Brain insulin resistance and Alzheimer’s disease: a systematic review

Andrade, Luis Jesuino de Oliveira; Oliveira, Luís Matos de; Bittencourt, Alcina Maria Vinhaes; Lourenço, Letícia Góes de Carvalho; Oliveira, Gabriela Correia Matos de

doi:10.1590/1980-5764-DN-2023-0032

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Brasil

Dementia & Neuropsychologia

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View & Review • Dement. neuropsychol. 18 • 2024 • https://doi.org/10.1590/1980-5764-DN-2023-0032 copy

Brain insulin resistance and Alzheimer’s disease: a systematic review

Resistência insulínica cerebral e a doença de Alzheimer: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT.

The disability of cells to react to insulin, causing glucose intolerance and hyperglycemia, is referred to as insulin resistance. This clinical condition, which has been well-researched in organs such as adipose tissue, muscle, and liver, has been linked to neurodegenerative diseases like Alzheimer’s disease (AD) when it occurs in the brain.

Objective:

The authors aimed to gather data from the current literature on brain insulin resistance (BIR) and its likely repercussions on neurodegenerative disorders, more specifically AD, through a systematic review.

Methods:

A comprehensive search was conducted in multiple medical databases, including the Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online (Medline), and PubMed^®, employing the descriptors: “insulin resistance”, “brain insulin resistance”, “Alzheimer’s disease”, “neurodegeneration”, and “cognition”. The authors focused their search on English-language studies published between 2000 and 2023 that investigated the influence of BIR on neurodegenerative disorders or offered insights into BIR’s underlying mechanisms. Seventeen studies that met the inclusion criteria were selected.

Results:

The results indicate that BIR is a phenomenon observed in a variety of neurodegenerative disorders, including AD. Studies suggest that impaired glucose utilization and uptake, reduced adenosine triphosphate (ATP) production, and synaptic plasticity changes caused by BIR are linked to cognitive problems. However, conflicting results were observed regarding the association between AD and BIR, with some studies suggesting no association.

Conclusion:

Based on the evaluated studies, it can be concluded that the association between AD and BIR remains inconclusive, and additional research is needed to elucidate this relationship.

Keywords:
Alzheimer’ Disease; Insulin Resistance; Brain; Cognition; Systematic Review

