Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies

Sunny      Rathee; Debasis      Sen; Vishal      Pandey; Sanjay   K.   Jain
Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aβ plaques formed by misfolded tau proteins and Aβ peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aβ variants and binds to large soluble Aβ aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathophysiology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.
Keywords: Alzheimer’s disease, amyloid β, lecanemab, central nervous system, cholinesterase inhibitors, neurodegenerative disorder.
Graphical Abstract

[1]
Fish PV, Steadman D, Bayle ED, Whiting P. New approaches for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett  2019; 29(2): 125-33.
 [http://dx.doi.org/10.1016/j.bmcl.2018.11.034] [PMID: 30501965]

[2]
Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers  2021; 7(1): 33.
 [http://dx.doi.org/10.1038/s41572-021-00269-y] [PMID: 33986301]

[3]
Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell  2019; 179(2): 312-39.
 [http://dx.doi.org/10.1016/j.cell.2019.09.001] [PMID: 31564456]

[4]
Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci  2020; 27(1): 18.
 [http://dx.doi.org/10.1186/s12929-019-0609-7] [PMID: 31906949]

[5]
Imbimbo BP, Lombard J, Pomara N. Pathophysiology of Alzheimer’s disease. Neuroimaging Clin N Am  2005; 15(4): 727-753, ix.
 [http://dx.doi.org/10.1016/j.nic.2005.09.009] [PMID: 16443487]

[6]
Vaghul K. The child care conundrum: The costs and consequences of unmet early child care needs among parents working at academic institutions across the United States. Massachusetts Institute of Technology 2019.

[7]
Ebi KL, Vanos J, Baldwin JW, et al. Extreme weather and climate change: population health and health system implications. Annu Rev Public Health  2021; 42(1): 293-315.
 [http://dx.doi.org/10.1146/annurev-publhealth-012420-105026] [PMID: 33406378]

[8]
Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet  2021; 397(10284): 1577-90.
 [http://dx.doi.org/10.1016/S0140-6736(20)32205-4] [PMID: 33667416]

[9]
Bloom GS. Amyloid-β and Tau. JAMA Neurol  2014; 71(4): 505-8.
 [http://dx.doi.org/10.1001/jamaneurol.2013.5847] [PMID: 24493463]

[10]
Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: An emperor in need of clothes. Nat Neurosci  2012; 15(3): 349-57.
 [http://dx.doi.org/10.1038/nn.3028] [PMID: 22286176]

[11]
Khan UA, Liu L, Provenzano FA, et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat Neurosci  2014; 17(2): 304-11.
 [http://dx.doi.org/10.1038/nn.3606] [PMID: 24362760]

[12]
Song C, Shi J, Zhang P, et al. Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond. Transl Neurodegener  2022; 11(1): 18.
 [http://dx.doi.org/10.1186/s40035-022-00292-3] [PMID: 35300725]

[13]
Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther  2021; 13(1): 80.
 [http://dx.doi.org/10.1186/s13195-021-00813-8] [PMID: 33865446]

[14]
Tucker S, Möller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis  2014; 43(2): 575-88.
 [http://dx.doi.org/10.3233/JAD-140741] [PMID: 25096615]

[15]
Reitz C, Rogaeva E, Beecham GW. Late-onset vs nonmendelian early-onset Alzheimer disease. Neurol Genet  2020; 6(5): e512.
 [http://dx.doi.org/10.1212/NXG.0000000000000512] [PMID: 33225065]

[16]
Tcw J, Goate AM. Genetics of β-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med  2017; 7(6): a024539.
 [http://dx.doi.org/10.1101/cshperspect.a024539] [PMID: 28003277]

[17]
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 variants in Alzheimer’s disease: Systematic Re-evaluation according to ACMG guidelines. Front Aging Neurosci  2021; 13: 695808.
 [http://dx.doi.org/10.3389/fnagi.2021.695808] [PMID: 34220489]

[18]
Bellenguez C, Grenier-Boley B, Lambert JC. Genetics of Alzheimer’s disease: where we are, and where we are going. Curr Opin Neurobiol  2020; 61: 40-8.
 [http://dx.doi.org/10.1016/j.conb.2019.11.024] [PMID: 31863938]

[19]
Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life  2014; 66(9): 616-23.
 [http://dx.doi.org/10.1002/iub.1314] [PMID: 25328986]

[20]
Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry  2015; 77(1): 43-51.
 [http://dx.doi.org/10.1016/j.biopsych.2014.05.006] [PMID: 24951455]

[21]
Martins MM, Branco PS, Ferreira LM. Enhancing the therapeutic effect in alzheimer’s disease drugs: The role of polypharmacology and cholinesterase inhibitors. ChemistrySelect  2023; 8(10): e202300461.
 [http://dx.doi.org/10.1002/slct.202300461]

[22]
van Dyck CH. Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol Psychiatry  2018; 83(4): 311-9.
 [http://dx.doi.org/10.1016/j.biopsych.2017.08.010] [PMID: 28967385]

