientation	M	0.19 (0.44)	0.11 (0.37)	0.03 (0.16)	0.01 (0.12)*
	P	0.29 (0.53)	0.23 (0.47)	0.01 (0.11)	0.10 (0.30)
Word recognition	M	1.43 (1.13)	1.29 (1.19)	0.99 (0.96)	0.74 (0.62)
	P	1.44 (1.02)	1.14 (0.84)	0.91 (0.93)	0.92 (1.12)
Recall of test instructions	M	0.02 (0.13)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.02 (0.13)	0.00 (0.00)	0.00 (0.00)	0.01 (0.12)
MoCA-J	M	23.09 (1.84)	26.13 (2.50)	27.84 (1.34)	28.23 (1.52)
	P	22.96 (1.96)	25.83 (2.85)	27.90 (1.28)	28.08 (1.71)
HDS-R	M	28.07 (1.72)	27.00 (2.39)	29.12 (1.12)	29.04 (1.15)*
	P	28.02 (1.52)	27.50 (2.20)	28.95 (1.05)	28.49 (1.72)

Notes: Data represent numbers or means (with standard deviations). *P < 0.05 (vs placebo). Data were analyzed by the analysis of covariance (the scores at week 24 were adjusted for the baseline score).

Abbreviations: M, Met-Lys-Pro; P, placebo; ADAS-cog, cognitive subscale of the Alzheimer’s Disease Assessment Scale; MoCA-J, Japanese version of the Montreal Cognitive Assessment; HDS-R, Revised Hasegawa’s Dementia Scale.

Table 5 Subgroup Analysis of the Cognitive Tests by Medication Status

	Group	Without Medication		With Medication
		Baseline	Week 24	Baseline	Week 24
Number of participants	M	56	51	78	77
	P	52	43	82	82
ADAS-cog total score	M	4.01 (2.28)	3.05 (1.96)	4.13 (2.10)	3.27 (1.84)
	P	3.80 (2.21)	3.05 (1.99)	4.29 (2.01)	3.62 (2.14)
Word recall	M	2.29 (1.18)	1.75 (1.26)	2.36 (1.17)	3.27 (1.84)
	P	2.23 (1.16)	1.81 (1.13)	2.50 (1.25)	2.00 (1.13)
Spoken language ability	M	0.00 (0.00)	0.00 (0.00)	0.01 (0.11)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Comprehension of spoken language	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Word-finding difficulty	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Following commands	M	0.29 (0.49)	0.25 (0.48)	0.28 (0.48)	0.29 (0.45)
	P	0.25 (0.56)	0.16 (0.37)	0.34 (0.55)	0.26 (0.44)
Naming	M	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
	P	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Constructions	M	0.13 (0.57)	0.00 (0.00)	0.06 (0.25)	0.01 (0.11)
	P	0.12 (0.32)	0.05 (0.21)	0.09 (0.28)	0.10 (0.49)
Ideational praxis	M	0.11 (0.45)	0.02 (0.14)	0.08 (0.39)	0.04 (0.34)
	P	0.00 (0.00)	0.00 (0.00)	0.06 (0.36)	0.02 (0.22)
Orientation	M	0.07 (0.26)	0.00 (0.00)**	0.12 (0.36)	0.09 (0.33)
	P	0.13 (0.40)	0.16 (0.37)	0.12 (0.36)	0.15 (0.39)
Word recognition	M	1.13 (1.10)	1.03 (1.05)	1.21 (1.03)	0.93 (0.86)
	P	1.05 (1.02)	0.85 (0.93)	1.18 (0.99)	1.10 (1.05)
Recall of test instructions	M	0.00 (0.00)	0.00 (0.00)	0.01 (0.11)	0.00 (0.00)
	P	0.02 (0.14)	0.02 (0.15)	0.00 (0.00)	0.00 (0.00)
MoCA-J	M	26.55 (2.43)	27.59 (2.33)	25.29 (3.00)	27.18 (2.17)
	P	26.79 (2.52)	27.65 (2.01)	25.29 (3.00)	26.88 (2.70)
HDS-R	M	28.64 (1.33)	28.37 (2.02)	28.69 (1.33)	28.05 (2.06)
	P	28.79 (1.27)	28.47 (1.87)	28.43 (1.37)	27.88 (2.03)

Notes: Data represent numbers or means (with standard deviations). **P < 0.005 (vs placebo). Data were analyzed by the analysis of covariance (the scores at week 24 were adjusted for the baseline score).

Abbreviations: M, Met-Lys-Pro; P, placebo; ADAS-cog, cognitive subscale of the Alzheimer’s Disease Assessment Scale; MoCA-J, Japanese version of the Montreal Cognitive Assessment; HDS-R, Revised Hasegawa’s Dementia Scale.

Table 6 Summary of the SF-8 in the Intention-to-Treat Population

	Group	Baseline	Week 24	P value
Number of participants	M	134	128
	P	134	125
SF-8 (PCS)	M	61.97 (7.63)	62.90 (8.16)	0.263
	P	62.31 (7.15)	62.41 (8.17)
SF-8 (MCS)	M	51.90 (5.12)	50.92 (5.32)	0.233
	P	52.01 (4.75)	50.48 (5.59)

Notes: Data represent numbers or means (with standard deviations). P values were derived by the analysis of covariance (the scores at week 24 were adjusted for the baseline score).

Abbreviations: SF-8, Short Form-8; M, Met-Lys-Pro; P, placebo; PCS, Physical Component Summary; MCS, Mental Component Summary.

Table 7 Intervened Participants with Adverse Events by System Organ Class

System Organ Class	MKP	Placebo	P value
	(n = 134)	(n = 131)
	n (%)	n (%)
Infections and infestations	52 (38.8)	54 (41.2)	0.708
Nervous system disorders	16 (11.9)	14 (10.7)	0.847
Gastrointestinal disorders	13 (9.7)	15 (11.5)	0.693
Musculoskeletal and connective tissue disorders	7 (5.2)	9 (6.9)	0.615
Respiratory, thoracic and mediastinal disorders	5 (3.7)	8 (6.1)	0.408
General disorders and administration site conditions	2 (1.5)	1 (0.8)	1.000
Injury, poisoning and procedural complications	2 (1.5)	2 (1.5)	1.000
Cardiac disorders	1 (0.7)	1 (0.8)	1.000
Immune system disorders	1 (0.7)	2 (1.5)	0.619
Neoplasms benign, malignant and unspecified	1 (0.7)	2 (1.5)	0.619
Renal and urinary disorders	1 (0.7)	0 (0.0)	1.000
Reproductive system and breast disorders	1 (0.7)	0 (0.0)	1.000
Skin and subcutaneous tissue disorders	1 (0.7)	5 (3.8)	0.117
Ear and labyrinth disorders	0 (0.0)	1 (0.8)	0.494

Note: P values were derived by the Fisher’s exact test.

Abbreviation: MKP, Met-Lys-Pro.