Navigating the treatment landscape of Alzheimer's disease: Current strategies and future directions

Abstract

Alzheimer's disease (AD), a neurodegenerative disease leading to dementia, lacks a single definitive diagnosis. While current medications only manage symptoms, the ideal treatment would restore cognition. Traditional therapies targeting beta-amyloid haven't yielded significant results, while new approaches target tau protein tangles, protein degradation pathways, inflammation, and neurotrophic factor depletion. Autophagy, a cellular degradation and recycling process, has emerged as a crucial hallmark and contributor to the pathogenesis of AD. Notably, autophagy induction has emerged as a promising therapeutic approach, with inducers like celastrol and caudatin promoting the degradation of toxic protein aggregates. Additionally, innovative drug formulations, such as nanoparticles, are being explored for targeted drug delivery. Research is increasingly focusing on neuroinflammation and developing multi-targeted drugs to address various aspects of AD, potentially leading to preventive strategies in the early stages. This review summarizes the current state and emerging trends in AD drug development.

Keywords

Alzheimer's disease / neurofibrillary tangles / N-methyl-D aspartate receptors / presenilin / β-amyloid

References

[1] Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M. Improving healthcare for people living with dementia: Coverage, Quality and costs now and in the future (World Alzheimer Report 2016). Alzheimer's Disease International; 2016: 6-17. https://www.alzint.org/u/WorldAlzheimerReport2016.pdf

[2] Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013; 80(19): 1778-1783.

[3] Association As. Alzheimer's disease facts and figures. Alzheimer's Dementia. 2019; 15(3): 321-387. https://www.alz.org/media/documents/alzheimers-facts-and-figures-2019-r.pdf

[4] Halliday G. Pathology and hippocampal atrophy in Alzheimer's disease. Lancet Neurol. 2017; 16(11): 862-864.

[5] Takenoshita S, Terada S, Inoue T, et al. Prevalence and modifiable risk factors for dementia in persons with intellectual disabilities. Alzheimer's Res Ther. 2023; 15(1): 125.

[6] Hoyt KR, Obrietan K. Circadian clocks, cognition, and Alzheimer's disease: synaptic mechanisms, signaling effectors, and chronotherapeutics. Mol Neurodegener. 2022; 17(1): 35.

[7] Laczó J, Parizkova M, Moffat SD. Spatial navigation, aging and Alzheimer's disease. Aging. 2018; 10(11): 3050-3051.

[8] Mukherjee S, Ali S, Hashmi S, Jahan S. History, Origin and Types of Neurological Disorders. Applications of Stem Cells and Derived Exosomes in Neurodegenerative Disorders. Springer; 2023: 1-32.

[9] Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4): 239-259.

[10] Thal DR, Walter J, Saido TC, Fändrich M. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer's disease. Acta Neuropathol. 2015; 129: 167-182.

[11] Wang Z-X, Tan L, Liu J, Yu J-T. The essential role of soluble Aβ oligomers in Alzheimer's disease. Mol Neurobiol. 2016; 53: 1905-1924.

[12] Sengupta U, Nilson AN, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine. 2016; 6: 42-49.

[13] Tolar M, Hey J, Power A, Abushakra S. Neurotoxic soluble amyloid oligomers drive Alzheimer's pathogenesis and represent a clinically validated target for slowing disease progression. Int J Mol Sci. 2021; 22(12):6355.

[14] Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P. Amyloid β oligomers (AβOs) in Alzheimer's disease. J Neural Transm. 2018; 125: 177-191.

[15] Calabrò M, Rinaldi C, Santoro G, Crisafulli C. The biological pathways of Alzheimer disease: a review. AIMS Neurosci. 2021; 8(1): 86-132.

[16] Vecchio I, Sorrentino L, Paoletti A, Marra R, Arbitrio M. The state of the art on acetylcholinesterase inhibitors in the treatment of Alzheimer's disease. J Cent Nerv Syst Dis. 2021; 13:11795735211029113.

[17] Kabir MT, Sufian MA, Uddin MS, et al. NMDA receptor antagonists: repositioning of memantine as a multitargeting agent for Alzheimer's therapy. Curr Pharm Des. 2019; 25(33): 3506-3518.

[18] Pope SK, Shue VM, Beck C. Will a healthy lifestyle help prevent Alzheimer's disease? Annu Rev Public Health. 2003; 24(1): 111-132.

[19] Mir RH, Sawhney G, Pottoo FH, et al. Role of environmental pollutants in Alzheimer's disease: a review. Environ Sci Pollut Res. 2020; 27(36): 44724-44742.