[23]
Zhang Y, Thompson R, Zhang H, Xu H. APP processing in Alzheimer’s disease. Mol Brain  2011; 4(1): 3.
 [http://dx.doi.org/10.1186/1756-6606-4-3] [PMID: 21214928]

[24]
Frozza RL, Lourenco MV, De Felice FG. Challenges for Alzheimer’s disease therapy: insights from novel mechanisms beyond memory defects. Front Neurosci  2018; 12: 37.
 [http://dx.doi.org/10.3389/fnins.2018.00037] [PMID: 29467605]

[25]
Hampel H, Hardy J, Blennow K, et al. The amyloid-β pathway in Alzheimer’s disease. Mol Psychiatry  2021; 26(10): 5481-503.
 [http://dx.doi.org/10.1038/s41380-021-01249-0] [PMID: 34456336]

[26]
Zhao J, Liu X, Xia W, Zhang Y, Wang C. Targeting amyloidogenic processing of APP in Alzheimer’s disease. Front Mol Neurosci  2020; 13: 137.
 [http://dx.doi.org/10.3389/fnmol.2020.00137] [PMID: 32848600]

[27]
Ashe KH, Aguzzi A. Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion  2013; 7(1): 55-9.
 [http://dx.doi.org/10.4161/pri.23061] [PMID: 23208281]

[28]
Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet  1976; 308(8000): 1403.
 [http://dx.doi.org/10.1016/S0140-6736(76)91936-X] [PMID: 63862]

[29]
Zhang P, Xu S, Zhu Z, Xu J. Multi-target design strategies for the improved treatment of Alzheimer’s disease. Eur J Med Chem  2019; 176: 228-47.
 [http://dx.doi.org/10.1016/j.ejmech.2019.05.020] [PMID: 31103902]

[30]
Morrison AS, Lyketsos C. The pathophysiology of Alzheimer’s disease and directions in treatment. Adv Stud Nurs  2005; 3(8): 256-70.

[31]
Liu PP, Xie Y, Meng XY, Kang JS. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Target Ther  2019; 4(1): 29.
 [http://dx.doi.org/10.1038/s41392-019-0063-8] [PMID: 31637009]

[32]
Giacobini E, Gold G. Alzheimer disease therapy—moving from amyloid-β to tau. Nat Rev Neurol  2013; 9(12): 677-86.
 [http://dx.doi.org/10.1038/nrneurol.2013.223] [PMID: 24217510]

[33]
Reardon S. FDA approves Alzheimer’s drug lecanemab amid safety concerns. Nature Publishing Group 2023.

[34]
Gautam D, Naik UP, Naik MU, Yadav SK, Chaurasia RN, Dash D. Glutamate receptor dysregulation and platelet glutamate dynamics in alzheimer’s and parkinson’s diseases: insights into current medications. Biomolecules  2023; 13(11): 1609.
 [http://dx.doi.org/10.3390/biom13111609] [PMID: 38002291]

[35]
Huang Y, Shen W, Su J, et al. Modulating the balance of synaptic and extrasynaptic NMDA receptors shows positive effects against amyloid-β-induced neurotoxicity. J Alzheimers Dis  2017; 57(3): 885-97.
 [http://dx.doi.org/10.3233/JAD-161186] [PMID: 28269783]

[36]
Uddin MS, Lim LW. Glial cells in Alzheimer’s disease: From neuropathological changes to therapeutic implications. Ageing Res Rev  2022; 78: 101622.
 [http://dx.doi.org/10.1016/j.arr.2022.101622] [PMID: 35427810]

[37]
Doty KR, Guillot-Sestier MV, Town T. The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive? Brain Res  2015; 1617: 155-73.
 [http://dx.doi.org/10.1016/j.brainres.2014.09.008] [PMID: 25218556]

[38]
Jurga AM, Paleczna M, Kadluczka J, Kuter KZ. Beyond the GFAP-astrocyte protein markers in the brain. Biomolecules  2021; 11(9): 1361.
 [http://dx.doi.org/10.3390/biom11091361] [PMID: 34572572]

[39]
Bellaver B, Povala G, Ferreira PCL, et al. Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease. Nat Med  2023; 29(7): 1775-81.
 [http://dx.doi.org/10.1038/s41591-023-02380-x] [PMID: 37248300]

[40]
Haney MS, Pálovics R, Munson CN, et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature  2024; 628(8006): 154-61.
 [http://dx.doi.org/10.1038/s41586-024-07185-7] [PMID: 38480892]

[41]
Sun N, Victor MB, Park YP, Xiong X, Scannail AN, Leary N. Human microglial state dynamics in Alzheimer’s disease progression. Cell  2023; 186(20): 4386-403.
 [http://dx.doi.org/10.1016/j.cell.2023.08.037]

