Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

A Pilot Study of Exenatide Actions in Alzheimer’s Disease

Author(s): Roger J. Mullins, Maja Mustapic, Chee W. Chia, Olga Carlson, Seema Gulyani, Joyce Tran, Yazhou Li, Mark P. Mattson, Susan Resnick, Josephine M. Egan, Nigel H. Greig and Dimitrios Kapogiannis*

Volume 16, Issue 8, 2019

Page: [741 - 752] Pages: 12

DOI: 10.2174/1567205016666190913155950

Price: $65

Abstract

Background: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer’s Disease (AD).

Objective: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD.

Method: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone.

Results: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs.

Conclusion: The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.

Keywords: GLP-1 agonist, exenatide, memory, diabetes, placebo, Alzheimer's disease.

« Previous Next »
[1]
Alzheimer’s A. Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12(4): 459-509. 2016
[http://dx.doi.org/10.1016/j.jalz.2016.03.001] [PMID: 27570871]
[2]
Becker RE, Kapogiannis D, Greig NH. Does traumatic brain injury hold the key to the Alzheimer’s disease puzzle? Alzheimers Dement 14(4): 431-43. 2018
[http://dx.doi.org/10.1016/j.jalz.2017.11.007] [PMID: 29245000]
[3]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6): 595-608. 2016
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[4]
Mullins RJ, Diehl TC, Chia CW, Kapogiannis D. Insulin resistance as a link between amyloid-beta and tau pathologies in Alzheimer’s disease. Front Aging Neurosci 9: 118. 2017
[http://dx.doi.org/10.3389/fnagi.2017.00118] [PMID: 28515688]
[5]
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers. J Clin Invest 122(4): 1339-53. 2012
[http://dx.doi.org/10.1172/JCI57256] [PMID: 22476196]
[6]
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122(4): 1316-38. 2012
[http://dx.doi.org/10.1172/JCI59903] [PMID: 22476197]
[7]
Goldstein BJ. Insulin resistance as the core defect in type 2 diabetes mellitus. Am J Cardiol 90(5A): 3G-10G. 2002
[http://dx.doi.org/10.1016/S0002-9149(02)02553-5] [PMID: 12231073]
[8]
Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci 14(6): 750-6. 2011
[http://dx.doi.org/10.1038/nn.2801] [PMID: 21532579]
[9]
Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, et al. Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest 125(6): 2463-7. 2015
[http://dx.doi.org/10.1172/JCI79742] [PMID: 25938784]
[10]
Francis GJ, Martinez JA, Liu WQ, Xu K, Ayer A, Fine J, et al. Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain 131(Pt 12): 3311-34. 2008
[http://dx.doi.org/10.1093/brain/awn288] [PMID: 19015157]
[11]
Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 5(6): 514-6. 2002
[http://dx.doi.org/10.1038/nn0602-849] [PMID: 11992114]
[12]
De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 106(6): 1971-6. 2009
[http://dx.doi.org/10.1073/pnas.0809158106] [PMID: 19188609]
[13]
Miller BW, Willett KC, Desilets AR. Rosiglitazone and pioglitazone for the treatment of Alzheimer’s disease. Ann Pharmacother 45(11): 1416-24. 2011
[http://dx.doi.org/10.1345/aph.1Q238] [PMID: 22028424]
[14]
Landreth G, Jiang Q, Mandrekar S, Heneka M. PPARgamma agonists as therapeutics for the treatment of Alzheimer’s disease. Neurotherapeutics 5(3): 481-9. 2008
[http://dx.doi.org/10.1016/j.nurt.2008.05.003] [PMID: 18625459]
[15]
Talbot K, Wang HY. The nature, significance, and glucagon-like peptide-1 analog treatment of brain insulin resistance in Alzheimer’s disease. Alzheimers Dement 10(1)(Suppl.): S12-25. 2014