[20] Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L. Different brain regions are infected with fungi in Alzheimer's disease. Sci Rep. 2015; 5(1):15015.

[21] Mucke L. Alzheimer's disease. Nature. 2009; 461(7266): 895-897.

[22] Dingwall C. Spotlight on BACE: the secretases as targets for treatment in Alzheimer disease. J Clin Invest. 2001; 108(9): 1243-1246.

[23] Vassar R, Bennett BD, Babu-Khan S, et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286(5440): 735-741.

[24] Cruts M, Van Broeckhoven C. Presenilin mutations in Alzheimer's disease. Hum Mutat. 1998; 11(3): 183-190.

[25] Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer's disease. Alzheimer's Dementia: J Alzheimer's Assoc. 2014; 10(6): 861-868.

[26] Lipton S. The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res. 2005; 2(2): 155-165.

[27] Heneka MT, Carson MJ, El Khoury JE, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015; 14(4): 388-405.

[28] Nixon RA. Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging. 2005; 26(3): 373-382.

[29] Takahashi S. Metabolic contribution and cerebral blood flow regulation by astrocytes in the neurovascular unit. Cells. 2022; 11(5):813.

[30] Soldano A, Hassan BA. Beyond pathology: APP, brain development and Alzheimer's disease. Curr Opin Neurobiol. 2014; 27: 61-67.

[31] Kojro E, Fahrenholz F. The non-amyloidogenic pathway: structure and function of α-secretases. In: Alzheimer's Disease: Cellular and Molecular Aspects of Amyloid β. Springer; 2005: 105-127.

[32] Castro MA, Hadziselimovic A, Sanders CR. The vexing complexity of the amyloidogenic pathway. Prot Sci. 2019; 28(7): 1177-1193.

[33] Fiala JC. Mechanisms of amyloid plaque pathogenesis. Acta Neuropathol. 2007; 114(6): 551-571.

[34] Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer's Disease. Med Princ Pract. 2015; 24(1): 1-10.

[35] Villemagne VL. Amyloid imaging: past, present and future perspectives. Ageing Res Rev. 2016; 30: 95-106.

[36] Iyaswamy A, Thakur A, Guan XJ, et al. Fe65-engineered neuronal exosomes encapsulating corynoxine-b ameliorate cognition and pathology of Alzheimer's disease. Signal Transduct Target Ther. 2023; 8(1): 404.

[37] Raulin A-C, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu C-C. ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener. 2022; 17(1): 72.

[38] Parhizkar S, Holtzman DM, eds. APOE Mediated Neuroinflammation and Neurodegeneration in Alzheimer's Disease. Seminars in Immunology. Elsevier; 2022.

[39] Muralidar S, Ambi SV, Sekaran S, Thirumalai D, Palaniappan B. Role of tau protein in Alzheimer's disease: the prime pathological player. Int J Biiol Macromol. 2020; 163: 1599-1617.

[40] Selvarasu K, Singh AK, Dakshinamoorthy A, et al. Interaction of tau with Kinesin-1: effect of Kinesin-1 heavy chain elimination on autophagy-mediated mutant tau degradation. Biomedicines. 2023; 12(1):5.

[41] Toral-Rios D, Pichardo-Rojas PS, Alonso-Vanegas M, Campos-Peña V. GSK3β and tau protein in Alzheimer's disease and epilepsy. Front Cell Neurosci. 2020; 14:19.

[42] Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017; 549(7673): 523-527.

[43] Uddin MS, Kabir MT, Al Mamun A, Abdel-Daim MM, Barreto GE, Ashraf GM. APOE and Alzheimer's disease: evidence mounts that targeting APOE4 may combat Alzheimer's pathogenesis. Mol Neurobiol. 2019; 56(4): 2450-2465.

[44] Jagust W. Is amyloid-β harmful to the brain? Insights from human imaging studies. Brain. 2016; 139(1): 23-30.

[45] Qian J, Hyman BT, Betensky RA. Neurofibrillary tangle stage and the rate of progression of Alzheimer symptoms: modeling using an autopsy cohort and application to clinical trial design. JAMA Neurol. 2017; 74(5): 540-548.

[46] Uddin MS, Kabir MT, Rahman MS, et al. Revisiting the amyloid cascade hypothesis: from anti-Aβ therapeutics to auspicious new ways for Alzheimer's disease. Int J Mol Sci. 2020; 21(16):5858.

