Background/Objective: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals.
Methods: Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records.
Results: Plasma Aβ1 - 40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOEɛ4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype.
Discussion: Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer’s disease.
RoherAE, EshCL, KokjohnTA, CastanoEM, Van VickleGD, KalbackWM, PattonRL, LuehrsDC, DaugsID, KuoYM, EmmerlingMR, SoaresH, QuinnJF, KayeJ, ConnorDJ, SilverbergNB, AdlerCH, SewardJD, BeachTG, SabbaghMN (2009) Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimers Dement5, 18–29.
2.
StamatelopoulosK, SibbingD, RallidisLS, GeorgiopoulosG, StakosD, BraunS, GatsiouA, SopovaK, KotakosC, VarounisC, TellisCC, KastritisE, KellerT, KastratiA, DimmelerS, ZeiherAM, StellosK (2015) Amyloid-beta (1-40) and the risk of death from cardiovascular causes in patients with coronary heart disease. J Am Coll Cardiol65, 904–916.
3.
VassarR, BennettBD, Babu-KhanS, KahnS, MendiazEA, DenisP, TeplowDB, RossS, AmaranteP, LoeloffR, LuoY, FisherS, FullerJ, EdensonS, LileJ, JarosinskiMA, BiereAL, CurranE, BurgessT, LouisJC, CollinsF, TreanorJ, RogersG, CitronM (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science286, 735–741.
4.
ThalDR, RubU, OrantesM, BraakH (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology58, 1791–1800.
5.
DicksonDW (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurol56, 321–339.
6.
ThalDR, GhebremedhinE, OrantesM, WiestlerOD (2003) Vascular pathology in Alzheimer disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol62, 1287–1301.
7.
ThalDR, GriffinWS, de VosRA, GhebremedhinE (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol115, 599–609.
8.
ThalDR, GriffinWS, BraakH (2008) Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer’s disease. J Cell Mol Med12, 1848–1862.
9.
YaffeK, WestonA, Graff-RadfordNR, SatterfieldS, SimonsickEM, YounkinSG, YounkinLH, KullerL, AyonayonHN, DingJ, HarrisTB (2011) Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA305, 261–266.
10.
Graff-RadfordNR, CrookJE, LucasJ, BoeveBF, KnopmanDS, IvnikRJ, SmithGE, YounkinLH, PetersenRC, YounkinSG (2007) Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol64, 354–362.
11.
HerzigMC, WinklerDT, BurgermeisterP, PfeiferM, KohlerE, SchmidtSD, DannerS, AbramowskiD, Sturchler-PierratC, BurkiK, van DuinenSG, Maat-SchiemanML, StaufenbielM, MathewsPM, JuckerM (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci7, 954–960.
12.
HanssonO, StomrudE, VanmechelenE, OstlingS, GustafsonDR, ZetterbergH, BlennowK, SkoogI (2012) Evaluation of plasma Abeta as predictor of Alzheimer’s disease in older individuals without dementia: A population-based study. J Alzheimers Dis28, 231–238.
13.
VukicV, CallaghanD, WalkerD, LueLF, LiuQY, CouraudPO, RomeroIA, WekslerB, StanimirovicDB, ZhangW (2009) Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer’s brain is mediated by the JNK-AP1 signaling pathway. Neurobiol Dis34, 95–106.
14.
GiriR, ShenY, StinsM, Du YanS, SchmidtAM, SternD, KimKS, ZlokovicB, KalraVK (2000) beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am J Physiol Cell Physiol279, C1772–C1781.
15.
De MeyerGR, De CleenDM, CooperS, KnaapenMW, JansDM, MartinetW, HermanAG, BultH, KockxMM (2002) Platelet phagocytosis and processing of beta-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. Circ Res90, 1197–1204.
HanssonO, ZetterbergH, BuchhaveP, AndreassonU, LondosE, MinthonL, BlennowK (2007) Prediction of Alzheimer’s disease using the CSF Abeta42/Abeta40 ratio in patients with mild cognitive impairment. Dement Geriatr Cogn Disord23, 316–320.
18.
SongF, PoljakA, ValenzuelaM, MayeuxR, SmytheGA, SachdevPS (2011) Meta-analysis of plasma amyloid-beta levels in Alzheimer’s disease. J Alzheimers Dis26, 365–375.
19.
van OijenM, HofmanA, SoaresHD, KoudstaalPJ, BretelerMM (2006) Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: A prospective case-cohort study. Lancet Neurol5, 655–660.
20.
RembachA, FauxNG, WattAD, PertileKK, RumbleRL, TrounsonBO, FowlerCJ, RobertsBR, PerezKA, LiQX, LawsSM, TaddeiK, Rainey-SmithS, RobertsonJS, VandijckM, VandersticheleH, BarnhamKJ, EllisKA, SzoekeC, MacaulayL, RoweCC, VillemagneVL, AmesD, MartinsRN, BushAI, MastersCL, AIBL research group
(2014) Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer’s disease. Alzheimers Dement10, 53–61.
21.
VerbeekMM, KremerBP, RikkertMO, Van DomburgPH, SkehanME, GreenbergSM (2009) Cerebrospinal fluid amyloid beta(40) is decreased in cerebral amyloid angiopathy. Ann Neurol66, 245–249.