Reference	Year	Design	Sample size	Objective	Conclusions	Risk of bias as per QUADAS-2
Su et al.¹²12. Su F, Shu H, Ye Q, Wang Z, Xie C, Yuan B, et al. Brain insulin resistance deteriorates cognition by altering the topological features of brain networks. Neuroimage Clin. 2016;13:280-87. https://doi.org/10.1016/j.nicl.2016.12.009 https://doi.org/https://doi.org/10.1016/...	2016	Case-control	222	“Longitudinal study for an average of 35 months to assess cognitive decline over time”	“The results suggested that the restoration of insulin activity represents a promising therapeutic target for improve cognitive decline in AD”.	Good-quality
Niyasti et al.¹³13. Niyasti P, Saberi A, Hatamyain H, Ajamian F, Ghorbani Shirkouhi S, Mirzanejad L, et al. Association of insulin receptor substrate-1 gene polymorphism (rs1801278) with Alzheimer’s disease. J Alzheimers Dis Rep. 2022;6(1):73-80. https://doi.org/10.3233/ADR-210060 https://doi.org/https://doi.org/10.3233/...	2022	Case-control	300	“Polymerase chain reaction was performed to amplify a DNA segment of 263 base-pair length containing the single nucleotide polymorphism”	“Association of Insulin Receptor Substrate-1 Gene Polymorphism (rs1801278) present at the BIR is significantly associated with the risk of developing AD”	Good-quality
van der Velpen et al.¹⁴14. van der Velpen V, Teav T, Gallart-Ayala H, Mehl F, Konz I, Clark C, et al. Systemic and central nervous system metabolic alterations in Alzheimer’s disease. Alzheimers Res Ther. 2019;11(1):93. https://doi.org/10.1186/s13195-019-0551-7 https://doi.org/https://doi.org/10.1186/...	2019	Case-control	74	“Paired plasma and cerebrospinal fluid samples”	“The study showed the translational potential of the pathway quantitative to assess central nervous system metabolic defects which are part of the AD pathophysiology”.	Low-moderate
Andalib et al.¹⁵15. Andalib S, Ghayeghran A, Moadabi Y, Asadi K, Mohammadpour M, Ghorbani-Shirkouhi S. Association of Diabetes Mellitus type 2 and Alzheimer’s disease. Caspian Journal of Health Research. 2019;4(4):86-9. https://doi.org/10.29252/cjhr.4.4.86 https://doi.org/https://doi.org/10.29252...	2019	Case-control	243	“To test the hypothesis of association of late onset Alzheimer’s disease (AD) with DM2 in an Iranian population”	“The evidence from the present study suggested that DM2 was associated with AD in an Iranian population”	Good-quality
Mullins et al.¹⁶16. Mullins R, Reiter D, Kapogiannis D. Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer’s brain. Ann Clin Transl Neurol. 2018;5(3):262-72. https://doi.org/10.1002/acn3.530 https://doi.org/https://doi.org/10.1002/...	2018	Case-control	54	“Use Magnetic Resonance Spectroscopy to assess AD-related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites”	The study showed substantial elevations in glucose, lactate, and ascorbate levels within the posterior cingulate/precuneus of AD participants	Good-quality
Xu et al.¹⁷17. Xu J, Begley P, Church SJ, Patassini S, McHarg S, Kureishy N, et al. Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia. Sci Rep. 2016;6:27524. https://doi.org/10.1038/srep27524 https://doi.org/https://doi.org/10.1038/...	2016	Case-control	18	“To elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage”	“Elevation of brain glucose and deficient brain copper potentially contribute to the pathogenesis of neurodegeneration in AD”	Good-quality
Tortelli et al.¹⁸18. Tortelli R, Lozupone M, Guerra V, Barulli MR, Imbimbo BP, Capozzo R, et al. Midlife metabolic profile and the risk of late-life cognitive decline. J Alzheimers Dis. 2017;59(1):121-30. https://doi.org/10.3233/JAD-170153 https://doi.org/https://doi.org/10.3233/...	2017	Cohort	797	“To evaluate midlife metabolic profile and the risk of late-life cognitive decline”	“The control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife prevents late-life dementia”	Good-quality
Abner et al.¹⁹19. Abner EL, Nelson PT, Kryscio RJ, Schmitt FA, Fardo DW, Woltjer RL, et al. Diabetes is associated with cerebrovascular but not Alzheimer’s disease neuropathology. Alzheimers Dement. 2016;12(8):882-9. https://doi.org/10.1016/j.jalz.2015.12.006 https://doi.org/https://doi.org/10.1016/...	2016	Cohort	2,365	“SMART database that comprises a standardized set of data elements contributed by 11 longitudinal studies of aging and cognition”	“The study concluded that diabetes increases the risk of cerebrovascular but not AD”	Low-moderate
Chung et al.²⁰20. Chung SJ, Kim MJ, Kim J, Ryu HS, Kim YJ, Kim SY, et al. Association of type 2 diabetes GWAS loci and the risk of Parkinson’s and Alzheimer’s diseases. Parkinsonism Relat Disord. 2015;21(12):1435-40. https://doi,org/10.1016/j.parkreldis.2015.10.010 https://doi.org/https://doi,org/10.1016/...	2015	Case-control	900	“Investigate whether genome-wide significant loci of type 2 diabetes mellitus are associated with the risk of AD”	“The results suggest that genome-wide significant loci of type diabetes (insulin resistance) play no major role in the risk and cognitive impairment of AD”	Low-moderate