[47] Majdi A, Sadigh-Eteghad S, Rahigh Aghsan S, et al. Amyloid-β, tau, and the cholinergic system in Alzheimer's disease: seeking direction in a tangle of clues. Rev Neurosci. 2020; 31(4): 391-413.

[48] Pepeu G, Grossi C, Casamenti F. The brain cholinergic system in neurodegenerative diseases. Ann Res Rev Biol. 2015; 6(1): 1-19.

[49] Petrova T, Orellana C, Jelic V, et al. Cholinergic dysfunction, neurodegeneration, and amyloid-beta pathology in neurodegenerative diseases. Psychiatry Res. Neuroimaging. 2020; 302:111099.

[50] Hampel H, Mesulam M-M, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain. 2018; 141(7): 1917-1933.

[51] Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimer's Dis. 2017; 57(4): 1041-1048.

[52] Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence? Front Neurosci. 2015; 9:170294.

[53] Bhat AH, Dar KB, Anees S, et al. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother Biomed Pharmacother. 2015; 74: 101-110.

[54] Guan X, Deng Z, Liu J, et al. Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer's disease models. Acta Pharmacol Sin. 2024; 45(5): 900-913.

[55] Krishnamoorthi S, Iyaswamy A, Sreenivasmurthy SG, et al. PPARɑ ligand caudatin improves cognitive functions and mitigates Alzheimer's disease defects by inducing autophagy in mice models. J Neuroimmune Pharmacol. 2023; 18(3): 509-528.

[56] Pandaram A, Paul J, Wankhar W, et al. Aspartame causes developmental defects and teratogenicity in zebra fish embryo: role of impaired SIRT1/FOXO3a axis in neuron cells. Biomedicines. 2024; 12(4):855.

[57] Iyaswamy A, Wang X, Zhang H, et al. Molecular engineering of a theranostic molecule that detects Aβ plaques, inhibits Iowa and Dutch mutation Aβ self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease. J Mater Chem B. 2024; 12(31): 7543-7556.

[58] Kumar A, Nisha CM, Silakari C, et al. Current and novel therapeutic molecules and targets in Alzheimer's disease. J Formos Med Assoc. 2016; 115(1): 3-10.

[59] Kumar D, Ganeshpurkar A, Kumar D, Modi G, Gupta SK, Singh SK. Secretase inhibitors for the treatment of Alzheimer's disease: long road ahead. Eur J Med Chem. 2018; 148: 436-452.

[60] Vassar R. BACE 1: the β-secretase enzyme in Alzheimer's disease. J Mol Neurosci. 2004; 23: 105-114.

[61] Kumalo HM, Soliman ME. A comparative molecular dynamics study on BACE1 and BACE2 flap flexibility. J Recept Signal Transd. 2016; 36(5): 505-514.

[62] Ghosh AK, Cárdenas EL, Osswald HL. The design, development, and evaluation of BACE1 inhibitors for the treatment of Alzheimer's disease. In: Wolfe M, ed. Alzheimer's Disease II: Topics in Medicinal Chemistry. Springer; 2017: 27-85.

[63] Zhang X, Li Y, Xu H, Zhang Y. The γ-secretase complex: from structure to function. Front Cell Neurosci. 2014; 8:427.

[64] Geula C, Mesulam M. Special properties of cholinesterases in the cerebral cortex of Alzheimer's disease. Brain Res. 1989; 498(1): 185-189.

[65] Perry E, Perry R, Blessed G, Tomlinson B. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet. 1977; 309(8004): 189.

[66] Darvesh S, Hopkins DA, Geula C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci. 2003; 4(2): 131-138.

[67] Mesulam M, Geula C. Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia. Ann Neurol. 1994; 36(5): 722-727.

[68] Geula C, Mesulam M-M. Cholinesterases and the pathology of Alzheimer disease. Alzheimer Dis Assoc Disord. 1995; 9: 23-28.

[69] Friede RL. Enzyme histochemical studies of senile plaques. J Neuropathol Exp Neurol. 1965; 24(3): 477-491.

[70] Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology. 2010; 59(6): 367-374.

[71] Grooms SY, Opitz T, Bennett MVL, Zukin RS. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc Natl Acad Sci. 2000; 97(7): 3631-3636.

[72] Bolger GB, Rodgers L, Riggs M. Differential CNS expression of alternative mRNA isoforms of the mammalian genes encoding cAMP-specific phosphodiesterases. Gene. 1994; 149(2): 237-244.

[73] Kwak S, Weiss JH. Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol. 2006; 16(3): 281-287.