[42]
Fox NC, Crum WR, Scahill RI, Stevens JM, Janssen JC, Rossor MN. Imaging of onset and progression of Alzheimer’s disease with voxel-compression mapping of serial magnetic resonance images. Lancet  2001; 358(9277): 201-5.
 [http://dx.doi.org/10.1016/S0140-6736(01)05408-3] [PMID: 11476837]

[43]
Förstl H, Zerfaß R, Geiger-Kabisch C, Sattel H, Besthorn C, Hentschel F. Brain atrophy in normal ageing and Alzheimer’s disease. Volumetric discrimination and clinical correlations. Br J Psychiatry  1995; 167(6): 739-46.
 [http://dx.doi.org/10.1192/bjp.167.6.739] [PMID: 8829740]

[44]
Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res  2017; 95(1-2): 671-80.
 [http://dx.doi.org/10.1002/jnr.23827] [PMID: 27870425]

[45]
van de Rest O, Berendsen AAM, Haveman-Nies A, de Groot LCPGM. Dietary patterns, cognitive decline, and dementia: A systematic review. Adv Nutr  2015; 6(2): 154-68.
 [http://dx.doi.org/10.3945/an.114.007617] [PMID: 25770254]

[46]
Pope SK, Shue VM, Beck C. Will a healthy lifestyle help prevent Alzheimer’s disease? Annu Rev Public Health  2003; 24(1): 111-32.
 [http://dx.doi.org/10.1146/annurev.publhealth.24.100901.141015] [PMID: 12415146]

[47]
Baranowski BJ, Marko DM, Fenech RK, Yang AJT, MacPherson REK. Healthy brain, healthy life: A review of diet and exercise interventions to promote brain health and reduce Alzheimer’s disease risk. Appl Physiol Nutr Metab  2020; 45(10): 1055-65.
 [http://dx.doi.org/10.1139/apnm-2019-0910] [PMID: 32717151]

[48]
John A, Ali K, Marsh H, Reddy PH. Can healthy lifestyle reduce disease progression of Alzheimer’s during a global pandemic of COVID-19? Ageing Res Rev  2021; 70: 101406.
 [http://dx.doi.org/10.1016/j.arr.2021.101406] [PMID: 34242809]

[49]
Lucey BP, Bateman RJ. Amyloid-β diurnal pattern: Possible role of sleep in Alzheimer’s disease pathogenesis. Neurobiol Aging  2014; 35 (2): S29-34.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.035] [PMID: 24910393]

[50]
Borchardt V, Korhonen V, Helakari H, Nedergaard M, Myllylä T, Kiviniemi V. Inverse correlation of fluctuations of cerebral blood and water concentrations in humans. Eur Phys J Plus  2021; 136(5): 497.
 [http://dx.doi.org/10.1140/epjp/s13360-021-01480-2]

[51]
Chatzi C, Zhang Y, Hendricks WD, et al. Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L. eLife  2019; 8: e45920.
 [http://dx.doi.org/10.7554/eLife.45920] [PMID: 31232686]

[52]
Lin TW, Tsai SF, Kuo YM. Physical exercise enhances neuroplasticity and delays Alzheimer’s disease. Brain Plast  2018; 4(1): 95-110.
 [http://dx.doi.org/10.3233/BPL-180073] [PMID: 30564549]

[53]
Smith DH, Chen X-H, Nonaka M, et al. Accumulation of amyloid β and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol  1999; 58(9): 982-92.
 [http://dx.doi.org/10.1097/00005072-199909000-00008] [PMID: 10499440]

[54]
Van Den Heuvel C, Finnie JW, Blumbergs PC, et al. Upregulation of neuronal amyloid precursor protein (APP) and APP mRNA following magnesium sulphate (MgSO4) therapy in traumatic brain injury. J Neurotrauma  2000; 17(11): 1041-53.
 [http://dx.doi.org/10.1089/neu.2000.17.1041] [PMID: 11101207]

[55]
Edwards GA III, Gamez N, Escobedo G Jr, Calderon O, Moreno-Gonzalez I. Modifiable risk factors for Alzheimer’s disease. Front Aging Neurosci  2019; 11: 146.
 [http://dx.doi.org/10.3389/fnagi.2019.00146] [PMID: 31293412]

[56]
Chatterjee S, Mudher A. Alzheimer’s disease and type 2 diabetes: A critical assessment of the shared pathological traits. Front Neurosci  2018; 12: 383.
 [http://dx.doi.org/10.3389/fnins.2018.00383] [PMID: 29950970]

[57]
A Armstrong R. Risk factors for Alzheimer’s disease. Folia Neuropathol  2019; 57(2): 87-105.
 [http://dx.doi.org/10.5114/fn.2019.85929] [PMID: 31556570]

[58]
Mendez MF. Early-onset Alzheimer disease. Neurol Clin  2017; 35(2): 263-81.
 [http://dx.doi.org/10.1016/j.ncl.2017.01.005] [PMID: 28410659]

[59]
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. the Lancet  2011; 377(9770): 1019-31.

