The pathogenesis of Alzheimer’s disease (AD) is complex. Still it remains unclear, which resulted in all efforts for AD treatments with targeting the pathogenic factors unsuccessful over past decades. It has been evidenced that the innate immune is strongly implicated in the pathogenesis of AD. However, the role of adaptive immune in AD remains mostly unknown and the results obtained were controversial. In the review, we summarized recent studies and showed that the molecular and cellular alterations in AD patients and its animal models involving T cells and B cells as well as immune mediators of adaptive immune occur not only in the peripheral blood but also in the brain and the cerebrospinal fluid. The risk factors that cause AD contribute to AD progress by affecting the adaptive immune, indicating that adaptive immunity proposes a pivotal role in this disease. It may provide a possible basis for applying immunotherapy in AD and further investigates whether the immunotherapies are effective or off-target?
AharoniRArnonREilamR.2005. Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neurosci25(36):8217–28.
2.
AlexiouAChatzichronisSAshrafGM. 2020. Chapter 23: Prediction of Alzheimer’s disease. In: MartinCRPreedyVR, editors. Diagnosis and Management in Dementia. Academic Press. p. 365–78.
3.
AlexiouAMantzavinosVDGreigNHKamalMA. 2017. A bayesian model for the prediction and early diagnosis of Alzheimer’s disease. Front Aging Neurosci9:77.
4.
AlexiouASoursouGChatzichronisSGasparatosEKamalMAYarlaNS, and others. 2019. Role of GTPases in the regulation of mitochondrial dynamics in Alzheimer’s disease and CNS-related disorders. Mol Neurobiol56(6):4530–8.
5.
AliKMiddletonMPuréERaderDJ. 2005. Apolipoprotein E suppresses the type I inflammatory response in vivo. Circ Res97(9):922–7.
6.
AngelucciFCechovaKAmlerovaJHortJ.2019. Antibiotics, gut microbiota, and Alzheimer’s disease. J Neuroinflammation16(1):108.
7.
AshrafGMAzharAZiaQAliARehanMOwaisM, and others. 2018. Relationship between CNS and immunology: correlation with psychology. Curr Drug Metab19(10):847–55.
8.
BaruchKRosenzweigNKertserADeczkowskaASharifAMSpinradA, and others. 2015. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat Commun6:7967.
9.
BayerAJBullockRJonesRWWilkinsonDPatersonKRJenkinsL, and others. 2005. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology64(1):94.
10.
BektasASchurmanSHSenRFerrucciL.2017. Human T cell immunosenescence and inflammation in aging. J Leuk Biol102(4):977–88.
11.
BritschgiMOlinCEJohnsHTTakeda-UchimuraYLeMieuxMCRufibachK, and others. 2009. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer’s disease. Proc Natl Acad Sci U S A106(29):12145–50.
BrowneTCMcQuillanKMcManusRMO’ReillyJAMillsKHLynchMA. 2013. IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol190(5):2241–51.
14.
BrunoVBlackRLeonTNickFDanielsMMcLennanG, and others. 2009. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res6(2):144–51.
15.
BrysonKJLynchMA. 2015. Linking T cells to Alzheimer’s disease: from neurodegeneration to neurorepair. Curr Opin Pharmacol26:67–73.
16.
BuffaSBulatiMPellicanòMDunn-WaltersDKWuYCCandoreG, and others. 2011. B cell immunosenescence: different features of naive and memory B cells in elderly. Biogerontology12(5):473–83.
17.
ButovskyOJedrychowskiMPCialicRKrasemannSMurugaiyanGFanekZ, and others. 2015. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol77(1):75–99.
18.
Calderón-GarcidueñasLde la MonteSM. 2017. Apolipoprotein E4, gender, body mass index, inflammation, insulin resistance, and air pollution interactions: recipe for Alzheimer’s disease development in Mexico City young females. J Alzheimers Dis58(3):613–30.
19.