[74] Repaske DR, Corbin JG, Conti M, Goy MF. A cyclic GMP-stimulated cyclic nucleotide phosphodiesterase gene is highly expressed in the limbic system of the rat brain. Neuroscience. 1993; 56(3): 673-686.

[75] Rajasekaran K, Todorovic M, Kapur J. Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol. 2012; 72(1): 91-102.

[76] Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol. 2010; 6(10): 573-582.

[77] Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev. 2023; 103(2): 1565-1644.

[78] Van Rossum D, Hanisch U-K, QUIRION R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev. 1997; 21(5): 649-678.

[79] Skofitsch G, Jacobowitz DM. Autoradiographic distribution of 125I calcitonin gene-related peptide binding sites in the rat central nervous system. Peptides. 1985; 6(5): 975-986.

[80] van der Staay FJ, Rutten K, Bärfacker L, et al. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology. 2008; 55(5): 908-918.

[81] Kovács A, Telegdy G. Effects of intracerebroventricular administration of calcitonin gene-related peptide on passive avoidance behaviour in rats. Neuropeptides. 1992; 23(1): 51-54.

[82] Boess FG, Hendrix M, van der Staay F-J, et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology. 2004; 47(7): 1081-1092.

[83] Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006; 58(3): 488-520.

[84] Heckman PRA, Blokland A, Ramaekers J, Prickaerts J. PDE and cognitive processing: beyond the memory domain. Neurobiol Learn Mem. 2015; 119: 108-122.

[85] Dorner-Ciossek C, Kroker KS, Rosenbrock H. Role of PDE9 in cognition. Adv Neurobiol. 2017; 17: 231-254.

[86] Volpicelli LA, Levey AI. Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog Brain Res. 2004; 145: 59-66.

[87] Eglen RM. Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autacoid Pharmacol. 2006; 26(3): 219-233.

[88] Fisher A, Michaelson DM, Brandeis R, Haring R, Chapman S, Pittel Z. M1 muscarinic agonists as potential disease-modifying agents in Alzheimer's disease: rationale and perspectives. Ann NY Acad Sci. 2000; 920(1): 315-320.

[89] Samadi A, Estrada M, Pérez C, et al. Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: synthesis, biological assessment, and molecular modeling. Eur J Med Chem. 2012; 57: 296-301.

[90] Samadi A, de la Fuente Revenga M, Pérez C, et al. Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease. Eur J Med Chem. 2013; 67: 64-74.

[91] Varadaraju KR, Kumar JR, Mallesha L, et al. Virtual screening and biological evaluation of piperazine derivatives as human acetylcholinesterase inhibitors. Int J Alzheimer's Dis. 2013; 2013(1):653962.

[92] Engmann O. Crosstalk between Cdk5 and GSK3β: implications for Alzheimer's disease. Front Mol Neurosci. 2009; 2: 2.

[93] Prado-Prado F, Garcia I. Review of theoretical studies for prediction of neurodegenerative inhibitors. Mini-Rev Med Chem. 2012; 12(6): 452-466.

[94] Guillozet AL, Mesulam MM, Smiley JF, Mash DC. Butyrylcholinesterase in the life cycle of amyloid plaques. Ann Neurol. 1997; 42(6): 909-918.

[95] Hur J-Y. γ-Secretase in Alzheimer's disease. Exp Mol Med. 2022; 54(4): 433-446.

[96] Henley JM, Wilkinson KA. Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci. 2016; 17(6): 337-350.

[97] Chaudhary A, Maurya PK, Yadav BS, Singh S, Mani A. Current therapeutic targets for Alzheimer's disease. J Biomed. 2018; 3: 74-84.

[98] García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J, Franco R. Phosphodiesterases as therapeutic targets for Alzheimer's disease. ACS Chem Neurosci. 2012; 3(11): 832-844.

[99] Dwomoh L, Tejeda GS, Tobin AB. Targeting the M1 muscarinic acetylcholine receptor in Alzheimer's disease. Neuronal Signaling. 2022; 6(1):Ns20210004.

[100] Pan X, Kaminga AC, Wen SW, Wu X, Acheampong K, Liu A. Dopamine and dopamine receptors in Alzheimer's disease: a systematic review and network meta-analysis. Front Aging Neurosci. 2019; 11:175.

[101] Javoy-Agid F, Scatton B, Ruberg M, et al. Distribution of monoaminergic, cholinergic, and GABAergic markers in the human cerebral cortex. Neuroscience. 1989; 29(2): 251-259.