[http://dx.doi.org/10.1016/j.jalz.2013.12.007] [PMID: 24529520]
[16]
Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 60(4): 470-512. 2008
[http://dx.doi.org/10.1124/pr.108.000604] [PMID: 19074620]
[17]
Göke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem 268(26): 19650-5. 1993
[PMID: 8396143]
[18]
Kastin AJ, Akerstrom V, Pan W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci 18(1-2): 7-14. 2002
[http://dx.doi.org/10.1385/JMN:18:1-2:07] [PMID: 11931352]
[19]
Alvarez E, Martínez MD, Roncero I, Chowen JA, Garcia-Cuartero B, Gispert JD, et al. The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 92(4): 798-806. 2005
[http://dx.doi.org/10.1111/j.1471-4159.2004.02914.x] [PMID: 15686481]
[20]
Hamilton A, Hölscher C. Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. Neuroreport 20(13): 1161-6. 2009
[http://dx.doi.org/10.1097/WNR.0b013e32832fbf14] [PMID: 19617854]
[21]
Perry T, Lahiri DK, Chen D, Zhou J, Shaw KT, Egan JM, et al. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther 300(3): 958-66. 2002
[http://dx.doi.org/10.1124/jpet.300.3.958] [PMID: 11861804]
[22]
Perry T, Greig NH. Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer’s disease. Curr Alzheimer Res 2(3): 377-85. 2005
[http://dx.doi.org/10.2174/1567205054367892] [PMID: 15974903]
[23]
Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res 86(2): 326-38. 2008
[http://dx.doi.org/10.1002/jnr.21483] [PMID: 17803225]
[24]
Hamilton A, Patterson S, Porter D, Gault VA, Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res 89(4): 481-9. 2011
[http://dx.doi.org/10.1002/jnr.22565] [PMID: 21312223]
[25]
Hölscher C, Li L. New roles for insulin-like hormones in neuronal signalling and protection: new hopes for novel treatments of Alzheimer’s disease? Neurobiol Aging 31(9): 1495-502. 2010
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.08.023] [PMID: 18930564]
[26]
McClean PL, Gault VA, Harriott P, Hölscher C. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer’s disease. Eur J Pharmacol 630(1-3): 158-62. 2010
[http://dx.doi.org/10.1016/j.ejphar.2009.12.023] [PMID: 20035739]
[27]
During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 2003. 9(9): 1173-9.
[http://dx.doi.org/10.1038/nm919] [PMID: 12925848]
[28]
Isacson R, Nielsen E, Dannaeus K, Bertilsson G, Patrone C, Zachrisson O, et al. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. Eur J Pharmacol 650(1): 249-55. 2011
[http://dx.doi.org/10.1016/j.ejphar.2010.10.008] [PMID: 20951130]
[29]
Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J Alzheimers Dis 19(4): 1205-19. 2010
[http://dx.doi.org/10.3233/JAD-2010-1314] [PMID: 20308787]
[30]
Gengler S, McClean PL, McCurtin R, Gault VA, Hölscher C. Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol Aging 33(2): 265-76. 2012
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.02.014] [PMID: 20359773]
[31]
Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Choudhary K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 390(10103): 1664-75. 2017
[http://dx.doi.org/10.1016/S0140-6736(17)31585-4] [PMID: 28781108]
[32]
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 280-92. 2011
[http://dx.doi.org/10.1016/j.jalz.2011.03.003] [PMID: 21514248]
[33]
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 263-9. 2011
[http://dx.doi.org/10.1016/j.jalz.2011.03.005] [PMID: 21514250]
[34]
Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 2016. 87(5): 539-47.
[http://dx.doi.org/10.1212/WNL.0000000000002923] [PMID: 27371494]
[35]
Mullins R, Reiter D, Kapogiannis D. Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer’s brain. Ann Clin Transl Neurol 5(3): 262-72. 2018
