An epistatic interaction between the ɛ4 allele of apolipoprotein E (APOEɛ4) and the K-variant of butyrylcholinesterase (BCHE-K) genes has been previously reported to increase risk of Alzheimer’s disease (AD). However, these observations were largely from case-control studies with small sample sizes.
Objective:
To examine the interaction between APOEɛ4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study.
Methods:
The study sample for survival analysis included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 brain magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits.
Results:
A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOEɛ4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95%, CI=1.99–6.89, p < 0.001) compared to non-carriers of both genes (APOE ɛ4 x BCHE-K interaction p = 0.025). There was no APOE ɛ4-BCHE-K interaction effect on rate of cognitive decline and brain atrophy.
Conclusion:
The APOE and BCHE genes interact to influence risk of incident AD/MCI but not rates of brain atrophy and decline in cognitive performance before onset of cognitive impairment. This may suggest that the epistatic interaction between APOE ɛ4 and BCHE-K on AD risk is disease stage-dependent.
BertramL, TanziRE (2009) Genome-wide association studies in Alzheimer’s disease. Hum Mol Genet18, R137–R145.
2.
BertramL, LillCM, TanziRE (2010) The genetics of Alzheimer disease: Back to the future. Neuron68, 270–281.
3.
RosesAD, SaundersAM, AlbertsMA, StrittmatterWJ, SchmechelD, GorderE, Pericak-VanceMA (1995) Apolipoprotein E E4 allele and risk of dementia.374-375; author reply. JAMA273, 375–376.
4.
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.
5.
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.
6.
CaselliRJ, DueckAC, OsborneD, SabbaghMN, ConnorDJ, AhernGL, BaxterLC, RapcsakSZ, ShiJ, WoodruffBK, LockeDE, SnyderCH, AlexanderGE, RademakersR, ReimanEM (2009) Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med361, 255–263.
7.
ReimanEM, UeckerA, CaselliRJ, LewisS, BandyD, de LeonMJ, De SantiS, ConvitA, OsborneD, WeaverA, ThibodeauSN (1998) Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer’s disease. Ann Neurol44, 288–291.
8.
MorrisJC, RoeCM, XiongC, FaganAM, GoateAM, HoltzmanDM, MintunMA (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol67, 122–131.
9.
LiuCC, LiuCC, KanekiyoT, XuH, BuG (2013) Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat Rev Neurol9, 106–118.
WangZ, JiangY, WangX, DuY, XiaoD, DengY, WangJ (2015) Butyrylcholinesterase K variant and Alzheimer’s disease risk: A meta-analysis. Med Sci Monit21, 1408–1413.
13.
BartelsCF, JensenFS, LockridgeO, van der SpekAF, RubinsteinHM, LubranoT, La DuBN (1992) DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites. Am J Hum Genet50, 1086–1103.
14.
GhebremedhinE, ThalDR, SchultzC, BraakH (2002) Age-dependent association between butyrylcholinesterase K-variant and Alzheimer disease-related neuropathology in human brains. Neurosci Lett320, 25–28.
15.
KambohMI (2004) Molecular genetics of late-onset Alzheimer’s disease. Ann Hum Genet68, 381–404.
ThambisettyM, AnY, NallsM, SojkovaJ, SwaminathanS, ZhouY, SingletonAB, WongDF, FerrucciL, SaykinAJ, ResnickSM, Baltimore Longitudinal Study of A, the Alzheimer’s Disease Neuroimaging Initiative (2013) Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. Biol Psychiatry73, 422–428.
18.
GandyS, HaroutunianV, DeKoskyST, SanoM, SchadtEE (2013) CR1 and the “vanishing amyloid” hypothesis of Alzheimer’s disease. Biol Psychiatry73, 393–395.
19.
RayganiAV, ZahraiM, SoltanzadehA, DoostiM, JavadiE, PourmotabbedT (2004) Analysis of association between butyrylcholinesterase K variant and apolipoprotein E genotypes in Alzheimer’s disease. Neurosci Lett371, 142–146.
20.