[60]
Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med  2016; 18(5): 421-30.
 [http://dx.doi.org/10.1038/gim.2015.117] [PMID: 26312828]

[61]
Qing H, Li N-M, Liu K-F, Qiu Y-J, Zhang H-H, Nakanishi H. Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer’s disease pathogenesis. Neural Regen Res  2019; 14(4): 658-65.
 [http://dx.doi.org/10.4103/1673-5374.247469] [PMID: 30632506]

[62]
Silva MVF, Loures CMG, Alves LCV, de Souza LC, Borges KBG, Carvalho MG. Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci  2019; 26(1): 33.
 [http://dx.doi.org/10.1186/s12929-019-0524-y]

[63]
Cahill L. Why sex matters for neuroscience. Nat Rev Neurosci  2006; 7(6): 477-84.
 [http://dx.doi.org/10.1038/nrn1909] [PMID: 16688123]

[64]
Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules  2020; 25(24): 5789.
 [http://dx.doi.org/10.3390/molecules25245789] [PMID: 33302541]

[65]
Wolk DA, Dickerson BC. Clinical features and diagnosis of Alzheimer disease. 2016. Available from: https://medilib.ir/uptodate/show/5071

[66]
Viola KL, Klein WL. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol  2015; 129(2): 183-206.
 [http://dx.doi.org/10.1007/s00401-015-1386-3] [PMID: 25604547]

[67]
Palmqvist S, Mattsson N, Hansson O. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain  2016; 139(4): 1226-36.
 [http://dx.doi.org/10.1093/brain/aww015] [PMID: 26936941]

[68]
Johnson KA, Fox NC, Sperling RA, Klunk WE. Brain imaging in Alzheimer disease. Cold Spring Harb Perspect Med  2012; 2(4): a006213.
 [http://dx.doi.org/10.1101/cshperspect.a006213] [PMID: 22474610]

[69]
Cockrell JR, Folstein MF. Mini-mental state examination. Principles and Practice of Geriatric Psychiatry.  Wiley Online Library 2002; pp. 140-1.
 [http://dx.doi.org/10.1002/0470846410.ch27(ii)]

[70]
Richards D, Sabbagh MN. Florbetaben for PET imaging of beta-amyloid plaques in the brain. Neurol Ther  2014; 3(2): 79-88.
 [http://dx.doi.org/10.1007/s40120-014-0022-9] [PMID: 26000224]

[71]
Ossenkoppele R, van der Kant R, Hansson O. Tau biomarkers in Alzheimer’s disease: Towards implementation in clinical practice and trials. Lancet Neurol  2022; 21(8): 726-34.
 [http://dx.doi.org/10.1016/S1474-4422(22)00168-5] [PMID: 35643092]

[72]
Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA  2020; 324(8): 772-81.
 [http://dx.doi.org/10.1001/jama.2020.12134] [PMID: 32722745]

[73]
Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med  2020; 26(3): 387-97.
 [http://dx.doi.org/10.1038/s41591-020-0762-2] [PMID: 32123386]

[74]
Visser PJ, Reus LM, Gobom J, et al. Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease. Mol Neurodegener  2022; 17(1): 27.
 [http://dx.doi.org/10.1186/s13024-022-00521-3] [PMID: 35346299]

[75]
Rice L, Bisdas S. The diagnostic value of FDG and amyloid PET in Alzheimer’s disease : A systematic review. Eur J Radiol  2017; 94: 16-24.
 [http://dx.doi.org/10.1016/j.ejrad.2017.07.014] [PMID: 28941755]

[76]
Pákáski M, Kálmán J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer’s disease. Neurochem Int  2008; 53(5): 103-11.
 [http://dx.doi.org/10.1016/j.neuint.2008.06.005] [PMID: 18602955]

[77]
Mash DC, Flynn DD, Potter LT. Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation. Science  1985; 228(4703): 1115-7.
 [http://dx.doi.org/10.1126/science.3992249] [PMID: 3992249]

[78]
Teaktong T, Graham AJ, Court JA, et al. Nicotinic acetylcholine receptor immunohistochemistry in Alzheimer’s disease and dementia with Lewy bodies: differential neuronal and astroglial pathology. J Neurol Sci  2004; 225(1-2): 39-49.
 [http://dx.doi.org/10.1016/j.jns.2004.06.015] [PMID: 15465084]

[79]
Andrieu S, Coley N, Lovestone S, Aisen PS, Vellas B. Prevention of sporadic Alzheimer’s disease: lessons learned from clinical trials and future directions. Lancet Neurol  2015; 14(9): 926-44.
 [http://dx.doi.org/10.1016/S1474-4422(15)00153-2] [PMID: 26213339]

[80]
Danysz W, Parsons CG, MÖbius HJÖ, StÖffler A, Quack GÜ. Neuroprotective and symptomatological action of memantine relevant for alzheimer’s disease  a unified glutamatergic hypothesis on the mechanism of action. Neurotox Res  2000; 2(2-3): 85-97.
 [http://dx.doi.org/10.1007/BF03033787] [PMID: 16787834]

