Iranian Journal of Neurology 2017. 16(3):.

Taming Alzheimer’s disease: New perspectives, newer horizons
Debraj Sen, Anusree Majumder, Vijinder Arora, Neha Yadu, Ritwik Chakrabarti

Abstract


Alzheimer’s disease (AD) is the leading cause of dementia. However, current therapies do not prevent progression of the disease. New research into the pathogenesis of the disease has brought about a greater understanding of the “amyloid cascade” and associated receptor abnormalities, the role of genetic factors, and revealed that the disease process commences 10 to 20 years prior to the appearance of clinical signs. This greater understanding of the disease has prompted development of novel disease-modifying therapies (DMTs) which may prevent onset or delay progression of the disease. Using genetic biomarkers like apolipoprotein E (ApoE) ε4, biochemical biomarkers like cerebrospinal fluid (CSF) amyloid and tau proteins, and imaging biomarkers like magnetic resonance imaging (MRI) and positron emission tomography (PET), it is now possible to detect preclinical AD and also monitor its progression in asymptomatic people. These biomarkers can be used in the selection of high-risk populations for clinical trials and also to monitor the efficacy and side-effects of DMT. To validate and standardize these biomarkers and select the most reliable, repeatable, easily available, cost-effective and complementary options is the challenge ahead.


Keywords


Alzheimer Disease; Amyloid; Biomarkers; Cerebrospinal Fluid; Magnetic Resonance Imaging; Positron Emission Tomography

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References

Abbott A. Dementia: a problem of our age. Nature 2011; 475: S2-4.

DJ Selkoe. Preventing Alzheimer’s disease. Science 2012; 337:1488-92.

Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003; 60:1119-22.

Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 2011; 10: 698-712.

Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 1994; 13: 45-53.

Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS et al.Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416: 535-9.

Chen Y, Neve RN, Zheng H, Griffin WTS, Barger SW and Mrak RE. Cycle on Wheels: Is APP Key to the AppBp1 Pathway? Austin Alzheimers J Parkinsons Dis 2014; 1: 7.

Holtzman DM, Morris JC, Goate AM. Alzheimer's disease: the challenge of the second century. Sci Transl Med 2011; 3: 77sr71.

Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer's disease: dual pathway hypothesis. Neuron 2008; 60: 534-42.

Hyman BT. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol 2011; 68: 799-801.

Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem 2008; 104: 1433-9.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921-23.

Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997; 278: 1349-56.

Price DL, Sisodia SS. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci 1998; 21:479-505.

Tanzi RE, Kovacs DM, Kim TW, Moir RD, Guenette SY, Wasco W. The gene defects responsible for familial Alzheimer's disease. Neurobiol Dis 1996; 159-68.

Griffin WS, Sheng JG, McKenzie JE, Royston MC, Gentleman SM, Brumback RA et al. Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis. Neurobiol Aging 1998; 19:401-5.

Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH et al.Candidate gene for the chromosome1 familial Alzheimer's disease locus, Science 1995; 269: 973-7.

Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995; 375: 754-60.

Braskie MN, Jahanshad N, Barysheva M, McMahon KL, de Zubicaray GI, Martin NGet al. Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults. J Neurosci 2011; 31: 6764-70.

Guerreiro R, Wojtas A, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C et al. TREM2 variants in Alzheimer's disease. NEnglJMed 2013; 386: 117-27.

Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010; 330: 1774.

Ittner LM, Gotz J. Amyloid-beta and tau–a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 2011; 12:65-72.

Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010; 142:387-97.

Marquer C, Laine J, Dauphinot L, Hanbouch L, Lemercier-Neuillet C, Pierrot N et al. Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes. Molecular Neurodegeneration 2014; 9: 60.

Casoli T, DiStefano G, Spazzafumo L, Balietti M, Giorgetti B, Giuli C et al. Contribution of non-reference alleles in mtDNA of Alzheimer’s disease patients. Ann Clin Transl Neurol 2014; 1:284-9.

Beck TN, Nicolas E, Kopp MC, Golemis EA. Adaptors for disorders of the brain ? The cancer signalling proteins NEDD9, CASS4, and PTK2B in Alzheimer’s disease. Oncoscience 2014; 1: 486-503.