CaoCArendashGWDicksonAMamcarzMBLinXEthellDW. 2009. Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer’s mice without infiltrating the CNS. Neurobiol Dis34(1):63–70.
20.
CaoWZhengH.2018. Peripheral immune system in aging and Alzheimer’s disease. Mol Neurodegener13(1):51.
21.
CiccocioppoFBolognaGErcolinoEPierdomenicoLSimeonePLanutiP, and others. 2020. Neurodegenerative diseases as proteinopathies-driven immune disorders. Neural Regen Res15(5):850–6.
22.
CiccocioppoFLanutiPPierdomenicoLSimeonePBolognaGErcolinoE, and others. 2019. The characterization of regulatory T-cell profiles in Alzheimer’s disease and multiple sclerosis. Sci Rep9(1):8788.
23.
Cicin-SainLBrienJDUhrlaubJLDrabigAMaranduTFNikolich-ZugichJ.2012. Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog8(8):e1002849.
24.
CoderBWangWWangLWuZZhugeQSuDM. 2017. Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging. Oncotarget8(4):7116–37.
25.
CoderBDWangHRuanLSuDM. 2015. Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation. J Immunol (1950)194(12):5825–37.
26.
CrespoJSunHWellingTHTianZZouW.2013. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol25(2):214–21.
27.
CrookeSNOvsyannikovaIGPolandGAKennedyRB. 2019. Immunosenescence and human vaccine immune responses. Immunity Ageing16(1):25.
28.
DansokhoCAit AhmedDAidSToly-NdourCChaigneauTCalleV, and others. 2016. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain139(Pt 4):1237–51.
29.
De MartinisMSirufoMM. 2019. Food allergies and ageing. Int J Mol Sci20(22):5580.
30.
DeleidiMJäggleMRubinoG.2015. Immune aging, dysmetabolism, and inflammation in neurological diseases. Front Neurosci9:172.
31.
DerhovanessianETheetenHHähnelKVan DammePCoolsNPawelecG.2012. Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Vaccine31(4):685–90.
32.
Di BenedettoSMüllerLWengerEDüzelSPawelecG. 2017. Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehav Rev75:114–28.
33.
DorothéeGSarazinMAucouturierP.2013. Disease-specific adaptive immune biomarkers in Alzheimer’s disease and related pathologies. Rev Neurol (Paris)169(10):715–8.
34.
DrabkinMJMeyerJIKanthNLobelSFogelJGrossmanJ, and others. 2018. Age-stratified patterns of thymic involution on multidetector CT. J Thorac Imaging33(6):409–16.
35.
DuganHLHenryCWilsonPC. 2020. Aging and influenza vaccine-induced immunity. Cell Immunol348:103998.
36.
EduardoFManuelFMarceloAIvánP.2017. Immune system dysfunction in the elderly. An Acad Bras Ciênc89(1):285–99.
37.
EganMFKostJTariotPNAisenPSCummingsJLVellasB, and others. 2018. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med378(18):1691–703.
38.
EganMFMukaiYVossTKostJStoneJFurtekC, and others. 2019. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther11(1):68–12.
39.
EthellDWShippyDCaoCCracchioloJRRunfeldtMBlakeB, and others. 2006. Abeta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer’s mice. Neurobiol Dis23(2):351–61.
40.
FarlowMArnoldSEvan DyckCHAisenPSSniderBJPorsteinssonAP, and others. 2012. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement8(4):261–71.
41.
FerrettiMTMerliniMSpäniCGerickeCSchweizerNEnzmannG, and others. 2016. T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer’s disease-like cerebral amyloidosis. Brain Behav Immun54:211–25.
42.
FisherYNemirovskyABaronRMonsonegoA.2010. T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer’s disease. PLoS One5(5):e10830.
43.
FisherYStromingerIBitonSNemirovskyABaronRMonsonegoA.2014. Th1 polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance. J Immunol192(1):92–102.
44.
FitznerDSchnaarsMvan RossumDKrishnamoorthyGDibajPBakhtiM, and others. 2011. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci124(Pt 3):447–58.