[81]
Hyde C, Peters J, Bond M, et al. Evolution of the evidence on the effectiveness and cost-effectiveness of acetylcholinesterase inhibitors and memantine for Alzheimer’s disease: systematic review and economic model. Age Ageing  2013; 42(1): 14-20.
 [http://dx.doi.org/10.1093/ageing/afs165] [PMID: 23179169]

[82]
Se Thoe E, Fauzi A, Tang YQ, Chamyuang S, Chia AYY. A review on advances of treatment modalities for Alzheimer’s disease. Life Sci  2021; 276: 119129.
 [http://dx.doi.org/10.1016/j.lfs.2021.119129] [PMID: 33515559]

[83]
Karran E, De Strooper B. The amyloid cascade hypothesis: Are we poised for success or failure? J Neurochem  2016; 139(S2) (Suppl. 2): 237-52.
 [http://dx.doi.org/10.1111/jnc.13632] [PMID: 27255958]

[84]
Loera-Valencia R, Piras A, Ismail MAM, et al. Targeting Alzheimer’s disease with gene and cell therapies. J Intern Med  2018; 284(1): 2-36.
 [http://dx.doi.org/10.1111/joim.12759] [PMID: 29582495]

[85]
Worker A, Dima D, Combes A, et al. Test–retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing and Alzheimer’s disease populations. Hum Brain Mapp  2018; 39(4): 1743-54.
 [http://dx.doi.org/10.1002/hbm.23948] [PMID: 29341323]

[86]
Carrara SC, Ulitzka M, Grzeschik J, Kornmann H, Hock B, Kolmar H. From cell line development to the formulated drug product: The art of manufacturing therapeutic monoclonal antibodies. Int J Pharm  2021; 594: 120164.
 [http://dx.doi.org/10.1016/j.ijpharm.2020.120164] [PMID: 33309833]

[87]
Nelson PN, Reynolds GM, Waldron EE, Ward E, Giannopoulos K, Murray PG. Demystified  Monoclonal antibodies. Mol Pathol  2000; 53(3): 111-7.
 [http://dx.doi.org/10.1136/mp.53.3.111] [PMID: 10897328]

[88]
Liu JKH. The history of monoclonal antibody development : Progress, remaining challenges and future innovations. Ann Med Surg  2014; 3(4): 113-6.
 [http://dx.doi.org/10.1016/j.amsu.2014.09.001] [PMID: 25568796]

[89]
Shepard HM, Phillips GL, Thanos CD, Feldmann M. Developments in therapy with monoclonal antibodies and related proteins. Clin Med  2017; 17(3): 220-32.
 [http://dx.doi.org/10.7861/clinmedicine.17-3-220] [PMID: 28572223]

[90]
Buss NAPS, Henderson SJ, McFarlane M, Shenton JM, de Haan L. Monoclonal antibody therapeutics: History and future. Curr Opin Pharmacol  2012; 12(5): 615-22.
 [http://dx.doi.org/10.1016/j.coph.2012.08.001] [PMID: 22920732]

[91]
García Merino A. Monoclonal antibodies. Basic features. Neurologia  2011; 26(5): 301-6.
 [PMID: 21193249]

[92]
Bayer V. An Overview of Monoclonal Antibodies. Semin Oncol Nurs  2019; 35(5): 150927.

[93]
Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. MAbs  2020; 12(1): 1703531.

[94]
Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs  2021; 13(1): 1860476.
 [http://dx.doi.org/10.1080/19420862.2020.1860476]

[95]
Takeda M. Development of monoclonal antibody therapeutics for alzheimer’s disease. Taiwan J Psych  2022; 36(4): 148-56.
 [http://dx.doi.org/10.4103/TPSY.TPSY_31_22]

[96]
Cao Y-P, Wang J-C, Zhu K, Zhang H-Y, Wang G-Q, Liu H-Y. Early active immunization with Aβ 3–10 -KLH vaccine reduces tau phosphorylation in the hippocampus and protects cognition of mice. Neural Regen Res  2020; 15(3): 519-27.
 [http://dx.doi.org/10.4103/1673-5374.266061] [PMID: 31571664]

[97]
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. nature  1999; 400(6740): 173-7.