[102] Boas SM, Joyce KL, Cowell RM. The NRF2-dependent transcriptional regulation of antioxidant defense pathways: relevance for cell type-specific vulnerability to neurodegeneration and therapeutic intervention. Antioxidants. 2021; 11(1):8.

[103] Pratt KG, Zhu P, Watari H, Cook DG, Sullivan JM. A novel role for γ-secretase: selective regulation of spontaneous neurotransmitter release from hippocampal neurons. J Neurosci. 2011; 31(3): 899-906.

[104] Xu X, Martin F, Friedman JS. The familial Parkinson's disease gene DJ-1 (PARK7) is expressed in red cells and plays a role in protection against oxidative damage. Blood Cells Mol Dis. 2010; 45(3): 227-232.

[105] Wang F, Gao Z, Li X, et al. NDRG2 is involved in anti-apoptosis induced by electroacupuncture pretreatment after focal cerebral ischemia in rats. Neurol Res. 2013; 35(4): 406-414.

[106] Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008; 5(3): 458-469.

[107] Mitchell ES, Neumaier JF. 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacol Ther. 2005; 108(3): 320-333.

[108] Vieira MNN, Lyra e Silva NM, Ferreira ST, De Felice FG. Protein tyrosine phosphatase 1B (PTP1B): a potential target for Alzheimer's therapy? Front Aging Neurosci. 2017; 9:7.

[109] Bian J-T, Zhao H-L, Zhang Z-X, Bi X-H, Zhang J-W. Association of NAD (P) H: quinone oxidoreductase 1 polymorphism and Alzheimer's disease in Chinese. J Mol Neurosci. 2008; 34(3): 235-240.

[110] Boskovic Z, Meier S, Wang Y, et al. Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors. Neuronal Signal. 2019; 3(1):NS20180066.

[111] De la Rosa-Prieto C, Saiz-Sanchez D, Ubeda-Banon I, Flores-Cuadrado A, Martinez-Marcos A. Neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-β in the olfactory bulb of APP/PS1 mouse model of Alzheimer's disease. Front Neurosci. 2016; 10:227.

[112] Sáez-Orellana F, Octave J-N, Pierrot N. Alzheimer's disease, a lipid story: involvement of peroxisome proliferator-activated receptor α. Cells. 2020; 9(5):1215.

[113] Xia M, Qin S, Wu L, Mackay CR, Hyman BT. Immunohistochemical study of the β-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains. Am J Pathol. 1998; 153(1): 31-37.

[114] Loera-Valencia R, Eroli F, Garcia-Ptacek S, Maioli S. Brain renin–angiotensin system as novel and potential therapeutic target for Alzheimer's disease. Int J Mol Sci. 2021; 22(18):10139.

[115] Yoshimoto M, Iwai A, Kang D, Otero DA, Xia Y, Saitoh T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci. 1995; 92(20): 9141-9145.

[116] Mehan S, Meena H, Sharma D, Sankhla R. JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer's and various neurodegenerative abnormalities. J Mol Neurosci. 2011; 43(3): 376-390.

[117] Rohn TT. The triggering receptor expressed on myeloid cells 2:“TREM-ming” the inflammatory component associated with Alzheimer's disease. Oxid Med Cell Longevity. 2013; 2013(1):860959.

[118] Shinde T. Lecanemab: a novel therapeutic approach for Alzheimer's. Int J Sci R Tech. 2024; 1(11): 240-246.

[119] Yadollahikhales G, Rojas JC. Anti-amyloid immunotherapies for Alzheimer's disease: a 2023 clinical update. Neurotherapeutics. 2023; 20(4): 914-931.

[120] Iyaswamy A, Wang X, Krishnamoorthi S, et al. Theranostic F-SLOH mitigates Alzheimer's disease pathology involving TFEB and ameliorates cognitive functions in Alzheimer's disease models. Redox Biol. 2022; 51:102280.

[121] Yang C, Su C, Iyaswamy A, et al. Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: implications for Alzheimer's disease therapy. Acta Pharm Sin B. 2022; 12(4): 1707-1722.

[122] Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimer's Res Ther. 2014; 6(4): 37.

[123] Kennedy ME, Stamford AW, Chen X, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016; 8(363): 363ra150.

[124] Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer's disease. N Engl J Med. 2018; 378(18): 1691-1703.

[125] Doggrell SA. Lessons that can be learnt from the failure of verubecestat in Alzheimer's disease. Expert Opin Pharmacother. 2019; 20(17): 2095-2099.

