Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer’s disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients.
Objective:
This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD.
Methods:
A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma.
Results:
AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%.
Conclusion:
This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD.
ScheltensP, De StrooperB, KivipeltoM, HolstegeH, ChételatG, TeunissenCE, CummingsJ, van der FlierWM (2021) Alzheimer’s disease. Lancet397, 1577–1590.
2.
HurJY (2022) gamma-Secretase in Alzheimer’s disease. Exp Mol Med54, 433–446.
3.
LiY, BohmC, DoddR, ChenF, QamarS, Schmitt-UlmsG, FraserPE, St George-HyslopPH (2014) Structural biology of presenilin 1 complexes. Mol Neurodegener9, 59.
4.
WahlsterL, ArimonM, Nasser-GhodsiN, PostKL, Serrano-PozoA, UemuraK, BerezovskaO (2013) Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease. Acta Neuropathol125, 187–199.
5.
BettcherBM, TanseyMG, DorotheeG, HenekaMT (2021) Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus. Nat Rev Neurol17, 689–701.
6.
LiuYH, ZengF, WangYR, ZhouHD, GiuntaB, TanJ, WangYJ (2013) Immunity and Alzheimer’s disease: Immunological perspectives on the development of novel therapies. Drug Discov Today18, 1212–1220.
7.
San Segundo-AcostaP, Montero-CalleA, Jernbom-FalkA, Alonso-NavarroM, PinE, AnderssonE, HellstromC, Sanchez-MartinezM, RabanoA, Solis-FernandezG, Pelaez-GarciaA, Martinez-UserosJ, Fernandez-AceneroMJ, ManbergA, NilssonP, BarderasR (2021) Multiomics profiling of Alzheimer’s disease serum for the identification of autoantibody biomarkers. J Proteome Res20, 5115–5130.
8.
LiuYH, WangJ, LiQX, FowlerCJ, ZengF, DengJ, XuZQ, ZhouHD, DoeckeJD, VillemagneVL, LimYY, MastersCL, WangYJ (2021) Association of naturally occurring antibodies to beta-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease. Sci Adv7, eabb0457.
9.
WangBZ, ZailanFZ, WongBYX, NgKP, KandiahN (2020) Identification of novel candidate autoantibodies in Alzheimer’s disease. Eur J Neurol27, 2292–2296.
10.
HansenN, MalchowB, ZerrI, StockerW, WiltfangJ, TimausC (2021) Neural cell-surface and intracellular autoantibodies in patients with cognitive impairment from a memory clinic cohort. J Neural Transm (Vienna)128, 357–369.
11.
DiamondB, HonigG, MaderS, BrimbergL, VolpeBT (2013) Brain-reactive antibodies and disease. Annu Rev Immunol31, 345–385.
12.
JianJM, FanDY, TianDY, ChengY, SunPY, TanCR, ZengGH, HeCY, WangYR, ZhuJ, YaoXQ, WangYJ, LiuYH (2022) Naturally-occurring antibodies against Bim are decreased in Alzheimer’s disease and attenuate AD-type pathology in a mouse model. Neurosci Bull38, 1025–1040.
13.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCRJr., KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
14.
AlbertMS, DeKoskyST, DicksonD, DuboisB, FeldmanHH, FoxNC, GamstA, HoltzmanDM, JagustWJ, PetersenRC, SnyderPJ, CarrilloMC, ThiesB, PhelpsCH (2011) 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. Alzheimers Dement7, 270–279.
DeMarshallCA, NageleEP, SarkarA, AcharyaNK, GodseyG, GoldwaserEL, KosciukM, ThayasivamU, HanM, BelinkaB, NageleRG, Alzheimer’s Disease Neuroimaging Initiative
(2016) Detection of Alzheimer’s disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers. Alzheimers Dement (Amst)3, 51–62.
18.
LiuYH, BuXL, LiangCR, WangYR, ZhangT, JiaoSS, ZengF, YaoXQ, ZhouHD, DengJ, WangYJ (2015) An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: The dust-raising effect. J Neuroinflammation12, 153.
19.
JianJM, FanDY, ChengY, ShenYY, ChenDW, LiHY, ChenY, ZhangY, ZengGH, TanCR, LiuYH, WangYJ (2022) Circulating naturally occurring antibodies to P2RY2 are decreased in Alzheimer’s disease. J Alzheimers Dis87, 711–719.
20.