45.
FülöpTDupuisGWitkowskiJMLarbiA.2016. The role of immunosenescence in the development of age-related diseases. Rev Invest Clin68(2):84–91.
46.
FulopTWitkowskiJMOlivieriFLarbiA.2018. The integration of inflammaging in age-related diseases. Semin Immunol40:17–35.
47.
GamesDBardFGrajedaHGuidoTKhanKSorianoF, and others. 2000. Prevention and reduction of AD-type pathology in PDAPP mice immunized with Aβ1-42. Ann N Y Acad Sci920(1):274–84.
48.
GateDSaligramaNLeventhalOYangACUngerMSMiddeldorpJ, and others. 2020. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature577(7790):399–404.
49.
GhochikyanAMkrtichyanMPetrushinaIMovsesyanNKarapetyanACribbsDH, and others. 2006. Prototype Alzheimer’s disease epitope vaccine induced strong Th2-type anti-Abeta antibody response with Alum to Quil A adjuvant switch. Vaccine24(13):2275–82.
50.
GiubileiFAntoniniGMontesperelliCSepe-MontiMCannoniSPichiA, and others. 2003. T cell response to amyloid-beta and to mitochondrial antigens in Alzheimer’s disease. Dement Geriatr Cogn Disord16(1):35–8.
51.
GoetzlEJSchwartzJBAbnerELJichaGAKapogiannisD.2018. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol83(3):544–52.
52.
GoodwinKViboudCSimonsenL.2006. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine24(8):1159–69.
53.
GrantJLGhosnEEAxtellRCHergesKKuipersHFWoodlingNS, and others. 2012. Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med4(145):145ra105.
54.
GuerreiroRWojtasABrasJCarrasquilloMRogaevaEMajounieE, and others. 2013. TREM2 variants in Alzheimer’s disease. N Engl J Med368(2):117–27.
55.
Guillot-SestierMVTownT.2013. Innate immunity in Alzheimer’s disease: a complex affair. CNS Neurol Disord Drug Targets12(5):593–607.
56.
HedlundGLinkHZhuJXiaoBG. 2001. Effects of Linomide on immune cells and cytokines inhibit autoimmune pathologies of the central and peripheral nervous system. Int Immunopharmacol1(6):1123–30.
57.
HerlineKPrelliFMehtaPMacMurrayCGoñiFWisniewskiT.2018. Immunotherapy to improve cognition and reduce pathological species in an Alzheimer’s disease mouse model. Alzheimers Res Ther10(1):54.
58.
HickeyWF. 2001. Basic principles of immunological surveillance of the normal central nervous system. Glia36(2):118–24.
59.
HolmesCBocheDWilkinsonDYadegarfarGHopkinsVBayerA, and others. 2008. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet372(9634):216–23.
60.
HonigLSVellasBWoodwardMBoadaMBullockRBorrieM, and others. 2018. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med378(4):321–30.
61.
HoskinJLSabbaghMNAl-HasanYDecourtB. 2019. Tau immunotherapies for Alzheimer’s disease. Expert Opin Investig Drugs28(6):545–54.
62.
KellnerAMatschkeJBernreutherCMochHFerrerIGlatzelM.2009. Autoantibodies against beta-amyloid are common in Alzheimer’s disease and help control plaque burden. Ann Neurol65(1):24–31.
63.
KimJEltoraiAEJiangHLiaoFVerghesePBKimJ, and others. 2012. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J Exp Med209(12):2149–56.
64.
KimJKimARShinEC. 2015. Cytomegalovirus infection and memory T cell inflation. Immune Netw15(4):186–90.
65.
KipnisJCohenHCardonMZivYSchwartzM.2004. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A101(21):8180–5.
66.
KonttinenHCabral-da-SilvaMECOhtonenSWojciechowskiSShakirzyanovaACaligolaS, and others. 2019. PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia. Stem Cell Rep13(4):669–83.
67.