[126] Wessels AM, Tariot PN, Zimmer JA, et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: the AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol. 2020; 77(2): 199-209.

[127] Timmers M, Streffer JR, Russu A, et al. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study. Alzheimer's Res Ther. 2018; 10(1): 85.

[128] Novak G, Streffer JR, Timmers M, et al. Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study. Alzheimer's Res Ther. 2020; 12(1): 58.

[129] DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci. 2001; 98(15): 8850-8855.

[130] Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimer's Dementia. 2012; 8(4): 261-271.

[131] Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014; 370(4): 311-321.

[132] Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer's disease. N Engl J Med. 2018; 378(4): 321-330.

[133] Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in aAzheimer's disease. Neurobiol Dis. 2017; 107: 41-56.

[134] Burstein AH, Grimes I, Galasko DR, Aisen PS, Sabbagh M, Mjalli AM. Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurol. 2014; 14:12.

[135] Umbricht D. Letter to the editor referring to PS Aisen and R. Raman, Futility Analyses in Alzheimer's disease (AD) Clinical Trials: A Risky Business. The Journal of Prevention of Alzheimer's Disease, 2020. J Prevent Alzheimer's Dis. 2020; 7: 299-300.

[136] Yasmin S, Jayaprakash V. Thiazolidinediones and PPAR orchestra as antidiabetic agents: from past to present. Eur J Med Chem. 2017; 126: 879-893.

[137] Neumann KF, Rojo L, Navarrete LP, Farías G, Reyes P, Maccioni RB. Insulin resistance and Alzheimer's disease: molecular links & clinical implications. Curr Alzheimer Res. 2008; 5(5): 438-447.

[138] Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al. Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice. Brain. 2005; 128(Pt 6): 1442-1453.

[139] Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011; 32(9): 1626-1633.

[140] Crenshaw DG, Gottschalk WK, Lutz MW, et al. Using genetics to enable studies on the prevention of Alzheimer's disease. Clin Pharmacol Ther. 2013; 93(2): 177-185.

[141] Meneses A. Effects of the 5-HT6 receptor antagonist Ro 04-6790 on learning consolidation. Behav Brain Res. 2001; 118(1): 107-110.

[142] Rodríguez JJ, Noristani HN, Verkhratsky A. The serotonergic system in ageing and Alzheimer's disease. Prog Neurobiol. 2012; 99(1): 15-41.

[143] Maher-Edwards G, Zvartau-Hind M, Hunter AJ, et al. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, Sb-742457, in Alzheimer's disease. Curr Alzheimer Res. 2010; 7(5): 374-385.

[144] Wilkinson D, Windfeld K, Colding-Jørgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014; 13(11): 1092-1099.

[145] Atri A, Frölich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018; 319(2): 130-142.

[146] Khoury R, Grysman N, Gold J, Patel K, Grossberg GT. The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update. Expert Opin Invest Drugs. 2018; 27(6): 523-533.

[147] Iqbal K, Flory M, Khatoon S, et al. Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers. Ann Neurol. 2005; 58(5): 748-757.

[148] Reger MA, Watson GS, Frey WH, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006; 27(3): 451-458.

[149] Ghosh P, Singh R, Ganeshpurkar A, et al. Cellular and molecular influencers of neuroinflammation in Alzheimer's disease: recent concepts & roles. Neurochem Int. 2021; 151:105212.

[150] Norins LC. Repurposing licensed drugs for use against Alzheimer's disease. J Alzheimer's Dis. 2021; 81(3): 921-932.

[151] Paranjpe MD, Taubes A, Sirota M. Insights into computational drug repurposing for neurodegenerative disease. Trends Pharmacol Sci. 2019; 40(8): 565-576.

[152] Bolognesi M, Rosini M, Andrisano V, et al. MTDL design strategy in the context of Alzheimer's disease: from lipocrine to memoquin and beyond. Curr Pharm Des. 2009; 15(6): 601-613.

[153] Ibrahim M, Gabr M. Multitarget therapeutic strategies for Alzheimer's disease. Neural Regen Res. 2019; 14(3): 437-440.

[154] Reitz C. Toward precision Medicine in Alzheimer's disease. Ann Transl Med. 2016; 4(6): 107.

[155] Hampel H, Caraci F, Cuello AC, et al. A path toward precision medicine for neuroinflammatory mechanisms in alzheimer's disease. Front Immunol. 2020; 11:456.

[156] Sayas CL, Ávila J. GSK-3 and Tau: a key duet in Alzheimer's disease. Cells. 2021; 10(4):721.