Schrijvers et al.²¹21. Schrijvers EM, Witteman JC, Sijbrands EJ, Hofman A, Koudstaal PJ, Breteler MMB. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology. 2010;75(22):1982-7. https://doi.org/10.1212/WNL.0b013e3181ffe4f6 https://doi.org/https://doi.org/10.1212/...	2010	Cohort	3,139	“Investigate whether fasting glucose and insulin levels and IR are associated with the risk of AD and whether this risk is constant over time”	“The study suggests that insulin metabolism influences the clinical manifestation of AD only within 3 years”	Good-quality
Willette et al.²²22. Willette AA, Johnson SC, Birdsill AC, Sager MA, Christian B, Baker LD, et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 2015;11(5):504-10.e1. https://doi.org/10.1016/j.jalz.2014.03.011 https://doi.org/https://doi.org/10.1016/...	2015	Cross-sectional	186	“Assess whether the IR is associated with amyloid binding in three AD-sensitive brain areas”	“The study demonstrated that IR may contribute to amyloid deposition in brain regions affected by AD”	Good-quality
Morris et al.²³23. Morris JK, Vidoni ED, Perea RD, Rada R, Johnson DK, Lyons K, et al. Insulin resistance and gray matter volume in neurodegenerative disease. Neuroscience. 2014;270:139-47. https://doi.org/10.1016/j.neuroscience.2014.04.006 https://doi.org/https://doi.org/10.1016/...	2014	Cross-sectional	42	“To compare IR in aging and aging-related neurodegenerative diseases, and to determine the relationship between IR and gray matter volume in each cohort using an unbiased, voxel-based approach”	“The study supports a potential relationship between IR and brain structure in both normal aging and diagnosed neurodegenerative disease”	Good-quality
Kapogiannis et al.²⁴24. Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, Masharani U, et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J. 2015;29(2):589-96. https://doi.org/10.1096/fj.14-262048 https://doi.org/https://doi.org/10.1096/...	2015	Cross-sectional	26	“To assess brain IR in AD by level of serine-type 1 insulin receptor substrate (IRS-1) and its state of phosphorylation in neural-derived plasma exosomes”	“Insulin resistance reflected in R values from IRS-1 is higher for patients with AD, and accurately predicts development of AD up to 10 year prior to clinical onset”	Good-quality
Willette et al.²⁵25. Willette AA, Bendlin BB, Starks EJ, Birdsill AC, Johnson SC, Christian BT, et al. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer Disease. JAMA Neurol. 2015;72(9):1013-20. https://doi.org/10.1001/jamaneurol.2015.0613 https://doi.org/https://doi.org/10.1001/...	2015	Cross-sectional	150	“To determine if IR predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD, and to examine if IR predicts variation in regional glucose metabolism is associated with worse cognitive performance”	“The results show that IR is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance”	Good-quality
Johansson et al.²⁶26. Johansson P, Åberg D, Johansson JO, Mattsson N, Hansson O, Ahrén B, et al. Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer’s disease. Psychoneuroendocrinology. 2013;38(9):1729-37. https://doi.org/10.1016/j.psyneuen.2013.02.006 https://doi.org/https://doi.org/10.1016/...	2013	Cross-sectional	80	“Assess whether the serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 are increased in AD”	“Patients with AD as well as other dementias had high levels of IGF-I in serum but not in CSF. In AD patients, the IGF-I system was associated with biomarkers of AD disease status”	Good-quality
Faqih et al.²⁷27. Faqih NT, Ashoor AF, Alshaikh SA, Maglan AF, Jastaniah N. Association of Alzheimer’s Disease and Insulin Resistance in King Abdulaziz Medical City, Jeddah. Cureus. 2021;13(11):e19811. https://doi.org/10.7759/cureus.19811 https://doi.org/https://doi.org/10.7759/...	2021	Cohort	356	“Study the association between AD and IR and the relation between AD and diabetic patients treated with insulin”	“The results suggest that AD is associated with IR”	Good-quality
Hong et al.²⁸28. Hong S, Han K, Park CY. The insulin resistance by triglyceride glucose index and risk for dementia: population-based study. Alzheimers Res Ther. 2021;13(1):9. https://doi.org/10.1186/s13195-020-00758-4 https://doi.org/https://doi.org/10.1186/...	2021	Cohort	5,586,048	“Study the potential relationships between the triglyceride glucose index and dementia”	“Triglyceride glucose index was associated with an increased risk of dementia, including AD”	Good-quality

Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[1] Correspondence:
Luís Jesuíno de Oliveira Andrade; Email: luis_jesuino@yahoo.com.br.