22.
HymanBT, Gomez-IslaT, RebeckGW, BriggsM, ChungH, WestHL, GreenbergS, MuiS, NicholsS, WallaceR, GrowdonJH (1996) Epidemiological, clinical, and neuropathological study of apolipoprotein E genotype in Alzheimer’s disease. Ann N Y Acad Sci802, 1–5.
23.
BertramL, McQueenMB, MullinK, BlackerD, TanziRE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database. Nat Genet39, 17–23.
KimJ, BasakJM, HoltzmanDM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron63, 287–303.
26.
Martinez-MorilloE, HanssonO, AtagiY, BuG, MinthonL, DiamandisEP, NielsenHM (2014) Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. Acta Neuropathol127, 633–643.
27.
ZlokovicBV (2013) Cerebrovascular effects of apolipoprotein E: Implications for Alzheimer disease. JAMA Neurol70, 440–444.
HanssonO, ZetterbergH, VanmechelenE, VandersticheleH, AndreassonU, LondosE, WallinA, MinthonL, BlennowK (2010) Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging31, 357–367.
30.
BergD (2012) Is pre-motor diagnosis possible? The European experience. Parkinsonism Relat Disord18(Suppl 1), S195–S198.
31.
MillerSA, DykesDD, PoleskyHF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res16, 1215.
32.
DeMattosRB, BalesKR, CumminsDJ, PaulSM, HoltzmanDM (2002) Brain to plasma amyloid-beta efflux: A measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science295, 2264–2267.
33.
IadecolaC (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci5, 347–360.
34.
ZlokovicBV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci12, 723–738.
35.
JackCRJr, WisteHJ, WeigandSD, RoccaWA, KnopmanDS, MielkeMM, LoweVJ, SenjemML, GunterJL, PreboskeGM, PankratzVS, VemuriP, PetersenRC (2014) Age-specific population frequencies of cerebral beta-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: A cross-sectional study. Lancet Neurol13, 997–1005.
36.
BatesKA, LiVG, AmesQX, HudsonD, MastersP, MartinsCL, RN (2009) Clearance mechanisms of Alzheimer’s amyloid-beta peptide: Implications for therapeutic design and diagnostic tests. Mol Psychiatry14, 469–486.
37.
YamashiroK, MilsomAB, DucheneJ, PanayiotouC, UrabeT, HattoriN, AhluwaliaA (2010) Alterations in nitric oxide and endothelin-1 bioactivity underlie cerebrovascular dysfunction in ApoE-deficient mice. J Cereb Blood Flow Metab30, 1494–1503.
38.
KivipeltoM, HelkalaEL, LaaksoMP, HanninenT, HallikainenM, AlhainenK, SoininenH, TuomilehtoJ, NissinenA (2001) Midlife vascular risk factors and Alzheimer’s disease in later life: Longitudinal, population based study. BMJ322, 1447–1451.
ParisD, HumphreyJ, QuadrosA, PatelN, CrescentiniR, CrawfordF, MullanM (2003) Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer’s disease: Role of inflammation. Neurol Res25, 642–651.
43.
ZhaoWQ, TownsendM (2009) Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta1792, 482–496.
44.
BomfimTR, Forny-GermanoL, SathlerLB, Brito-MoreiraJ, HouzelJC, DeckerH, SilvermanMA, KaziH, MeloHM, McCleanPL, HolscherC, ArnoldSE, TalbotK, KleinWL, MunozDP, FerreiraST, De FeliceFG (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Invest122, 1339–1353.
45.
SatoN, TakedaS, Uchio-YamadaK, UedaH, FujisawaT, RakugiH, MorishitaR (2011) Role of insulin signaling in the interaction between Alzheimer disease and diabetes mellitus: A missing link to therapeutic potential. Curr Aging Sci4, 118–127.
46.
ZhangY, ZhouB, DengB, ZhangF, WuJ, WangY, LeY, ZhaiQ (2013) Amyloid-beta induces hepatic insulin resistance in vivo via JAK2. Diabetes62, 1159–1166.
47.
BitelCL, KasinathanC, KaswalaRH, KleinWL, FrederiksePH (2012) Amyloid-beta and tau pathology of Alzheimer’s disease induced by diabetes in a rabbit animal model. J Alzheimers Dis32, 291–305.
48.
Jimenez-PalomaresM, Ramos-RodriguezJJ, Lopez-AcostaJF, Pacheco-HerreroM, Lechuga-SanchoAM, PerdomoG, Garcia-AllozaM, Cozar-CastellanoI (2012) Increased Abeta production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab302, E1373–E1380.
49.
YanSS, ChenD, YanS, GuoL, DuH, ChenJX (2012) RAGE is a key cellular target for Abeta-induced perturbation in Alzheimer’s disease. Front Biosci (Schol Ed)4, 240–250.
50.
HanSH, KimYH, Mook-JungI (2011) RAGE: The beneficial and deleterious effects by diverse mechanisms of actions. Mol Cells31, 91–97.
51.
SuoZ, TanJ, PlaczekA, CrawfordF, FangC, MullanM (1998) Alzheimer’s beta-amyloid peptides induce inflammatory cascade in human vascular cells: The roles of cytokines and CD40. Brain Res807, 110–117.