[157] Lovestone S, Boada M, Dubois B, et al. A phase II trial of tideglusib in Alzheimer's disease. J Alzheimer's Dis. 2015; 45(1): 75-88.

[158] Ferrer I, Gomez-Isla T, Puig B, et al. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. Curr Alzheimer Res. 2005; 2(1): 3-18.

[159] Hu J, Geng M, Li J, et al. Acidic oligosaccharide sugar chain, a marine-derived acidic oligosaccharide, inhibits the cytotoxicity and aggregation of amyloid beta protein. J Pharmacol Sci. 2004; 95(2): 248-255.

[160] Wang S, Li J, Xia W, Geng M. A marine-derived acidic oligosaccharide sugar chain specifically inhibits neuronal cell injury mediated by β-amyloid-induced astrocyte activation in vitro. Neurol Res. 2007; 29(1): 96-102.

[161] Wang X, Sun G, Feng T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression. Cell Res. 2019; 29(10): 787-803.

[162] Cabrera-Pardo JR, Fuentealba J, Gavilán J, Cajas D, Becerra J, Napiórkowska M. Exploring the multi–target neuroprotective chemical space of benzofuran scaffolds: a new strategy in drug development for Alzheimer's disease. Front Pharmacol. 2020; 10:1679.

[163] Bhatia R, Chakrabarti SS, Kaur U, Parashar G, Banerjee A, Rawal RK. Multi-target directed ligands (MTDLs): promising coumarin hybrids for Alzheimer's disease. Curr Alzheimer Res. 2021; 18(10): 802-830.

[164] Uddin MS, Al Mamun A, Kabir MT, Ashraf GM, Bin-Jumah MN, Abdel-Daim MM. Multi-target drug candidates for multifactorial Alzheimer's disease: AChE and NMDAR as molecular targets. Mol Neurobiol. 2021; 58: 281-303.

[165] Marasco D, Vicidomini C, Krupa P, et al. Plant isoquinoline alkaloids as potential neurodrugs: A comparative study of the effects of benzo [c] phenanthridine and berberine-based compounds on β-amyloid aggregation. Chemico-biological interactions. 2021; 334:109300.

[166] Thapa P, Upadhyay SP, Suo WZ, et al. Chalcone and its analogs: therapeutic and diagnostic applications in Alzheimer's disease. Bioorg Chem. 2021; 108:104681.

[167] Li F, Li Y, Deng Z, et al. Traditional uses, phytochemistry, pharmacology and clinical applications of cortex juglandis mandshuricae: a comprehensive review. J Ethnopharmacol. 2022; 285:114887.

[168] G. Serrano F, Tapia-Rojas C, J. Carvajal F, et al. Rhein-huprine derivatives reduce cognitive impairment, synaptic failure and amyloid pathology in AβPPswe/PS-1 mice of different ages. Curr Alzheimer Res. 2016; 13(9): 1017-1029.

[169] Mukherjee S, Mishra AK, Peer GDG, et al. The interplay of the unfolded protein response in neurodegenerative diseases: a therapeutic role of curcumin. Front Aging Neurosci. 2021; 13:767493.

[170] Li X, Chu S, Liu Y, Chen N. Neuroprotective effects of anthraquinones from rhubarb in central nervous system diseases. Evid-Based Complement Alternat Med: eCAM. 2019; 2019:3790728.

[171] Akbar M, Shabbir A, Rehman K, Akash MSH, Shah MA. Neuroprotective potential of berberine in modulating Alzheimer's disease via multiple signaling pathways. J Food Biochem. 2021; 45(10):e13936.

[172] Noori T, Dehpour AR, Sureda A, Sobarzo-Sanchez E, Shirooie S. Role of natural products for the treatment of Alzheimer's disease. Eur J Pharmacol. 2021; 898:173974.

[173] Xiao S, Chan P, Wang T, et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer's dementia. Alzheimer's Res Ther. 2021; 13(1): 62.

[174] Steen E, Terry BM, J. Rivera E, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease–is this type 3 diabetes? J Alzheimer's Dis. 2005; 7(1): 63-80.

[175] Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol. 2011; 225(1): 54-62.

[176] Chen Y, Deng Y, Zhang B, Gong C-X. Deregulation of brain insulin signaling in Alzheimer's disease. Neurosci Bull. 2014; 30(2): 282-294.

[177] Chen Y, Zhang J, Zhang B, Gong C-X. Targeting insulin signaling for the treatment of Alzheimer's disease. Curr Top Med Chem. 2015; 16(5): 485-492.

