. 2024 Aug 1;15(4):1688–1725. doi: 10.14336/AD.2023.0814

Table 2.

Summary of studies on insulin-related biomarkers in Alzheimer’s disease, using various assays in plasma, serum, cerebrospinal fluid, or brain homogenates.

Cohort (n)	Higher levels in	Body fluid or tissue	Summary of main results	Additional notes	Ref.
*Insulin*
NCI/MCI,AD (21/19) NINCDS/ADRDA criteria	Ctrl	CSF	NCI > MCI/AD (.005)		[251]
NCI/MCI,AD (21/19) NINCDS/ADRDA criteria	=	Serum	ns		[251]
SCI/aMCI/AD (45/44/49)	AD (women)	CSF	aMCI < SCI < AD (.059) Women: Significantly different with MMSE	Women: higher levels associated with worsen global cognition APOE4 non carriers: correlation with CSF p-tau and t-tau	[242]
Non-elderly/elderly (116/96) with 65years-old as threshold, with MetS MoCA		Plasma		Non-elderly MetS: correlation with MoCA	[344]
Ctrl/sporadic AD (60/60) neuropsychological evaluation (DSM) + MRI	AD	Serum	Ctrl < AD (<.0001)		[249]
Ctrl/other dementia/stable MCI /AD (15/13/32/60)	=	Serum	ns		[252]
Ctrl/other dementia/stable MCI /AD (15/13/32/60)	=	CSF	ns		[252]
Ctrl/AD (12/16) Braak staging	Ctrl	CSF	Ctrl > AD (.0009)		[247]
Ctrl/AD (12/16) Braak staging	Ctrl	Brain homogenate	B0-1 (Ctrl) > B6 (AD) (.05)		[247]
Ctrl like or AD like (29/30)		CSF		CSF Ctrl like: inverse association between WMHs and insulin CSF levels (parieto-occipital region)	[245]
Ctrl/aMCI (20/29) with 4 weeks high-SFA/glucose (HIGH) diet or a low SFA/glucose (LOW)	AD	CSF	HIGH diet: Ctrl < MCI/AD LOW diet: Ctrl < MCI/AD		[244]
	AD	Plasma	HIGH diet: Ctrl = MCI/AD LOW diet: Ctrl < MCI/AD		[244]
Ctrl/AD (24/21) Braak staging	Ctrl	FCx	B0-1 (Ctrl) > B2-3/B4-5/B6 (<.001)		[345]
Ctrl/AD (26/28) Braak staging	Ctrl	FCx, Hpc, Hyp	Ctrl > AD (Hyp .01; Hpc .002; ns FCx)		[346]
Ctrl/AD (16/27)	=	CSF	ns		[253]
Ctrl/mild AD/severe AD (25/14/11) Or Ctrl/homozE4/non-homozE4 (14/6/19)	AD	Plasma	Ctrl, mild AD < moderate/severe AD (.05) APOE4: normal, homoz ApoE4 < non homoz E4		[250]
	Ctrl	CSF	Ctrl > mild AD > moderate/severe AD (.05) APOE4 : ns		[250]
Ctrl/AD (26/54)	AD	CSF	Ctrl < AD (.001)		[254]
Ctrl/AD (26/54)	AD	Plasma (after OGTT/fasted)	Ctrl < AD (.001)(after OGTT); ns (fasted)		[254]
*Leptin*
Ctrl with neurological but not degenerative disease/AD (23/26)	=	Plasma	ns		[347]
Cross-sec study 669 participants		Plasma		Associated with cognitive impairment	[348]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	=	CSF	ns		[251]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	Ctrl	Serum	Ctrl > MCI/AD (.0002)		[251]
Ctrl/AD (25/30) Turkish MMSE, CDR, GDS	=	Plasma	ns		[349]
Ctrl/MCI with T2DM (63/61) MoCA	Ctrl	Plasma	Women: Ctrl > MCI	Associated with MoCA (higher levels associated with better cognition)	[350]
NCI/MCI/AD (21/8/13) NINCDS/ADRDA criteria	AD	CSF	MCI < Ctrl < AD (.05) Women > Men	↘ Leptin receptor in AD (CSF and hpc)	[351]
Ctrl/ AD (60/60) neuropsycho evaluation (DSM-IV) + MRI	Ctrl	Serum	Ctrl > AD (<.0001)		[249]
Ctrl/AD (12/16) Braak staging	=	CSF	ns		[247]
Ctrl/AD (12/16) Braak staging	AD	Brain homogenate	B0-1/B2-4 < AD (B6) (<.05)		[247]
Ctrl/AD (37/41) NINCDS-ADRDA criteria	Ctrl	Plasma	Ctrl > AD		[352]
785 participants 111 incident dementia (89 AD)	Ctrl	Plasma	Ctrl > dementia/AD		[353]
*Adiponectin*
Ctrl with neurological but not degenerative disease/AD (23/26)	=	Plasma	ns		[347]