[http://dx.doi.org/10.1002/acn3.530] [PMID: 29560372]
[36]
Schulte RF, Boesiger P. ProFit: two-dimensional prior-knowledge fitting of J-resolved spectra. NMR Biomed 19(2): 255-63. 2006
[http://dx.doi.org/10.1002/nbm.1026] [PMID: 16541464]
[37]
Chia CW, Carlson OD, Kim W, et al. Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58(6): 1342-9. 2009
[http://dx.doi.org/10.2337/db08-0958] [PMID: 19276444]
[38]
Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2. 2013
[39]
Kapogiannis D, Boxer A, Schwartz JB, et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J 29(2): 589-96. 2015
[http://dx.doi.org/10.1096/fj.14-262048] [PMID: 25342129]
[40]
Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement 11(6): 600-7. 2015
[http://dx.doi.org/10.1016/j.jalz.2014.06.008]
[41]
Goetzl EJ, Boxer A, Schwartz JB, et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 2015. 85(1): 40-7.
[http://dx.doi.org/10.1212/WNL.0000000000001702] [PMID: 26062630]
[42]
Mustapic M, Eitan E, Werner JK Jr, et al. Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes. Front Neurosci 11: 278. 2017
[http://dx.doi.org/10.3389/fnins.2017.00278] [PMID: 28588440]
[43]
Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 154(2): 103-12. 2011
[http://dx.doi.org/10.7326/0003-4819-154-2-201101180-00300] [PMID: 21138825]
[44]
Kyriacou A, Ahmed AB. Exenatide Use in the Management of Type 2 Diabetes Mellitus. Pharmaceuticals (Basel) 3(8): 2554-67. 2010
[http://dx.doi.org/10.3390/ph3082554] [PMID: 27713366]
[45]
Maurer TS, Debartolo DB, Tess DA, Scott DO. Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab Dispos 33(1): 175-81. 2005
[http://dx.doi.org/10.1124/dmd.104.001222] [PMID: 15502010]
[46]
Elahi D, Ruff DA, Carlson OD, Meneilly GS, Habener JF, Egan JM. Does GLP-1 suppress its own basal secretion? Endocr Res 41(1): 16-20. 2016
[http://dx.doi.org/10.3109/07435800.2015.1038353] [PMID: 26186406]
[47]
Spaan PE, Raaijmakers JG, Jonker C. Early assessment of dementia: the contribution of different memory components. Neuropsychology 19(5): 629-40. 2005
[http://dx.doi.org/10.1037/0894-4105.19.5.629] [PMID: 16187881]
[48]
Lortie JJ, Remington R, Hoffmann H, Shea TB. Lack of Correlation of WAIS Digit Span with Clox 1 and the Dementia Rating Scale in MCI. Int J Alzheimers Dis 2012829743 2012
[http://dx.doi.org/10.1155/2012/829743] [PMID: 22577593]
[49]
Kiewel NA, Wisdom NM, Bradshaw MR, Pastorek NJ, Strutt AM. A retrospective review of digit span-related effort indicators in probable Alzheimer’s disease patients. Clin Neuropsychol 26(6): 965-74. 2012
[http://dx.doi.org/10.1080/13854046.2012.694478] [PMID: 22703555]
[50]
Mullins RJ, Mustapic M, Goetzl EJ, Kapogiannis D. Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer’s disease. Hum Brain Mapp 38(4): 1933-40. 2017
[http://dx.doi.org/10.1002/hbm.23494] [PMID: 28105773]
[51]
Eitan E, Tosti V, Suire CN, et al. In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles. Aging Cell 16(6): 1430-3. 2017
[http://dx.doi.org/10.1111/acel.12657] [PMID: 28921841]
[52]
Grill JD, Karlawish J. Addressing the challenges to successful recruitment and retention in Alzheimer’s disease clinical trials. Alzheimers Res Ther 2(6): 34. 2010
[http://dx.doi.org/10.1186/alzrt58] [PMID: 21172069]
[53]
Gejl M, Gjedde A, Egefjord L, et al. In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci 8: 108. 2016
[http://dx.doi.org/10.3389/fnagi.2016.00108] [PMID: 27252647]

Rights & Permissions Print Cite
Article Metrics
105
8
© 2024 Bentham Science Publishers | Privacy Policy