Peripheral Blood Biomarkers Coupled with the Apolipoprotein E4 Genotype Are Strongly Associated with Semantic and Episodic Memory Impairments in Elderly Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease
Restricted accessResearch articleFirst published online October 1, 2019
Peripheral Blood Biomarkers Coupled with the Apolipoprotein E4 Genotype Are Strongly Associated with Semantic and Episodic Memory Impairments in Elderly Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease
The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer’s disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear.
Objective:
This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory.
Methods:
The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD, and 62 healthy controls.
Results:
Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, albumin, and glucose coupled with ApoE4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments.
Conclusions:
Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers.
(2013) Diagnostic and statistical manual of mental disorders: DSM-5, American Psychiatric Association, Arlington, VA.
4.
CerejeiraJ, LagartoL, Mukaetova-LadinskaEB (2012) Behavioral and psychological symptoms of dementia, Front Neurol3, 73.
5.
Pérez RomeroA, González GarridoS (2018) The importance of behavioural and pyschological symptoms in Alzheimer disease, Neurología33, 378–384.
6.
SelkoeDJ, HardyJ (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years, EMBO Mol Med8, 595–608.
7.
TakahashiRH, NagaoT, GourasGK (2017) Plaque formation and the intraneuronal accumulation of beta-amyloid in Alzheimer’s disease, Pathol Int67, 185–193.
8.
KimJ, BasakJM, HoltzmanDM (2009) The role of apolipoprotein E in Alzheimer’s disease, Neuron63, 287–303.
9.
KanekiyoT, XuH, BuG (2014) ApoE and Aβ in Alzheimer’s disease: Accidental encounters or partners?Neuron81, 740–754.
10.
BrandonJA, FarmerBC, WilliamsHC, JohnsonLA (2018) APOE and Alzheimer’s disease: Neuroimaging of metabolic and cerebrovascular dysfunction, Front Aging Neurosci10, 180.
11.
FarrerLA, CupplesLA, HainesJL, HymanB, KukullWA, MayeuxR, MyersRH, Pericak-VanceMA, RischN, van DuijnCM (1997) 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, JAMA278, 1349–1356.
12.
TangwongchaiS, SupasitthumrongT, HemrunrojS, TunvirachaisakulC, ChuchuenP, HoungngamN, SnabboonT, TawankanjanachotI, LikitchareonY, PhanthumchindadK, MaesM (2018) In Thai nationals, the ApoE4 allele affects multiple domains of neuropsychological, biobehavioral, and social functioning thereby contributing to Alzheimer’s disorder, while the ApoE3 allele protects against neuropsychiatric symptoms and psychosocial deficits, Mol Neurobiol55, 6449–6462.
13.
AniwattanapongD, TangwongchaiS, SupasitthumrongT, HemrunrojS, TunvirachaisakulC, TawankanjanachotI, ChuchuenP, SnabboonT, CarvalhoAF, MaesM (2019) Validation of the Thai version of the short Boston Naming Test (T-BNT) in patients with Alzheimer’s dementia and mild cognitive impairment: Clinical and biomarker correlates, Aging Ment Health23, 840–850.
14.
PetersenRC (2004) Mild cognitive impairment as a diagnostic entity, J Intern Med256, 183–194.
15.
PetersenRC, CaraccioloB, BrayneC, GauthierS, JelicV, FratiglioniL (2014) Mild cognitive impairment: A concept in evolution, J Intern Med275, 214–228.
16.
NeugroschlJ, WangS (2011) Alzheimer’s disease: Diagnosis and treatment across the spectrum of disease severity, Mt Sinai J Med78, 596–612.
17.
TarawnehR, HoltzmanDM (2012) The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment.a, Cold Spring Harb Perspect Med2, 006148.
18.
JahnH (2013) Memory loss in Alzheimer’s disease, Dialogues Clin Neurosci15, 445–454.
19.
JeffersonAL, BeiserAS, SeshadriS, WolfPA, AuR (2015) APOE and mild cognitive impairment: The Framingham Heart Study, Age Ageing44, 307–311.
20.