535 non-demented elderly, with neuropsychological tests		Plasma		Women: inverse association with cognitive outcomes	[354]
Ctrl/sporadic AD (60/60) neuropsychological evaluation (DSM) + MRI	AD	Serum	Ctrl < AD (<.0001)		[249]
NCI/MCI/AD (51/65/41)	MCI/AD	Serum	NCI < MCI, AD (<.001)		[355]
NCI/MCI/AD (28/18/27) NINCDS-ADRD	MCI/AD	Plasma	NCI < MCI, AD		[356]
NCI/MCI/AD (28/18/27) NINCDS-ADRD	MCI	CSF	NCI < MCI (ns AD)		[356]
Ctrl/AD (37/41) NINCDS-ADRDA criteria	=	Plasma	ns		[352]
*Ghrelin*
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	=	CSF	ns		[251]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	AD	Serum	Ctrl < MCI/AD (<.0001)		[251]
NCI/MCI (30/22) neuropsychological tests	=	Serum	ns (total ghrelin)		[357]
NCI/MCI (30/22) neuropsychological tests	MCI	Serum	NCI < MCI (<.001) (acylated ghrelin)		[357]
Ctrl/AD (12/16) Braak staging	Ctrl	CSF	Ctrl > AD (.005)		[247]
Ctrl/AD (12/16) Braak staging	=	Brain homogenate	ns		[247]
*GIP*
Cross sectional studies, 3001 older people MMSE and AQT		Serum (2h OGTT/fasted)		Correlation with MMSE (2h OGTT) (higher levels are associated with better cognition); ns (fasted)	[358]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	MCI/AD	CSF	Ctrl < MCI/AD (.02)		[251]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	=	Serum	ns		[251]
Ctrl/AD (12/16) Braak staging	=	CSF	ns		[247]
Ctrl/AD (12/16) Braak staging	mild NFT pathology	Brain homogenate	B0-1/6 < B3-4 (<.01)		[247]
*GLP-1*
Cross sectional studies, 3001 older people MMSE and AQT		Plasma (2h OGTT/fasted)		Correlation with MMSE (2h OGTT) (higher levels are associated with better cognition); ns (fasted)	[358]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	=	CSF	ns		[251]
Ctrl/MCI,AD (21/19) NINCDS/ADRDA criteria	MCI/AD	Serum	Ctrl < MCI/AD (<.0001)		[251]
Ctrl/AD (12/16) Braak staging	Ctrl	CSF	Ctrl > AD (.012)		[247]
Ctrl/AD (12/16) Braak staging	Ctrl	Brain homogenate	B0-1 (Ctrl) > B6 (AD) (.05)		[247]
*IGF-1*
Ctrl/AD (36/ 40)		CSF		Correlation with CSF t-tau, p-tau	[255]
Ctrl/other dementia/stable MCI /AD (15/13/32/60)	=	CSF	ns		[252]
Ctrl/other dementia/stable MCI /AD (15/13/32/60)	AD	Serum	Ctrl < AD (.01)	Inverse correlation with CSF Aβ₄₂	[252]
Ctrl/AD (41 total)	AD	CSF	Ctrl < AD (.0001)		[257]
Ctrl/AD (41 total)	AD	Serum	Ctrl < AD (.0001)		[257]
Ctrl/AD (24/21) Braak staging	Ctrl	FCx	B0-1 (Ctrl) > B4-5/B6 (<.001)		[345]
Ctrl/AD (26/28) Braak staging	Ctrl	FCx, Hpc, Hyp	Ctrl > AD (Hyp .07; FCx .006; ns Hpc)		[346]
Ctrl/AD (10/10)	=	CSF	ns		[256]
Ctrl/AD (10/10)	AD	Serum	Ctrl < AD (<.01)		[256]
*IGF-2*
Ctrl/other dementia/stable MCI/AD (20/15/13/32)	=	Serum	ns		[258]
Ctrl/other dementia/stable MCI/AD (20/15/13/32)	AD	CSF	Men: Con,MCI < AD	Correlation with t-tau and p-Tau	[258]
Ctrl/AD (72/92)	AD	CSF	Ctrl < AD (.005)		[259]
Ctrl/AD (24/21) Braak staging	Ctrl	FCx	B0-1 (Ctrl) > B2-3/B4-5/B6 (<.05)		[345]
Ctrl/AD (26/28) Braak staging	Ctrl	FCx, Hpc, Hyp	Ctrl > AD (Hyp .01; Hpc .04; ns FCx)		[346]
Ctrl/AD (10/10)	AD	CSF	Ctrl < AD (<.01)		[256]
Ctrl/AD (10/10)	AD	Serum	Ctrl < AD (<.01)		[256]
*IGFBP-1*
Ctrl/other dementia/stable MCI/AD (20/15/13/32)	=	CSF	ns		[258]
Ctrl/other dementia/stable MCI/AD (20/15/13/32)	=	serum	ns		[258]
Ctrl/AD (41 total)	AD	CSF	Ctrl < AD (.0001)		[257]