KrasemannSMadoreCCialicRBaufeldCCalcagnoNEl FatimyR, and others. 2017. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity47(3):566–581.e9.
68.
LambertJCGrenier-BoleyBChourakiVHeathSZelenikaDFievetN, and others. 2010. Implication of the immune system in Alzheimer’s disease: evidence from genome-wide pathway analysis. J Alzheimers Dis20(4):1107–18.
69.
LambertJCIbrahim-VerbaasCAHaroldDNajACSimsRBellenguezC, and others. 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet45(12):1452–8.
70.
LarbiAPawelecGWitkowskiJMSchipperHMDerhovanessianEGoldeckD, and others. 2009. Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer’s disease. J Alzheimers Dis17(1):91–103.
71.
LauratEPoirierBTupinECaligiuriGHanssonGKBariétyJ, and others. 2001. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation104(2):197–202.
72.
LaurentCDorothéeGHunotSMartinEMonnetYDuchampM, and others. 2017. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain140(1):184–200.
73.
LevyMKolodziejczykAAThaissCAElinavE.2017. Dysbiosis and the immune system. Nat Rev Immunol17(4):219–32.
74.
LiuYJGuoDWTianLShangDSZhaoWDLiB, and others. 2010. Peripheral T cells derived from Alzheimer’s disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-α-dependent. Neurobiol Aging31(2):175–88.
75.
LuegGGrossCCLohmannHJohnenAKemmlingADeppeM, and others. 2015. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer’s disease. Neurobiol Aging36(1):81–9.
76.
MaezawaINivisonMMontineKSMaedaNMontineTJ. 2006. Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J20(6):797–9.
77.
MafteiMThurmFSchnackCTumaniHOttoMElbertT, and others. 2013. Increased levels of antigen-bound β-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer’s disease patients. PLoS One8(7):e68996.
78.
MagroneTMagroneMRussoMAJirilloE.2020. Peripheral immunosenescence and central neuroinflammation: a dangerous liaison. A dietary approach. Endocr Metab Immune Disord Drug Targets20(90):1391–411.
79.
MalamonJSKrieteA.2020. Erosion of gene co-expression networks reveal deregulation of immune system processes in late-onset alzheimer’s disease. Front Neurosci14:228.
80.
ManSMMaYRShangDSZhaoWDLiBGuoDW, and others. 2007. Peripheral T cells overexpress MIP-1α to enhance its transendothelial migration in Alzheimer’s disease. Neurobiol Aging28(4):485–96.
81.
MantzavinosVAlexiouA.2017. Biomarkers for Alzheimer’s disease diagnosis. Curr Alzheimer Res14(11):1149–54.
82.
MarshSEAbudEMLakatosAKarimzadehAYeungSTDavtyanH, and others. 2016. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A113(9):E1316–25.
83.
MauchDHNäglerKSchumacherSGöritzCMüllerECOttoA, and others. 2001. CNS synaptogenesis promoted by glia-derived cholesterol. Science294(5545):1354–7.
84.
McElhaneyJEEffrosRB. 2009. Immunosenescence: what does it mean to health outcomes in older adults?Curr Opin Immunol21(4):418–24.
85.
McManusRMHigginsSCMillsKHLynchMA. 2014. Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice. Neurobiol Aging35(1):109–21.
86.
Mietelska-PorowskaAWojdaU.2017. T lymphocytes and inflammatory mediators in the interplay between brain and blood in Alzheimer’s disease: potential pools of new biomarkers. J Immunol Res2017:4626540.
87.
MinogueAMJonesRSKellyRJMcDonaldCLConnorTJLynchMA. 2014. Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice. Neurobiol Aging35(6):1442–52.
88.
MoirRDTseitlinKASosciaSHymanBTIrizarryMCTanziRE. 2005. Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer’s disease patients. J Biol Chem280(17):17458–63.
89.
MonsonegoAImitolaJPetrovicSZotaVNemirovskyABaronR, and others. 2006. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A103(13):5048–53.
90.