FalahatiF, FerreiraD, MuehlboeckJS, EriksdotterM, SimmonsA, WahlundLO, WestmanE (2017) Monitoring disease progression in mild cognitive impairment: Associations between atrophy patterns, cognition, APOE and amyloid, Neuroimage Clin16, 418–428.
21.
MorrisGP, ClarkIA, VisselB (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease, Acta Neuropathol Commun2, 135.
22.
LaiKSP, LiuCS, RauA, LanctotKL, KohlerCA, PakoshM, CarvalhoAF, HerrmannN (2017) Peripheral inflammatory markers in Alzheimer’s disease: A systematic review and meta-analysis of 175 studies, J Neurol Neurosurg Psychiatry88, 876–882.
23.
MorrisG, BerkM, MaesM, PuriBK (2019) Could Alzheimer’s disease originate in the periphery and if so how so?Mol Neurobiol56, 406–434.
24.
NeumannH, DalyMJ (2013) Variant TREM2 as risk factor for Alzheimer’s disease, N Engl J Med368, 182–184.
25.
HolmesC, CunninghamC, ZotovaE, WoolfordJ, DeanC, KerrS, CullifordD, PerryVH (2009) Systemic inflammation and disease progression in Alzheimer disease, Neurology73, 768–774.
VasantharekhaR, PriyankaHP, SwarnalingamT, SrinivasanAV, ThyagaRajanS (2017) Interrelationship between Mini-Mental State Examination scores and biochemical parameters in patients with mild cognitive impairment and Alzheimer’s disease, Geriatr Gerontol Int17, 1737–1745.
28.
TangneyCC, AggarwalNT, LiH, WilsonRS, DecarliC, EvansDA, MorrisMC (2011) Vitamin B12, cognition, and brain MRI measures: A cross-sectional examination, Neurology77, 1276–1282.
29.
FauxNG, EllisKA, PorterL, FowlerCJ, LawsSM, MartinsRN, PertileKK, RembachA, RoweCC, RumbleRL, SzoekeC, TaddeiK, TaddeiT, TrounsonBO, VillemagneVL, WardV, AmesD, MastersCL, BushAI (2011) Homocysteine, vitamin B12, and folic acid levels in Alzheimer’s disease, mild cognitive impairment, and healthy elderly: Baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study, J Alzheimers Dis27, 909–922.
GroberE, HallCB, HahnSR, LiptonRB (2011) Memory impairment and executive dysfunction are associated with inadequately controlled diabetes in older adults, J Prim Care Community Health2, 229–233.
32.
CranePK, WalkerR, HubbardRA, LiG, NathanDM, ZhengH, HaneuseS, CraftS, MontineTJ, KahnSE, McCormickW, McCurrySM, BowenJD, LarsonEB (2013) Glucose levels and risk of dementia, N Engl J Med369, 540–548.
33.
PappasC, AndelR, InfurnaFJ, SeetharamanS (2017) Glycated haemoglobin (HbA1c), diabetes and trajectories of change in episodic memory performance, J Epidemiol Community Health71, 115–120.
34.
AfsarB, ElsurerR (2015) Association between serum bicarbonate and pH with depression, cognition and sleep quality in hemodialysis patients, Ren Fail37, 957–960.
35.
TunvirachaisakulC, SupasitthumrongT, TangwongchaiS, HemrunrojS, ChuchuenP, TawankanjanachotI, LikitchareonY, PhanthumchindaK, SriswasdiS, MaesM (2018) Characteristics of mild cognitive impairment using the Thai version of the Consortium to Establish a Registry for Alzheimer’s Disease Tests: A multivariate and machine learning study, Dement Geriatr Cogn Disord45, 38–48.
36.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCR, 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.
37.
Medical technology assessment project committee (2008) The Comparison of the Test Performance Between the MMSE-Thai 2002 and the TMSE for Dementia Screening in the Elderly, Thai Geriatric Medicine Institute, Ministry of Public Health, Bangkok, Thailand.
38.
MorrisJC (1993) The Clinical Dementia Rating (CDR): Current version and scoring rules, Neurology43, 2412–2414.
39.