[98]
Monsonego A, Weiner HL. Immunotherapeutic approaches to Alzheimer’s disease. Science  2003; 302(5646): 834-8.
 [http://dx.doi.org/10.1126/science.1088469] [PMID: 14593170]

[99]
Citron M. Alzheimer’s disease: Strategies for disease modification. Nat Rev Drug Discov  2010; 9(5): 387-98.
 [http://dx.doi.org/10.1038/nrd2896] [PMID: 20431570]

[100]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature  2016; 537(7618): 50-6.
 [http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]

[101]
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): 311-21.
 [http://dx.doi.org/10.1056/NEJMoa1312889] [PMID: 24450890]

[102]
Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology  2018; 90(21): e1889-97.
 [http://dx.doi.org/10.1212/WNL.0000000000005550] [PMID: 29695589]

[103]
Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther  2017; 9(1): 95.
 [http://dx.doi.org/10.1186/s13195-017-0318-y] [PMID: 29221491]

[104]
Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement  2023; 9(2): e12385.
 [http://dx.doi.org/10.1002/trc2.12385] [PMID: 37251912]

[105]
Buccellato FR, D’Anca M, Tartaglia GM, Del Fabbro M, Scarpini E, Galimberti D. Treatment of Alzheimer’s disease: Beyond symptomatic therapies. Int J Mol Sci  2023; 24(18): 13900.
 [http://dx.doi.org/10.3390/ijms241813900] [PMID: 37762203]

[106]
McDade E, Cummings JL, Dhadda S, et al. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res Ther  2022; 14(1): 191.
 [http://dx.doi.org/10.1186/s13195-022-01124-2] [PMID: 36544184]

[107]
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med  2023; 388(1): 9-21.
 [http://dx.doi.org/10.1056/NEJMoa2212948] [PMID: 36449413]

[108]
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Focus Am Psychiatr Publ  2013; 11(1): 96-106.
 [http://dx.doi.org/10.1176/appi.focus.11.1.96]

[109]
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. J Psychiatr Res  1975; 12(3): 189-98.
 [http://dx.doi.org/10.1016/0022-3956(75)90026-6] [PMID: 1202204]

[110]
Dubois B, Hampel H, Feldman HH, et al. Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement  2016; 12(3): 292-323.
 [http://dx.doi.org/10.1016/j.jalz.2016.02.002] [PMID: 27012484]

[111]
Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: Appropriate use recommendations. J Prev Alzheimers Dis  2023; 10(3): 362-77.
 [PMID: 37357276]

[112]
Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med  2000; 6(8): 916-9.
 [http://dx.doi.org/10.1038/78682] [PMID: 10932230]

[113]
Black RS, Sperling RA, Safirstein B, et al. A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord  2010; 24(2): 198-203.
 [http://dx.doi.org/10.1097/WAD.0b013e3181c53b00] [PMID: 20505438]

[114]
Barakos J, Purcell D, Suhy J, et al. Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with anti-amyloid beta therapy. J Prev Alzheimers Dis  2022; 9(2): 211-20.
 [PMID: 35542992]

[115]
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med  2014; 370(4): 322-33.
 [http://dx.doi.org/10.1056/NEJMoa1304839] [PMID: 24450891]

[116]
Rinne JO, Brooks DJ, Rossor MN, et al. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: A phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol  2010; 9(4): 363-72.
 [http://dx.doi.org/10.1016/S1474-4422(10)70043-0] [PMID: 20189881]

[117]
Shi M, Chu F, Zhu F, Zhu J. Impact of anti-amyloid-β monoclonal antibodies on the pathology and clinical profile of Alzheimer’s disease: A focus on aducanumab and lecanemab. Front Aging Neurosci  2022; 14: 870517.
 [http://dx.doi.org/10.3389/fnagi.2022.870517] [PMID: 35493943]

[118]
Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol  2022; 79(1): 13-21.
 [http://dx.doi.org/10.1001/jamaneurol.2021.4161] [PMID: 34807243]

[119]
Beshir SA, Aadithsoorya A, Parveen A, Goh SSL, Hussain N, Menon VB. Aducanumab therapy to treat Alzheimer’s disease: A narrative review. Int J Alzheimers Dis  2022; 2022: 9343514.
 [http://dx.doi.org/10.1155/2022/9343514]

[120]
Herline K. Passive Immunization to Improve Cognition and Reduce Pathological Species in a Mouse Model of Alzheimer’s Disease. New York University 2018.

[121]
Novakovic D, Feligioni M, Scaccianoce S, et al. Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Des Devel Ther  2013; 7: 1359-64.
 [PMID: 24255592]

[122]
Klein G, Delmar P, Voyle N, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: A PET substudy interim analysis. Alzheimers Res Ther  2019; 11(1): 101.
 [http://dx.doi.org/10.1186/s13195-019-0559-z] [PMID: 31831056]

[123]
Tian Hui Kwan A, Arfaie S, Therriault J, Rosa-Neto P, Gauthier S. Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement Geriatr Cogn Disord  2020; 49(4): 334-48.
 [http://dx.doi.org/10.1159/000511506] [PMID: 33321511]

[124]
Mukherjee A, Biswas S, Roy I. Immunotherapy: An emerging treatment option for neurodegenerative diseases. Drug Discov Today  2024; 29(5): 103974.
 [http://dx.doi.org/10.1016/j.drudis.2024.103974] [PMID: 38555032]

[125]
Mably AJ, Liu W, Mc Donald JM, et al. Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice. Neurobiol Dis  2015; 82: 372-84.
 [http://dx.doi.org/10.1016/j.nbd.2015.07.008] [PMID: 26215784]