MonsonegoAMaronRZotaVSelkoeDJWeinerHL. 2001. Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer’s disease. Proc Natl Acad Sci U S A98(18):10273–8.
91.
MonsonegoANemirovskyAHarpazI.2013. CD4 T cells in immunity and immunotherapy of Alzheimer’s disease. Immunology139(4):438–46.
92.
MonsonegoAZotaVKarniAKriegerJIBar-OrABitanG, and others. 2003. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest112(3):415–22.
93.
NemirovskyAShapiroJBaronRKompanietsAMonsonegoA.2012. Active Aβ vaccination fails to enhance amyloid clearance in a mouse model of Alzheimer’s disease with Aβ42-driven pathology. J Neuroimmunol247(1–2):95–9.
94.
NicollJARBucklandGRHarrisonCHPageAHarrisSLoveS, and others. 2019. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease. Brain142(7):2113–26.
95.
Nikolich-ŽugichJ. 2017. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol19(1):10–19.
96.
ObersteinTJTahaLSpitzerPHellsternJHerrmannMKornhuberJ, and others. 2018. Imbalance of circulating Th17 and regulatory T cells in Alzheimer’s disease: a case control study. Front Immunol9:1213.
97.
OhSJLeeJKShinOS. 2019. Aging and the immune system: the impact of immunosenescence on viral infection, immunity and vaccine immunogenicity. Immune Netw19(6):1–18.
98.
OrgogozoJMGilmanSDartiguesJFLaurentBPuelMKirbyLC, and others. 2003. Subacute meningoencephalitis in a subset of patients with AD after A 42 immunization. Neurology61(1):46–54.
99.
PalmerDB. 2013. The effect of age on thymic function. Front Immunol4:316.
100.
PalmerSAlberganteLBlackburnCCNewmanTJ. 2018. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A115(8):1883–8.
101.
PanzaFFrisardiVSolfrizziVImbimboBPLogroscinoGSantamatoA, and others. 2012. Immunotherapy for Alzheimer’s disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy4(2):213–38.
102.
ParkSNahmMH. 2011. Older adults have a low capacity to opsonize pneumococci due to low IgM antibody response to pneumococcal vaccinations. Infect Immun79(1):314–20.
103.
PawelecG. 2018. Age and immunity: what is “immunosenescence”?Exp Gerontol105:4–9.
104.
PawelecGDerhovanessianELarbiA.2010. Immunosenescence and cancer. Crit Rev Oncol Hematol75(2):165–72.
105.
PedersenJTSigurdssonEM. 2015. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med21(6):394–402.
106.
PonnappanSPonnappanU.2011. Aging and immune function: molecular mechanisms to interventions. Antioxid Redox Signal14(8):1551–85.
107.
PooleSSinghraoSKChukkapalliSRiveraMVelskoIKesavaluL, and others. 2015. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers Dis43(1):67–80.
108.
PovovaJAmbrozPBarMPavukovaVSeryOTomaskovaH, and others. 2012. Epidemiological of and risk factors for Alzheimer’s disease: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub156(2):108–14.
109.
PrataLGPLOvsyannikovaIGTchkoniaTKirklandJL. 2018. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin Immunol40:101275.
110.
QuBXGongYMooreCFuMGermanDCChangLY, and others. 2014. Beta-amyloid auto-antibodies are reduced in Alzheimer’s disease. J Neuroimmunol274(1–2):168–73.
111.
RealeMIarloriCFelicianiCGambiD.2008. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease. J Alzheimers Dis14(2):147–59.
112.
RezzaniRNardoLFaveroGPeroniMRodellaLF. 2013. Thymus and aging: morphological, radiological, and functional overview. Age (Dordrecht, Netherlands)36(1):313–51.
113.
RichartzEStranskyEBatraASimonPLewczukPBuchkremerG, and others. 2005. Decline of immune responsiveness: a pathogenetic factor in Alzheimer’s disease?J Psychiatr Res39(5):535–43.