FillenbaumGG, van BelleG, MorrisJC, MohsRC, MirraSS, DavisPC, TariotPN, SilvermanJM, ClarkCM, Welsh-BohmerKA, HeymanA (2008) CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) The first 20 years, Alzheimers Dement4, 96–109.
40.
CorderEH, SaundersAM, StrittmatterWJ, SchmechelDE, GaskellPC, SmallGW, RosesAD, HainesJL, Pericak-VanceMA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science261, 921–923.
41.
RosesAD (1996) Apolipoprotein E alleles as risk factors in Alzheimer’s disease, Annu Rev Med47, 387–400.
42.
BenjaminiY, HochbergY (1995), Controlling The False Discovery Rate - A Practical And Powerful Approach To Multiple Testing.
43.
SmallBJ, RosnickCB, FratiglioniL, BackmanL (2004) Apolipoprotein E and cognitive performance: A meta-analysis, Psychol Aging19, 592–600.
44.
BarnesLL, ArvanitakisZ, YuL, KellyJ, De JagerPL, BennettDA (2013) Apolipoprotein E and change in episodic memory in blacks and whites, Neuroepidemiology40, 211–219.
45.
BoylePA, BuchmanAS, WilsonRS, KellyJF, BennettDA (2010) The APOE epsilon4 allele is associated with incident mild cognitive impairment among community-dwelling older persons, Neuroepidemiology34, 43–49.
46.
LiuCC, LiuCC, KanekiyoT, XuH, BuG (2013) Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy, Nat Rev Neurol9, 106–118.
47.
WilsonRS, BieniasJL, Berry-KravisE, EvansDA, BennettDA (2002) The apolipoprotein E epsilon 2 allele and decline in episodic memory, J Neurol Neurosurg Psychiatry73, 672–677.
48.
MaturaS, PrvulovicD, JurcoaneA, HartmannD, MillerJ, ScheibeM, O’DwyerL, Oertel-KnochelV, KnochelC, ReinkeB, KarakayaT, FusserF, PantelJ (2014) Differential effects of the ApoE4 genotype on brain structure and function, Neuroimage89, 81–91.
49.
EllisRJ, OlichneyJM, ThalLJ, MirraSS, MorrisJC, BeeklyD, HeymanA (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: The CERAD experience, Part XV, Neurology46, 1592–1596.
50.
ViswanathanA, GreenbergSM (2011) Cerebral amyloid angiopathy in the elderly, Ann Neurol70, 871–880.
51.
HardyJ, SelkoeDJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics, Science297, 353–356.
52.
ButterfieldDA, DrakeJ, PocernichC, CastegnaA (2001) Evidence of oxidative damage in Alzheimer’s disease brain: Central role for amyloid beta-eptide. Trends Mol Med7, 548–554.
53.
ButterfieldDA, LauderbackCM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: Potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med32, 1050–1060.
54.
MonsellSE, KukullWA, RoherAE, MaaroufCL, SerranoG, BeachTG, CaselliRJ, MontineTJ, ReimanEM (2015) Characterizing apolipoprotein E ɛ4 carriers and noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia and minimal β-amyloid peptide plaques, JAMA Neurol72, 1124–1131.
55.
DobreM, GaussoinSA, BatesJT, ChoncholMB, CohenDL, HostetterTH, RaphaelKL, TaylorAA, LernerAJ, WrightJTJr, RahmanM (2018) Serum bicarbonate concentration and cognitive function in hypertensive adults, Clin J Am Soc Nephrol13, 596–603.
56.
SozioSM, McAdams-DeMarcoM (2018) The role of bicarbonate in cognition: Acidosis may be corrosive to the brain, Clin J Am Soc Nephrol13, 527–528.
57.
PotharajaroenS, TangwongchaiS, TayjasanantT, ThawitsriT, AndersonG, MaesM (2018) Bright light and oxygen therapies decrease delirium risk in critically ill surgical patients by targeting sleep and acid-base disturbances, Psychiatry Res261, 21–27.
LiuY, ChenL-M (2014) Towards bridging the gap between acid-base transporters and neuronal excitability modulation, Int J Physiol Pathophysiol Pharmacol6, 221–225.
60.