RinneJO, BrooksDJ, RossorMN, FoxNC, BullockR, KlunkWE, MathisCA, BlennowK, BarakosJ, OkelloAA, Rodriguez Martinez de LianoS, LiuE, KollerM, GreggKM, SchenkD, BlackR, GrundmanM (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load inpatients with Alzheimer’s disease treated with bapineuzumab: A phase2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol9, 363–372.
21.
SperlingR, SallowayS, BrooksDJ, TampieriD, BarakosJ, FoxNC, RaskindM, SabbaghM, HonigLS, PorsteinssonAP, LieberburgI, ArrighiHM, MorrisKA, LuY, LiuE, GreggKM, BrashearHR, KinneyGG, BlackR, GrundmanM (2012) Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: A retrospective analysis. Lancet Neurol11, 241–249.
22.
MintunMA, LoAC, Duggan EvansC, WesselsAM, ArdayfioPA, AndersenSW, ShcherbininS, SparksJ, SimsJR, BrysM, ApostolovaLG, SallowaySP, SkovronskyDM (2021) Donanemab in early Alzheimer’s disease. N Engl J Med384, 1691–1704.
23.
SallowayS, SperlingR, FoxNC, BlennowK, KlunkW, RaskindM, SabbaghM, HonigLS, PorsteinssonAP, FerrisS, ReichertM, KetterN, NejadnikB, GuenzlerV, MiloslavskyM, WangD, LuY, LullJ, TudorIC, LiuE, GrundmanM, YuenE, BlackR, BrashearHR, Bapineuzumab 301 and 302 Clinical Trial Investigators
(2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med370, 322–333.
24.
FoxNC, BlackRS, GilmanS, RossorMN, GriffithSG, JenkinsL, KollerM, AN1792(QS-21)-201 Study
(2005) Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology64, 1563–1572.
25.
GilmanS, KollerM, BlackRS, JenkinsL, GriffithSG, FoxNC, EisnerL, KirbyL, RoviraMB, ForetteF, OrgogozoJM, AN1792(QS-21)-201 Study Team (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology64, 1553–1562.
26.
LiuE, WangD, SperlingR, SallowayS, FoxNC, BlennowK, ScheltensP, SchmidtME, StrefferJ, NovakG, EinsteinS, BoothK, KetterN, BrashearHR, ELN115727-301/302 Investigator Group (2018) Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab. Neurology90, e877–e886.
27.
IshiiM, IadecolaC (2020) Risk factor for Alzheimer’s disease breaks the blood-brain barrier. Nature581, 31–32.
28.
NationDA, SweeneyMD, MontagneA, SagareAP, D’OrazioLM, PachicanoM, SepehrbandF, NelsonAR, BuennagelDP, HarringtonMG, BenzingerTLS, FaganAM, RingmanJM, SchneiderLS, MorrisJC, ChuiHC, LawM, TogaAW, ZlokovicBV (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med25, 270–276.
29.
GoldwaserEL, AcharyaNK, WuH, GodseyGA, SarkarA, DeMarshallCA, KosciukMC, NageleRG (2020) Evidence that brain-reactive autoantibodies contribute to chronic neuronal internalization of exogenous amyloid-beta1-42 and key cell surface proteins during Alzheimer’s disease pathogenesis. J Alzheimers Dis74, 345–361.
30.
AlexopoulosP, ThierjungN, GrimmerT, OrtnerM, EconomouP, AssimakopoulosK, GourzisP, PolitisA, PerneczkyR, The Alzheimer’s Disease Neuroimaging Initiative (2018) Cerebrospinal fluid BACE1 activity and sAbetaPPbeta as biomarker candidates of Alzheimer’s disease. Dement Geriatr Cogn Disord45, 152–161.
31.
YanR, VassarR (2014) Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol13, 319–329.
32.
NyhartL (1987) The disciplinary breakdown of German morphology, 1870–1900. Isis78, 365–389.
33.
JanelidzeS, MattssonN, PalmqvistS, SmithR, BeachTG, SerranoGE, ChaiX, ProctorNK, EichenlaubU, ZetterbergH, BlennowK, ReimanEM, StomrudE, DageJL, HanssonO (2020) Plasma P-tau181 in Alzheimer’s disease: Relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med26, 379–386.
34.
PalmqvistS, JanelidzeS, QuirozYT, ZetterbergH, LoperaF, StomrudE, SuY, ChenY, SerranoGE, LeuzyA, Mattsson-CarlgrenN, StrandbergO, SmithR, VillegasA, Sepulveda-FallaD, ChaiX, ProctorNK, BeachTG, BlennowK, DageJL, ReimanEM, HanssonO (2020) Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA324, 772–781.