[126]
Morató X, Pytel V, Jofresa S, Ruiz A, Boada M. Symptomatic and disease-modifying therapy pipeline for Alzheimer’s disease: Towards a personalized polypharmacology patient-centered approach. Int J Mol Sci  2022; 23(16): 9305.
 [http://dx.doi.org/10.3390/ijms23169305] [PMID: 36012569]

[127]
Panza F, Solfrizzi V, Imbimbo BP, et al. Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease. Expert Rev Neurother  2014; 14(9): 973-86.
 [http://dx.doi.org/10.1586/14737175.2014.945522] [PMID: 25081412]

[128]
Landen JW, Zhao Q, Cohen S, et al. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to- moderate Alzheimer disease: A phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol  2013; 36(1): 14-23.
 [http://dx.doi.org/10.1097/WNF.0b013e31827db49b] [PMID: 23334070]

[129]
Sheytanova LM. Development of a human cell model of amyloid β seeding and aggregation to investigate Alzheimer’s disease pathology: UCL. University College London 2018.

[130]
van Oostveen WM, de Lange ECM. Imaging techniques in Alzheimer’s disease: A review of applications in early diagnosis and longitudinal monitoring. Int J Mol Sci  2021; 22(4): 2110.
 [http://dx.doi.org/10.3390/ijms22042110] [PMID: 33672696]

[131]
Mukhopadhyay S, Banerjee D. A primer on the evolution of aducanumab: the first antibody approved for treatment of Alzheimer’s disease. J Alzheimers Dis  2021; 83(4): 1537-52.
 [http://dx.doi.org/10.3233/JAD-215065] [PMID: 34366359]

[132]
Muñoz-Jiménez M, Zaarkti A, García-Arnés JA, García-Casares N. Antidiabetic drugs in Alzheimer’s disease and mild cognitive impairment: A systematic review. Dement Geriatr Cogn Disord  2020; 49(5): 423-34.
 [http://dx.doi.org/10.1159/000510677] [PMID: 33080602]

[133]
Domingues R, Pereira C, Cruz MT, Silva A. Therapies for Alzheimer’s disease: A metabolic perspective. Mol Genet Metab  2021; 132(3): 162-72.
 [http://dx.doi.org/10.1016/j.ymgme.2021.01.011] [PMID: 33549409]

[134]
Kabir MT, Uddin MS, Mamun AA, et al. Combination drug therapy for the management of Alzheimer’s disease. Int J Mol Sci  2020; 21(9): 3272.
 [http://dx.doi.org/10.3390/ijms21093272] [PMID: 32380758]

[135]
Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R. Metal toxicity links to Alzheimer’s disease and neuroinflammation. J Mol Biol  2019; 431(9): 1843-68.
 [http://dx.doi.org/10.1016/j.jmb.2019.01.018] [PMID: 30664867]

[136]
Faux NG, Ritchie CW, Gunn A, et al. PBT2 rapidly improves cognition in Alzheimer’s Disease: Additional phase II analyses. J Alzheimers Dis  2010; 20(2): 509-16.
 [http://dx.doi.org/10.3233/JAD-2010-1390] [PMID: 20164561]

[137]
Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB. Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment? Br J Clin Pharmacol  2011; 71(3): 365-76.
 [http://dx.doi.org/10.1111/j.1365-2125.2010.03830.x] [PMID: 21284695]

[138]
Zhong KL, Chen F, Hong H, et al. New views and possibilities of antidiabetic drugs in treating and/or preventing mild cognitive impairment and Alzheimer’s Disease. Metab Brain Dis  2018; 33(4): 1009-18.
 [http://dx.doi.org/10.1007/s11011-018-0227-1] [PMID: 29626315]

[139]
Plastino M, Fava A, Pirritano D, et al. Effects of insulinic therapy on cognitive impairment in patients with Alzheimer disease and Diabetes Mellitus type-2. J Neurol Sci  2010; 288(1-2): 112-6.
 [http://dx.doi.org/10.1016/j.jns.2009.09.022] [PMID: 19836029]

[140]
Hossain MS, Uddin MS, Kabir MT, Akhter S, Goswami S, Mamun AA. in vivo screening for analgesic and anti-inflammatory activities of Syngonium podophyllum L.: A remarkable herbal medicine. Ann Res Rev Biol  2017; 16(3): ARRB.35692.