114.
RichartzsalzburgerEBatraAStranskyELaskeCKohlerNBartelsM, and others. 2007. Altered lymphocyte distribution in Alzheimer’s disease. J Psychiatr Res41(1):174–8.
115.
RileyRLKhomtchoukKBlombergBB. 2017. Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age. Cell Immunol321:61–7.
116.
RogersJLuber-NarodJStyrenSDCivinWH. 1988. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging9(4):339–49.
117.
RosenkranzDWeyerSTolosaEGaenslenABergDLeyheT, and others. 2007. Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol188(1–2):117–27.
118.
Sadighi AkhaAA. 2018. Aging and the immune system: an overview. J Immunol Methods463:21–6.
119.
SardiFFassinaLVenturiniLInguscioMGuerrieroFRolfoE, and others. 2011. Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev11(2):149–53.
120.
SaresellaMCalabreseEMarventanoIPianconeFGattiAAlberoniM, and others. 2011. Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer’s disease. Brain Behav Immun25(3):539–47.
121.
SaresellaMCalabreseEMarventanoIPianconeFGattiACalvoMG, and others. 2010. PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis21(3):927–38.
122.
SchenkDBarbourRDunnWGordonGGrajedaHGuidoT, and others. 1999. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature (London)400(6740):173–7.
123.
SchmittTLSteinerEKlingerPSztankayAGrubeck-LoebensteinB.1996. The production of an amyloidogenic metabolite of the Alzheimer amyloid beta precursor protein (APP) in thyroid cells is stimulated by interleukin 1 beta, but inhibited by interferon gamma. J Clin Endocrinol Metab81(4):1666–9.
124.
SchwabADThurstonMJMachhiJOlsonKENammingaKLGendelmanHE, and others. 2020. Immunotherapy for Parkinson’s disease. Neurobiol Dis137:104760.
125.
SchwartzMDeczkowskaA.2016. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol37(10):668–79.
126.
SeledtsovVIvon DelwigAA. 2020. Immune memory limits human longevity: the role of memory СD4+ T cells in age-related immune abnormalities. Expert Rev Vaccines19(3):209–15.
127.
SevignyJChiaoPBussièreTWeinrebPHWilliamsLMaierM, and others. 2016. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature537(7618):50–6.
128.
SöllvanderSEkholm-PetterssonFBrundinRMWestmanGKilanderLPaulieS, and others. 2015. Increased number of plasma B cells producing autoantibodies against Aβ42 protofibrils in Alzheimer’s disease. J Alzheimers Dis48(1):63–72.
129.
SpäniCSuterTDerungsRFerrettiMTWeltTWirthF, and others. 2015. Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer’s disease lacking functional B and T cells. Acta Neuropathol Commun3:71.
130.
SpecialeLCalabreseESaresellaMTinelliCMarianiCSanvitoL, and others. 2006. Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging28(8):1163–9.
131.
TanJTownTAbdullahLWuYPlaczekASmallB, and others. 2002. CD45 isoform alteration in CD4+ T cells as a potential diagnostic marker of Alzheimer’s disease. J Neuroimmunol132(1–2):164–72.
132.
ThomasRWangWSuDM. 2020. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing17(1):1–17.
133.
TogoTAkiyamaHIsekiEKondoHIkedaKKatoM, and others. 2002. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol124(1–2):83–92.
134.
TolarMAbushakraSSabbaghM.2020. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement16:1553–60.
135.
TopalianSLHodiFSBrahmerJRGettingerSNSmithDCMcDermottDF, and others. 2012. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med366(26):2443–54.
136.
UddinMSAl MamunARahmanMABehlTPerveenAHafeezA, and others. 2020a. Emerging proof of protein misfolding and interactions in multifactorial Alzheimer’s disease. Curr Top Med Chem20(26):2380–90.
137.