WiebuschH, PoirierJ, SevignyP, SchappertK (1999) Further evidence for a synergistic association between APOE epsilon4 and BCHE-K in confirmed Alzheimer’s disease. Hum Genet104, 158–163.
21.
LehmannDJ, JohnstonC, SmithAD (1997) Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer’s disease. Hum Mol Genet6, 1933–1936.
22.
TilleyL, MorganK, GraingerJ, MarstersP, MorganL, LoweJ, XuerebJ, WischikC, HarringtonC, KalshekerN (1999) Evaluation of polymorphisms in the presenilin-1 gene and the butyrylcholinesterase gene as risk factors in sporadic Alzheimer’s disease. Eur J Hum Genet7, 659–663.
23.
JasieckiJ, Limon-SztencelA, ZukM, ChmaraM, CysewskiD, LimonJ, WasagB (2019) Synergy between the alteration in the N-terminal region of butyrylcholinesterase K variant and apolipoprotein E4 in late-onset Alzheimer’s disease. Sci Rep9, 5223.
24.
VijayaraghavanS, Darreh-ShoriT, RongveA, BergeG, SandoSB, WhiteLR, AuestadBH, WitoelarA, AndreassenOA, UlsteinID, AarslandD (2016) Association of Butyrylcholinesterase-K allele and Apolipoprotein E epsilon4 allele with cognitive decline in dementia with Lewy bodies and Alzheimer’s disease. J Alzheimers Dis50, 567–576.
25.
LaneR, FeldmanHH, MeyerJ, HeY, FerrisSH, NordbergA, Darreh-ShoriT, SoininenH, PirttilaT, FarlowMR, SfikasN, BallardC, GreigNH (2008) Synergistic effect of apolipoprotein E epsilon4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer’s disease. Pharmacogenet Genomics18, 289–298.
26.
De BeaumontL, PelleieuxS, Lamarre-TherouxL, DeaD, PoirierJ, Alzheimer’s Disease Cooperative Study (2016) Butyrylcholinesterase K and Apolipoprotein E-epsilon4 reduce the age of onset of Alzheimer’s disease, accelerate cognitive decline, and modulate donepezil response in mild cognitively impaired subjects. J Alzheimers Dis54, 913–922.
27.
RamananVK, RisacherSL, NhoK, KimS, SwaminathanS, ShenL, ForoudTM, HakonarsonH, HuentelmanMJ, AisenPS, PetersenRC, GreenRC, JackCR, KoeppeRA, JagustWJ, WeinerMW, SaykinAJ, Alzheimer’s Disease Neuroimaging Initiative (2014) APOE and BCHE as modulators of cerebral amyloid deposition: A florbetapir PET genome-wide association study. Mol Psychiatry19, 351–357.
28.
ShockNW, GruelichR, AndresR, ArenbergD, CostaPT, LakattaE, TobinJD (1984) Normal human aging. The Baltimore Longitudinal Study of Aging. US Government Printing Office, Washington, DC.
29.
FerrucciL (2008) The Baltimore Longitudinal Study of Aging (BLSA): A 50-year-long journey and plans for the future. J Gerontol A Biol Sci Med Sci63, 1416–1419.
30.
ResnickSM, GoldszalAF, DavatzikosC, GolskiS, KrautMA, MetterEJ, BryanRN, ZondermanAB (2000) One-year age changes in MRI brain volumes in older adults. Cereb Cortex10, 464–472.
31.
ArmstrongNM, AnY, Beason-HeldL, DoshiJ, ErusG, FerrucciL, DavatzikosC, ResnickSM (2019) Predictors of neurodegeneration differ between cognitively normal and subsequently impaired older adults. Neurobiol Aging75, 178–186.
32.
HixsonJE, VernierDT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res31, 545–548.
33.
KochW, EhrenhaftA, GriesserK, PfeuferA, MullerJ, SchomigA, KastratiA (2002) TaqMan systems for genotyping of disease-related polymorphisms present in the gene encoding apolipoprotein E. Clin Chem Lab Med40, 1123–1131.
34.