Jahangir Z, Ahmad W, Shabbiri K. Alternate phosphorylation/O-GlcNAc modification on human insulin IRSs: a road towards impaired insulin signaling in Alzheimer and Diabetes. Adv Bioinformatics 2014; 2014: 324753.

Faldu KG, Shah JS, Patel SS. Anti-viral agents in neurodegenerative disorders: new paradigm for targeting Alzheimer's Disease. Recent Pat Aniinfect Drug Discov 2015; Epub ahead of print.

Mohajeri MH, Troesch B, Weber P. Inadequate supply of vitamins and DHA in the elderly: implications for brain aging and Alzheimer-type dementia. Nutrition 2015; 31; 261-75.

Roe CM, Mintun MA, D'Angelo G, Xiong C, Grant EA, Morris JC. Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake. Arch Neurol 2008; 65: 1467-71.

Fotenos AF, Mintun MA, Snyder AZ, Morris JC, Buckner RL. Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol 2008; 65: 113-120.

Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, Head D. Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Ann Neurol 2010; 68: 311-8.

J Kang, Ryoo N, Shin DW, Trojanowski JQ, Shaw LM. Role of cerebrospinal fluid biomarkers in clinical trials for Alzheimer’s disease modifying therapies. Korean J Physiol Pharmacol 2014; 18: 447-56.

Kizuka Y, Kitazume S, Fujinawa R, Saito T, Iwata N, Saido TC et al. An aberrant sugar modification of BACE-1 blocks its lysosomal targeting in Alzheimer’s disease. EMBO Mol Med 2015; 7:175-89.

Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R et al. Multicenter, randomized, double blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamics markers. Clin

Ther 2012; 34:654-67.

Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res 2011; 8:592-606.

Geldmacher DS, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 2011; 68:45-50.

Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN et al.A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011; 77:1253-62.

Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B et al. Clearance of Alzheimer's amyloid-ss (1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106:1489-99.

Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003; 9:907-13.

Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C et al. Alzheimer's Disease Cooperative Study. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology 2014; 82:1536-42.

Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012; 11:597-604.

Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014; 370:322-33.

Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ,Porsteinsson APet al. Safety and biomarker effects of solanezumab in patients withAlzheimer's disease. Alzheimers Dement 2012; 8:261-71.

Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S et al. Intravenous immunoglobulin for treatment of mild-to moderate Alzheimer's disease: a phase 2, randomised, double blind, placebo-controlled, dose-finding trial. Lancet Neurol2013; 12:233-43.

Knight EM, Gandy S. Immunomodulation and AD-down but not out. J Clin Immunol 2014; 34: S70-3.

Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I et al. A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis 2009; 35:359-67.

Wischik CM, Bentham P, Wischik DJ, Seng KM. Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer’s disease over 50 weeks. Alzheimers Dement 2008; 4:T167.

Huang C, Chu H, Muheremu A, Zuo H. Neurorestorative strategies for Alzheimer’s disease. Neurol India 2015; 63: 583-8.

Nishteswar K, Joshi H, Karra RD. Role of indigenous herbs in the management of Alzheimer's disease. Anc Sci Life 2014; 34: 3-7.

Subedee L, Suresh RN, MK J, Hl K, Am S, VH P. Preventive role of Indian black pepper in animal models of Alzheimer's disease. J Clin Diagn Res 2015; 9: FF01-4.

Kumar A, Sharma V, Singh VP, Kaundal M, Gupta MK, Bariwal J et al. Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer's disease. Mech Ageing Dev 2015; 149; 75-87.

Huded CB, Bharath S, Chandra SR, Sivakumar PT, Varghese M, Subramanian S.Supportive CSF biomarker evidence to enhance the National Institute on Aging-Alzheimer's Association criteria for diagnosis of Alzheimer's type dementia-a study from Southern India. Asian J Psychiatr 2015; 13: 44-7.

Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 2004; 61: 95-102.

Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K et al. Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch Neurol 2002; 59: 1267-72.

Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A et al. Oxinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014; 71: 1498-505.

Pich EM, Jeromin A, Frisoni GB, Hill D, Lockhart A, Schmidt MEet al. Imaging as a biomarker in drug discovery for Alzheimer’s disease: is MRI a suitable technology? Alzheimer’s Res Ther 2014; 6:51.

Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C. 2009. Age, neuropathology, and dementia. New Engl J Med 360: 2302-9.

Frisoni GB, Fox NC, Jack CR Jr, Scheltens P, Thompson PM: The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol 2010, 6:67-77.

Haris M, Yadav SK, Rizwan A, Singh A, Cai A, Kaura D et al. T1rho MRI and CSF biomarkers in diagnosis of Alzheimer’s disease. Neuroimage Clin 2015; 7:598-604.

Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012; 11:241-9.

Sperling RA, Bates JF, Chua EF, Cocchiarella AJ, Rentz DM, Rosen BR et al. fMRI studies of associative encoding in young and elderly controls and mild Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74:44-50.

Solé-Padullés C, Bartrés-Faz D, Junqué C, Vendrell P, Rami L, Clemente IC et al. Brain structure and function related to cognitive reserve variables in normal aging, mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 2009; 30:1114-24.

Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL et al. Activation of brain regions vulnerable to Alzheimer’s disease: the effect of mild cognitive impairment. Neurobiol Aging 2006; 27:1604-12.

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL: A default mode of brain function. Proc Natl Acad Sci USA 2001, 98:676-82.

Daselaar SM, Prince SE, Cabeza R. When less means more: Deactivations during encoding that predict subsequent memory. Neuroimage 2004; 23: 921-7.

Miller SL, Celone K, DePeau K, Diamond E, Dickerson BC et al. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci 2008; 105: 2181-6.

Fleisher AS, Sherzai A, Taylor C, Langbaum JB, Chen K, Buxton RB. Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups. Neuroimage 2009; 47: 1678-90.

Sperling RA, Dickerson BC, Pihlajamaki M, Vannini P, LaViolette PS, Vitolo OV et al. Functional alterations in memory networks in early Alzheimer’s disease. Neuromolecular Med 2010; 12: 27-43.

Fleisher AS, Sherzai A, Taylor C, Langbaum JB, Chen K, Buxton RB. Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups. Neuroimage 2009; 47:1678-90.

Binnewijzend MA, Kuijer JP, Benedictus MR, van der Flier WM, Wink AM, Wattjes MP et al. Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: a marker for disease severity. Radiology 2013; 267:221-30.

Wolk DA, Detre JA: Arterial spin labeling MRI: an emerging biomarker for Alzheimer’s disease and other neurodegenerative conditions. Curr Opin Neurol 2012; 25:421-8.

Johnson KA, Fox NC, Sperling RA, Klunk WE. Brain imaging in Alzheimer’s disease. Cold Spring Harb Perspect Med 2012; 2:a006213.

Reiman EM, Alzheimer’s Disease Biomarkers Working Group for the Alliance for Aging R: Fluorodeoxyglucose positron emission tomography: emerging roles in the evaluation of putative Alzheimer’s disease-modifying treatments. Neurobiol Aging 2011; 32:S44–S47.

Dukart J, Kherif F, Mueller K, Adaszewski S, Schroeter ML, Frackowiak RS et al. Alzheimer’s Disease Neuroimaging I: Generative FDG-PET and MRI model of aging and disease progression in Alzheimer’s disease. PLoS Comput Biol 2013; 9:e1002987.

Vlassenko AG, Benzinger TLS, Morris JC.PET amyloid-beta imaging in preclinical Alzheimer's disease. Biochim Biophys Acta 2012; 1822: 370-9.

Vlassenko AG, Vaishnavi SN, Couture L, Sacco D, Shannon BJ, Mach RH et al. Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta) deposition. Proc Natl Acad Sci USA 2010; 107:17763-7.

Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME. Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci USA 2010; 107: 17757-62.

Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69:198-207.

Wood H. Alzheimer disease: [C]PBB3 - a new PET ligand that identifies tau pathology in the brains of patients with AD. Nat Rev Neurol 2013; 9:599.

Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis 2013; 34:457-68.

Hye A, Riddoch-Contreras J, Baird AL, Ashton NJ, Bazenet C, Leung R et al. Plasma proteins predict conversion to dementia from prodromal disease. Alzheimers Dement2014; 10; 799-807.e2


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