[178] Butkinaree C, Park K, Hart GW. O-linked β-N-acetylglucosamine (O-GlcNAc): extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochim Biophys Acta (BBA)-Gen Sub. 2010; 1800(2): 96-106.

[179] Jacobsen KT, Iverfeldt K. O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP). Biochem Biophys Res Commun. 2011; 404(3): 882-886.

[180] Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong C-X. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci. 2004; 101(29): 10804-10809.

[181] Liu F, Shi J, Tanimukai H, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009; 132(7): 1820-1832.

[182] Tallent MK, Varghis N, Skorobogatko Y, et al. In vivo modulation of O-GlcNAc levels regulates hippocampal synaptic plasticity through interplay with phosphorylation. J Biol Chem. 2009; 284(1): 174-181.

[183] Yang X, Ongusaha PP, Miles PD, et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008; 451(7181): 964-969.

[184] Pan D, Gu J-H, Zhang J, et al. Thiamme2-G, a Novel O-GlcNAcase inhibitor, reduces tau hyperphosphorylation and rescues cognitive impairment in mice. J Alzheimer's Dis. 2021; 81(1): 273-286.

[185] Yuzwa SA, Shan X, Jones BA, et al. Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice. Mol Neurodegener. 2014; 9:42.

[186] Kazim SF, Blanchard J, Dai C-L, et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2014; 71: 110-130.

[187] Baazaoui N, Iqbal K. Prevention of amyloid-β and tau pathologies, associated neurodegeneration, and cognitive deficit by early treatment with a neurotrophic compound. J Alzheimer's Dis. 2017; 58(1): 215-230.

[188] Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014; 13(8): 788-794.

[189] Sperling RA, Jack CR, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med. 2011; 3(111): 111cm33-1cm33cm33.

[190] Hsu D, Marshall GA. Primary and secondary prevention trials in Alzheimer disease: looking back, moving forward. Curr Alzheimer Res. 2017; 14(4): 426-440.

[191] Lindberg DA. Integrative review of research related to meditation, spirituality, and the elderly. Geriatr Nurs. 2005; 26(6): 372-377.

[192] Forette F, Seux M-L, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998; 352(9137): 1347-1351.

[193] Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S. Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med. 2016; 374(6): 523-532.

[194] Goldstein FC, Ashley AV, Endeshaw YW, Hanfelt J, Lah JJ, Levey AI. Effects of hypertension and hypercholesterolemia on cognitive functioning in patients with Alzheimer disease. Alzheimer Dis Assoc Disord. 2008; 22(4): 336-342.

[195] McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2009; 1(2): 1-40.

[196] Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360(9346): 1623-1630.

[197] Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011; 10(11): 969-977.

[198] Craft S. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012; 69(1): 29-38.

[199] Pérez MJ, Quintanilla RA. Therapeutic actions of the thiazolidinediones in Alzheimer's disease. PPAR Res. 2015; 2015(1):957248.

[200] Singh B, Parsaik AK, Mielke MM, et al. Association of mediterranean diet with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. J Alzheimer's Dis. 2014; 39(2): 271-282.

[201] Morris MC, Tangney CC, Wang Y, et al. MIND diet slows cognitive decline with aging. Alzheimer's Dement: J Alzheimer's Assoc. 2015; 11(9): 1015-1022.

[202] Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008; 300(9): 1027-1037.

[203] Scarmeas N. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009; 302(6): 627-637.

[204] Rebok GW, Ball K, Guey LT, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014; 62(1): 16-24.

[205] Farina N, Llewellyn D, Isaac MGEKN, Tabet N. Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017; 1(4): 1-51.

[206] Dysken MW, Guarino PD, Vertrees JE, et al. Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data. Alzheimer's Dement: J Alzheimer's Assoc. 2014; 10(1): 36-44.

[207] Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014; 311(1): 33-44.

[208] DeKosky ST. A randomized controlled trial. JAMA. 2008; 300(19): 2253-2262.

[209] Williamson JD, Vellas B, Furberg C, Nahin R, Dekosky ST. Comparison of the design differences between the Ginkgo evaluation of memory study and the GuidAge study. J Nutr Health Aging. 2008; 12: S73-S79.

[210] Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Rev Neurol. 2009; 5(3): 140-152.

[211] Yurko-Mauro K, McCarthy D, Rom D, et al. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimer's Dement: J Alzheimer's Assoc. 2010; 6(6): 456-464.

[212] Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015; 385(9984): 2255-2263.

[213] Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013; 368(13): 1169-1171.

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