DodgeJC, TreleavenCM, FidlerJA, TamsettTJ, BaoC, SearlesM, TaksirTV, MisraK, SidmanRL, ChengSH, ShihabuddinLS (2013) Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis, Proc Natl Acad Sci U S A110, 10812–10817.
61.
TanakaT, NarazakiM, KishimotoT (2014) IL-6 in inflammation, immunity, and disease, Cold Spring Harb Perspect Biol6, a016295.
62.
MaesM, DeVosN, WautersA, DemedtsP, MauritsVW, NeelsH, BosmansE, AltamuraC, LinA, SongC, VandenbrouckeM, ScharpeS (1999) Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer’s disease, J Psychiatr Res33, 397–405.
63.
CojocaruIM, CojocaruM, MiuG, SapiraV (2011) Study of interleukin-6 production in Alzheimer’s disease, Rom J Intern Med49, 55–58.
64.
MurayamaH, ShinkaiS, NishiM, TaniguchiY, AmanoH, SeinoS, YokoyamaY, YoshidaH, FujiwaraY, ItoH (2017) Albumin, hemoglobin, and the trajectory of cognitive function in community-dwelling older Japanese: A 13-year longitudinal study, J Prev Alzheimers Dis4, 93–99.
65.
RibyLM, MarriottA, BullockR, HancockJ, SmallwoodJ, McLaughlinJ (2009) The effects of glucose ingestion and glucose regulation on memory performance in older adults with mild cognitive impairment, Eur J Clin Nutr63, 566–571.
66.
de GrootLCPGM, van der ZwaluwNL, van de RestO, KesselsRPC (2015) Effects of glucose load on cognitive functions in elderly people, Nutr Rev73, 92–105.
67.
RawlingsAM, SharrettAR, MosleyTH, BallewSH, DealJA, SelvinE (2017) Glucose peaks and the risk of dementia and 20-year cognitive decline, Diabetes Care40, 879–886.
68.
BarbagalloM, DominguezLJ (2014) Type 2 diabetes mellitus and Alzheimer’s disease, World J Diabetes5, 889–893.
69.
MergenthalerP, LindauerU, DienelGA, MeiselA (2013) Sugar for the brain: The role of glucose inhysiological and pathological brain function. Trends Neurosci36, 587–597.
Quincozes-SantosA, BoberminLD, de AssisAM, GoncalvesCA, SouzaDO (2017) Fluctuations in glucose levels induce glial toxicity with glutamatergic, oxidative and inflammatory implications, Biochim Biophys Acta Mol Basis Dis1863, 1–14.
72.
BahniwalM, LittleJP, KlegerisA (2017) High glucose enhances neurotoxicity and inflammatory cytokine secretion by stimulated human astrocytes, Curr Alzheimer Res14, 731–741.
73.
SirivichayakulS, KanchanatawanB, ThikaS, CarvalhoAF, MaesM (2019) Eotaxin, an endogenous cognitive deteriorating chemokine (ECDC), is a major contributor to cognitive decline in normal people and to executive, memory, and sustained attention deficits, formal thought disorders, and psychopathology in schizophrenia patients, Neurotox Res35, 122–138.
74.
AraujoJR, MartelF, BorgesN, AraujoJM, KeatingE (2015) Folates and aging: Role in mild cognitive impairment, dementia and depression, Ageing Res Rev22, 9–19.
75.
KimH, KimG, JangW, KimSY, ChangN (2014) Association between intake of B vitamins and cognitive function in elderly Koreans with cognitive impairment, Nutr J13, 118.
KoGTC, WaiHPS, TangJSF (2006) Effects of age on plasma glucose levels in non-diabetic Hong Kong Chinese, Croat Med J47, 709–713.
78.
CabrerizoS, CuadrasD, Gomez-BustoF, Artaza-ArtabeI, Marin-CiancasF, MalafarinaV (2015) Serum albumin and health in older people: Review and meta analysis, Maturitas81, 17–27.
79.
AhnSY, RyuJ, BaekSH, HanJW, LeeJH, AhnS, KimK-i, ChinHJ, NaKY, ChaeD-W, KimKW, KimS (2014) Serum anion gap is predictive of mortality in an elderly population, Exp Gerontol50, 122–127.
