Subtypes Based on Six Apolipoproteins in Non-Demented Elderly Are Associated with Cognitive Decline and Subsequent Tau Accumulation in Cerebrospinal Fluid
Restricted accessResearch articleFirst published online November 12, 2019
Subtypes Based on Six Apolipoproteins in Non-Demented Elderly Are Associated with Cognitive Decline and Subsequent Tau Accumulation in Cerebrospinal Fluid
Apolipoproteins (APOs) have been implicated in the pathogenesis of Alzheimer’s disease (AD). In the present study, we aimed to investigate if patterns of cerebrospinal fluid (CSF) APOs (APOA-I, APOC-III, APOD, APOE, APOH, and APOJ) levels are associated with changes over time in cognition, memory performance, neuroimaging markers, and AD-related pathologies (CSF Aβ42, t-tau, and p-tau) in non-demented older adults. At baseline, a total of 241 non-demented older adults with CSF APOs data was included in the present analysis. Hierarchical agglomerative cluster analysis including the six CSF APOs was carried out. Among non-demented older adults, we identified two clusters. Compare with the first cluster, the second cluster had higher levels of APOs in CSF. Additionally, the second cluster showed a more benign disease course, including slower cognitive decline and slower p-tau accumulation in CSF. Our data highlight the importance of APOs in the pathogenesis of AD.
KochM, JensenMK (2016) HDL-cholesterol and apolipoproteins in relation to dementia. Curr Opin Lipidol27, 76–87.
2.
MartinsIJ, BergerT, SharmanMJ, VerdileG, FullerSJ, MartinsRN (2009) Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease. J Neurochem111, 1275–1308.
KochM, FurtadoJD, FalkK, LeypoldtF, MukamalKJ, JensenMK (2017) Apolipoproteins and their subspecies in human cerebrospinal fluid and plasma. Alzheimers Dement (Amst)6, 182–187.
5.
MuenchhoffJ, SongF, PoljakA, CrawfordJD, MatherKA, KochanNA, YangZ, TrollorJN, ReppermundS, MastonK, TheobaldA, Kirchner-AdelhardtS, KwokJB, RichmondRL, McEvoyM, AttiaJ, SchofieldPW, BrodatyH, SachdevPS (2017) Plasma apolipoproteins and physical and cognitive health in very old individuals. Neurobiol Aging55, 49–60.
6.
JohanssonP, AlmqvistEG, BjerkeM, WallinA, JohanssonJO, AndreassonU, BlennowK, ZetterbergH, SvenssonJ (2017) Reduced cerebrospinal fluid concentration of apolipoprotein A-I in patients with Alzheimer’s disease. J Alzheimers Dis59, 1017–1026.
7.
NikitidouE, KhoonsariPE, ShevchenkoG, IngelssonM, KultimaK, ErlandssonA (2017) Increased release of apolipoprotein E in extracellular vesicles following amyloid-beta protofibril exposure of neuroglial co-cultures. J Alzheimers Dis60, 305–321.
8.
Sadigh-EteghadS, TalebiM, FarhoudiM (2012) Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer‘s disease. A meta-analysis. Neurosciences (Riyadh)17, 321–326.
9.
LambertJC, HeathS, EvenG, CampionD, SleegersK, HiltunenM, CombarrosO, ZelenikaD, BullidoMJ, TavernierB, LetenneurL, BettensK, BerrC, PasquierF, FievetN, Barberger-GateauP, EngelborghsS, De DeynP, MateoI, FranckA, HelisalmiS, PorcelliniE, HanonO, de PancorboMM, LendonC, DufouilC, JaillardC, LeveillardT, AlvarezV, BoscoP, MancusoM, PanzaF, NacmiasB, BossuP, PiccardiP, AnnoniG, SeripaD, GalimbertiD, HannequinD, LicastroF, SoininenH, RitchieK, BlancheH, DartiguesJF, TzourioC, GutI, Van BroeckhovenC, AlperovitchA, LathropM, AmouyelP (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet41, 1094–1099.
SunY, ShiJ, ZhangS, TangM, HanH, GuoY, MaC, LiuX, LiT (2005) The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer’s disease in a Chinese population. Neurosci Lett380, 219–222.
12.
HelisalmiS, HiltunenM, VepsalainenS, IivonenS, CorderEH, LehtovirtaM, MannermaaA, KoivistoAM, SoininenH (2004) Genetic variation in apolipoprotein D and Alzheimer’s disease. J Neurol251, 951–957.
13.
ShihYH, TsaiKJ, LeeCW, ShieshSC, ChenWT, PaiMC, KuoYM (2014) Apolipoprotein C-III is an amyloid-beta-binding protein and an early marker for Alzheimer’s disease. J Alzheimers Dis41, 855–865.
14.