Ctrl/AD (41 total)	AD	Serum	Ctrl < AD (.0001)		[257]
*IGFBP-2*
1596 participants with 131 dementia cases including 98 AD cases	AD	Plasma		Associated with an increased risk of dementia and AD	[260]
NCI/MCI/AD (58/197/99) NINCDS/ADRDA criteria	=	CSF	ns		[246]
NCI/MCI/AD (58/197/99) NINCDS/ADRDA criteria	MCI	Plasma	AD, NCI < MCI (<.0001)	Inverse correlation with episodic memory performance Amyloid-negative individuals (CSF Aβ₄₂): Inverse correlation with hpc volume	[246]
Ctrl/MCI/AD (45/134/66)				Correlation with t-tau	[359]
Ctrl/other dementia/stable MCI/AD (20/15/13/32)	=	Serum	ns		[258]
Ctrl/other dementia/stable MCI/AD (20/15/13/32)	AD (men)	CSF	Men: MCI < AD	Correlation with t-tau and p-Tau	[258]
Ctrl/AD (72/92)	AD	CSF	Ctrl < AD (.005)		[259]
NCI/MCI/AD (211/149/331)	AD	Plasma		Associated with cognitive decline and AD diagnosis	[262]
Ctrl/AD from the AIBL cohort (754/207)	AD	Plasma	Ctrl < AD (<.0001)		[261]
Ctrl/AD (8/8) Braak staging	Ctrl	TCx	Ctrl > AD (.05)		[360]
Ctrl/AD (41 participants)	AD	CSF	Ctrl < AD (.0001)		[257]
Ctrl/AD (41 participants)	AD	Serum	Ctrl < AD (.0001)		[257]
Ctrl/AD (10/10)	AD	CSF	Ctrl < AD (<.001)		[256]
*IGFBP-3*
Ctrl/Other dementia/stableMCI /AD (15/13/32/60)	=	CSF	ns		(Johansson et al. 2013)
Ctrl/Other dementia/stableMCI /AD (15/13/32/60)	sMCI/AD	Serum	Ctrl < sMCI, AD (.01)	Inverse correlation with CSF Aβ₄₂	(Johansson et al. 2013)
Ctrl/AD (41 total)	AD	CSF	Ctrl < AD (.0001)		[257]
*IGFBP-4,5*
Ctrl/AD (41 total)	AD	CSF	Ctrl < AD (.0001)		[257]
*IGFBP-6*
Ctrl/AD (41 total)	AD	CSF	Ctrl < AD (.0001)		[257]
Ctrl/AD (10/10)	AD	CSF	Ctrl < AD (<.001)		[256]
*FGF21*
569 participants (Ctrl/T2Dwo complications/T2Dw complications/AD (102/92/162/93/120)	=	Plasma	ns Ctrl versus AD (but higher in T2D versus AD) APOE4 status has no impact	Correlates with age as centenarian has the highest plasma level, and BMI	[361]
Ctrl/MCI (39/92) MoCA	MCI	Plasma	Ctrl < MCI (.004)		[362]
Nonelderly/elderly with 65 years-old as threshold, with MetS (116/96) MoCA		Plasma		Non-elderly MetS: Inverse correlation with MoCA (lower levels associated with better cognition)	[344]

Background colors: Red cells = Higher levels observed in MCI and/or AD; Purple cells = Brain tissue instead of CSF or blood Abbreviations: (a)MCI, (amnestic) mild cognitive impairment; AD, Alzheimer’s disease; Aβ, β-amyloid; CDR, Clinical Dementia Rating; Ctrl/NCI, controle/no cognitive impairment; CSF, cerebrospinal fluid; DSM, Diagnostic and Statistical Manual of Mental Disorders; E4, apolipoprotein E4; ELISA, enzyme-linked immunosorbent assay; FCx, frontal cortex; FGF21, Fibroblast growth factor 21; GDS, Global Deterioration Scale; GIP, Glucose-dependent insulinotropic polypeptide; GLP-1, Glucagon-like peptide 1; Hpc, hippocampus; Hyp, hypothalamus; IGF, Insulin-like growth factor; IGFBP, Insulin-like growth factor binding protein; LIA, line immunoassay; MetS, metabolic syndrome; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; NFT, neurofibrillary tangles; NINCDS-ADRD, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association; OGTT, Oral glucose tolerance test; RIA, radioimmunoassay; SCI, subjective cognitive decline; SFA, saturated fatty acids; T2D, type 2 diabetes; TCx, temporal cortex; WMHs, white matter hyperintensities.