UddinMSHasanaSAhmadJHossainMFRahmanMMBehlT, and others. 2020b. Anti-neuroinflammatory potential of polyphenols by inhibiting NF-κB to halt Alzheimer’s disease. Curr Pharm Des. doi:10.2174/1381612826666201118092422. Epub Nov 17.
138.
UlrichJDUllandTK. 2018. ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med215(4):1047–58.
139.
VallejoAN. 2005. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev205(1):158–69.
140.
VandenbergheRRinneJOBoadaMKatayamaSScheltensPVellasB, and others. 2016. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther8(1):18.
141.
WalkerEMSlisarenkoNGerretsGLKissingerPJDidierES. 2019. Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells. Geroscience41(6):739–57.
142.
WangSWLiuDQZhangLXJiMZhangYXDongQX, and others. 2017. A vaccine with Aβ oligomer-specific mimotope attenuates cognitive deficits and brain pathologies in transgenic mice with Alzheimer’s disease. Alzheimers Res Ther9(1):41.
143.
WangXSunGFengTZhangJHuangXWangT, and others. 2019. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res29(10):787–803.
144.
WatadABragazziNLAdawiMAmitalHToubiEPoratBS, and others. 2017. Autoimmunity in the elderly: insights from basic science and clinics—a mini-review. Gerontology (Basel)63(6):515–23.
145.
WebersAHenekaMTGleesonPA. 2020. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer’s disease. Immunol Cell Biol98(1):28–41.
146.
WengNP. 2006. Aging of the immune system: how much can the adaptive immune system adapt?Immunity24(5):495–9.
147.
WestfallSIqbalUSebastianMPasinettiGM. 2019. Gut microbiota mediated allostasis prevents stress-induced neuroinflammatory risk factors of Alzheimer’s disease. Prog Mol Biol Transl Sci168:147–81.
148.
WojsiatJPrandelliCLaskowska-KaszubKMartín-RequeroAWojdaU.2015. Oxidative stress and aberrant cell cycle in Alzheimer’s disease lymphocytes: diagnostic prospects. J Alzheimers Dis46(2):329–50.
149.
WongMYLewisMDohertyJJShiYCashikarAGAmelianchikA, and others. 2020. 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner. J Neuroinflammation17(1):192.
150.
YangHYangHXieZWeiLBiJ.2013. Systemic transplantation of human umbilical cord derived mesenchymal stem cells-educated T regulatory cells improved the impaired cognition in AβPPswe/PS1dE9 transgenic mice. PLoS One8(7):e69129.
151.
YangPGuoYSunYYuBZhangHWuJ others. 2019. Active immunization with norovirus P particle-based amyloid-β chimeric protein vaccine induces high titers of anti-Aβ antibodies in mice. BMC Immunol20(1):9.
152.
YokoyamaJSWangYSchorkAJThompsonWKKarchCMCruchagaC, and others. 2016. Association between genetic traits for immune-mediated diseases and Alzheimer disease. JAMA Neurol73(6):691–7.
153.
ZhangHLWuJZhuJ.2010. The immune-modulatory role of apolipoprotein E with emphasis on multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Dev Immunol2010:186813.
154.
ZhangJKongQZhangZGePBaDHeW.2003. Telomere dysfunction of lymphocytes in patients with Alzheimer disease. Cogn Behav Neurol16(3):170–6.
155.
ZhangLChenCMakMSLuJWuZChenQ, and others. 2020. Advance of sporadic Alzheimer’s disease animal models. Med Res Rev40(1):431–58.
156.
ZhaoNRenYYamazakiYQiaoWLiFFeltonLM, and others. 2020. Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron106(5):727–742.e6.
157.
ZhuFLiCChuFTianXZhuJ.2020. Target dysbiosis of gut microbes as a future therapeutic manipulation in Alzheimer’s disease. Front Aging Neurosci12:544235.
158.
ZivYRonNButovskyOLandaGSudaiEGreenbergN, and others. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci9(2):268–75.
159.
ZouKKimDKakioAByunKGongJSKimJ, and others. 2003. Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain. J Neurochem87(3):609–19.