WangQ, ZhouW, ZhangJ; Alzheimer’s Disease Neuroimaging Initiative (2019) Higher apolipoprotein C-III levels in cerebrospinal fluid are associated with slower cognitive decline in mild cognitive impairment. J Alzheimers Dis67, 961–969.
SlotRE, Van HartenAC, KesterMI, JongbloedW, BouwmanFH, TeunissenCE, ScheltensP, VeerhuisR, van der FlierWM (2017) Apolipoprotein A1 in cerebrospinal fluid and plasma and progression to Alzheimer’s disease in non-demented elderly. J Alzheimers Dis56, 687–697.
17.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
18.
MorrisJC (1993) The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology43, 2412–2414.
19.
MattssonN, InselP, NoshenyR, TrojanowskiJQ, ShawLM, JackCRJr., TosunD, WeinerM (2014) Effects of cerebrospinal fluid proteins on brain atrophy rates in cognitively healthy older adults. Neurobiol Aging35, 614–622.
20.
SchmidtM (1996) Rey auditory verbal learning test: A handbook, Western Psychological ServicesLos Angeles, CA.
LandauSM, HarveyD, MadisonCM, KoeppeRA, ReimanEM, FosterNL, WeinerMW, JagustWJ (2011) Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol Aging32, 1207–1218.
BenjaminiY, HochbergY (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol57, 289–300.
28.
IqbalK, FloryM, KhatoonS, SoininenH, PirttilaT, LehtovirtaM, AlafuzoffI, BlennowK, AndreasenN, VanmechelenE, Grundke-IqbalI (2005) Subgroups of Alzheimer’s disease based on cerebrospinal fluid molecular markers. Ann Neurol58, 748–757.
29.
van der VliesAE, VerweyNA, BouwmanFH, BlankensteinMA, KleinM, ScheltensP, van der FlierWM (2009) CSF biomarkers in relationship to cognitive profiles in Alzheimer disease. Neurology72, 1056–1061.
30.
NettiksimmonsJ, HarveyD, BrewerJ, CarmichaelO, DeCarliC, JackCRJr., PetersenR, ShawLM, TrojanowskiJQ, WeinerMW, BeckettL (2010) Subtypes based on cerebrospinal fluid and magnetic resonance imaging markers in normal elderly predict cognitive decline. Neurobiol Aging31, 1419–1428.
31.
WallinAK, BlennowK, ZetterbergH, LondosE, MinthonL, HanssonO (2010) CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology74, 1531–1537.
32.
EscuderoJ, ZajicekJP, IfeachorE (2011) Early detection and characterization of Alzheimer’s disease in clinical scenarios using Bioprofile concepts and K-means. Conf Proc IEEE Eng Med Biol Soc2011, 6470–6473.
33.
PikeKE, EllisKA, VillemagneVL, GoodN, ChetelatG, AmesD, SzoekeC, LawsSM, VerdileG, MartinsRN, MastersCL, RoweCC (2011) Cognition and beta-amyloid in preclinical Alzheimer’s disease: Data from the AIBL study. Neuropsychologia49, 2384–2390.
NettiksimmonsJ, BeckettL, SchwarzC, CarmichaelO, FletcherE, DecarliC (2013) Subgroup of ADNI normal controls characterized by atrophy and cognitive decline associated with vascular damage. Psychol Aging28, 191–201.
36.
SkillbackT, ZetterbergH, BlennowK, MattssonN (2013) Cerebrospinal fluid biomarkers for Alzheimer disease and subcortical axonal damage in 5,542 clinical samples. Alzheimers Res Ther5, 47.
NohY, JeonS, LeeJM, SeoSW, KimGH, ChoH, YeBS, YoonCW, KimHJ, ChinJ, ParkKH, HeilmanKM, NaDL (2014) Anatomical heterogeneity of Alzheimer disease: Based on cortical thickness on MRIs. Neurology83, 1936–1944.
39.
RacineAM, KoscikRL, BermanSE, NicholasCR, ClarkLR, OkonkwoOC, RowleyHA, AsthanaS, BendlinBB, BlennowK, ZetterbergH, GleasonCE, CarlssonCM, JohnsonSC (2016) Biomarker clusters are differentially associated with longitudinal cognitive decline in late midlife. Brain139, 2261–2274.
40.
JongbloedW, van DijkKD, MulderSD, van de BergWD, BlankensteinMA, van der FlierW, VeerhuisR (2015) Clusterin levels in plasma predict cognitive decline and progression to Alzheimer’s disease. J Alzheimers Dis46, 1103–1110.
41.
HoeH-S, FreemanJ, RebeckGW (2006) Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons. Mol Neurodegener1, 18.
42.
OhkuboN, LeeY-D, MorishimaA, TerashimaT, KikkawaS, TohyamaM, SakanakaM, TanakaJ, MaedaN, VitekMP (2003) Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3β cascade. FASEB J17, 295–297.
43.
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.