[141]
Moore AH, Bigbee MJ, Boynton GE, et al. Non-steroidal anti-inflammatory drugs in Alzheimer’s disease and Parkinson’s disease: reconsidering the role of neuroinflammation. Pharmaceuticals  2010; 3(6): 1812-41.
 [http://dx.doi.org/10.3390/ph3061812] [PMID: 27713331]

[142]
Gannon M, Wang Q. Complex noradrenergic dysfunction in Alzheimer’s disease: Low norepinephrine input is not always to blame. Brain Res  2019; 1702: 12-6.
 [http://dx.doi.org/10.1016/j.brainres.2018.01.001] [PMID: 29307592]

[143]
Mohs RC, Shiovitz TM, Tariot PN, Porsteinsson AP, Baker KD, Feldman PD. Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study. Am J Geriatr Psychiatry  2009; 17(9): 752-9.
 [http://dx.doi.org/10.1097/JGP.0b013e3181aad585] [PMID: 19700948]

[144]
Álvarez A, Cacabelos R, Sanpedro C, García-Fantini M, Aleixandre M. Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging  2007; 28(4): 533-6.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2006.02.012] [PMID: 16569464]

[145]
Mufson E, Counts S, Fahnestock M, Ginsberg S. Cholinotrophic molecular substrates of mild cognitive impairment in the elderly. Curr Alzheimer Res  2007; 4(4): 340-50.
 [http://dx.doi.org/10.2174/156720507781788855] [PMID: 17908035]

[146]
Martel J-C, Assié M-B, Bardin L, Depoortère R, Cussac D, Newman-Tancredi A. 5-HT 1A receptors are involved in the effects of xaliproden on G-protein activation, neurotransmitter release and nociception. Br J Pharmacol  2009; 158(1): 232-42.
 [http://dx.doi.org/10.1111/j.1476-5381.2009.00249.x] [PMID: 19508400]

[147]
Elmawla A, Abd Elhameed D, Ibrahim SME, Radwan EHM, Elzehiri DA, El Fadawy HAM. Effect of cognitive stimulation therapy versus reminiscence therapy on cognitive and psychological outcomes in older adults with mild cognitive impairment: A quasi-experimental study. NILES j Geria Geront  2024; 7(2): 456-76.
 [http://dx.doi.org/10.21608/niles.2024.353919]

[148]
Scarmeas N, Anastasiou CA, Yannakoulia M. Nutrition and prevention of cognitive impairment. Lancet Neurol  2018; 17(11): 1006-15.
 [http://dx.doi.org/10.1016/S1474-4422(18)30338-7] [PMID: 30244829]

[149]
Swartz K, Collins LG. Caregiver Care. Am Fam Physician  2019; 99(11): 699-706.
 [PMID: 31150177]

[150]
Zhang Q, Liu C, Jing X, et al. Editorial: Neural mechanism and effect of acupuncture for central nervous system diseases. Front Neurosci  2024; 17: 1337612.
 [http://dx.doi.org/10.3389/fnins.2023.1337612] [PMID: 38260027]

[151]
Xu J, Gou S, Huang X, et al. Uncovering the impact of aggrephagy in the development of alzheimer’s disease: Insights into diagnostic and therapeutic approaches from machine learning analysis. Curr Alzheimer Res  2023; 20(9): 618-35.
 [http://dx.doi.org/10.2174/0115672050280894231214063023] [PMID: 38141185]

[152]
Zhao S, Ye B, Chi H, Cheng C, Liu J. Identification of peripheral blood immune infiltration signatures and construction of monocyte-associated signatures in ovarian cancer and Alzheimer’s disease using single-cell sequencing. Heliyon  2023; 9(7): e17454.
 [http://dx.doi.org/10.1016/j.heliyon.2023.e17454] [PMID: 37449151]

[153]
Satlin A, Fukushima T. Composition and method for treating alzheimer’s disease. 2019.

[154]
Roberts MI, Staddon JM, De Silva HAR, Spidel J, Aoyagi H, Akasofu S. Anti-tau antibodies and uses thereof. W.O.Patent 2021205359A1, 2020.

[155]
Yoshida N. High concentration anti-abeta protofibril antibody formulations and methods of use thereof. E.P. Patent 4252777A2, 2023.

[156]
Demattos RB, Lu J, Tang Y. Anti-N3pGlu amyloid beta peptide antibodies and uses thereof. W.O.Patent 2022192636A1, 2020. Available from: https://patents.google.com/patent/WO2022192636A1/en?oq=WO2022192636A1Anti-amyloid+beta+antibodies+and+uses+thereof

[157]
Biomarkers for alzheimer's disease treatment. W.O.Patent 2023283650A1, 2022. Available from: https://patents.google.com/patent/WO2023283650A1/en?oq=WO2023283650A1Biomarkers+for+Alzheimer%E2%80%99s+disease+treatment

[158]
Methods of treating neurological diseases. W.O.Patent 2023284710A1, 2022. Available from: https://patents.google.com/patent/WO2023284710A1/en?oq=WO2023284710A1Methods+of+treating+neurological+diseases

[159]
Anti-amyloid beta antibodies and uses thereof. W.O.Patent 2022192636A1, 2022. Available from: https://patents.google.com/patent/WO2022192636A1/en?oq=WO2022192636A1Anti-amyloid+beta+antibodies+and+uses+thereof
Cite As
Current Drug Targets

Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies

Abstract

Graphical Abstract