MelzerD, PerryJR, HernandezD, CorsiAM, StevensK, RaffertyI, LauretaniF, MurrayA, GibbsJR, PaolissoG, RafiqS, Simon-SanchezJ, LangoH, ScholzS, WeedonMN, ArepalliS, RiceN, WasheckaN, HurstA, BrittonA, HenleyW, van de LeemputJ, LiR, NewmanAB, TranahG, HarrisT, PanickerV, DayanC, BennettA, McCarthyMI, RuokonenA, JarvelinMR, GuralnikJ, BandinelliS, FraylingTM, SingletonA, FerrucciL (2008) A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet4, e1000072.
35.
TerraccianoA, BalaciL, ThayerJ, ScallyM, KokinosS, FerrucciL, TanakaT, ZondermanAB, SannaS, OllaN, ZunchedduMA, NaitzaS, BusoneroF, UdaM, SchlessingerD, AbecasisGR, CostaPTJr. (2009) Variants of the serotonin transporter gene and NEO-PI-R Neuroticism: No association in the BLSA and SardiNIA samples. Am J Med Genet B Neuropsychiatr Genet150B, 1070–1077.
36.
KawasC, GrayS, BrookmeyerR, FozardJ, ZondermanA (2000) Age-specific incidence rates of Alzheimer’s disease: The Baltimore Longitudinal Study of Aging. Neurology54, 2072–2077.
37.
BlessedG, TomlinsonBE, RothM (1968) The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry114, 797–811.
38.
MorrisJC (1997) Clinical dementia rating: A reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr9(Suppl 1), 173-176; discussion 177–178.
39.
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders: DSM-III-R, American Psychiatric Association, Washington, DC.
40.
McKhannG, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
41.
PetersenRC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med256, 183–194.
42.
ResnickSM, PhamDL, KrautMA, ZondermanAB, DavatzikosC (2003) Longitudinal magnetic resonance imaging studies of older adults: A shrinking brain. J Neurosci23, 3295–3301.
43.
DoshiJ, ErusG, OuY, ResnickSM, GurRC, GurRE, SatterthwaiteTD, FurthS, DavatzikosC, Alzheimer’s Neuroimaging Initiative (2016) MUSE: MUlti-atlas region Segmentation utilizing Ensembles of registration algorithms and parameters, and locally optimal atlas selection. Neuroimage127, 186–195.
44.
ErusG, DoshiJ, AnY, VerganelakisD, ResnickSM, DavatzikosC (2018) Longitudinally and inter-site consistent multi-atlas based parcellation of brain anatomy using harmonized atlases. Neuroimage166, 71–78.
45.
WilliamsOA, AnY, ArmstrongNM, ShaferAT, HelphreyJ, Kitner-TrioloM, FerrucciL, ResnickSM (2019) Apolipoprotein E epsilon4 allele effects on longitudinal cognitive trajectories are sex and age dependent. Alzheimers Dement15, 1558–1567.
46.
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.
47.
Cortina-BorjaM, SmithAD, CombarrosO, LehmannDJ (2009) The synergy factor: A statistic to measure interactions in complex diseases. BMC Res Notes2, 105.
48.
HolmesC, BallardC, LehmannD, David SmithA, BeaumontH, DayIN, Nadeem KhanM, LovestoneS, McCulleyM, MorrisCM, MunozDG, O’BrienK, RussC, Del SerT, WardenD (2005) Rate of progression of cognitive decline in Alzheimer’s disease: Effect of butyrylcholinesterase K gene variation. J Neurol Neurosurg Psychiatry76, 640–643.
49.
PodolyE, ShalevDE, Shenhar-TsarfatyS, BennettER, Ben AssayagE, WilgusH, LivnahO, SoreqH (2009) The butyrylcholinesterase K variant confers structurally derived risks for Alzheimer pathology. J Biol Chem284, 17170–17179.
50.
GuillozetAL, SmileyJF, MashDC, MesulamMM (1997) Butyrylcholinesterase in the life cycle of amyloid plaques. Ann Neurol42, 909–918.
51.
DiamantS, PodolyE, FriedlerA, LigumskyH, LivnahO, SoreqH (2006) Butyrylcholinesterase attenuates amyloid fibril formation in vitro. Proc Natl Acad Sci U S A103, 8628–8633.
