Prion protein gene M129 allele is a risk factor for Alzheimer’s disease

Prion protein gene polymorphism M129V represents a known risk factor for Creutzfeldt-Jakob disease. Recently, the meta-analysis revealed that homozygosity at codon 129 is connected with increased risk of Alzheimer’s disease (AD). To determine whether

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  J Neural Transm (2006) 113: 1747–1751DOI 10.1007/s00702-006-0540-4 Prion protein gene M129 allele is a risk factor for Alzheimer’s disease M. Gacia 1 ; 2 , K. Safranow 3 , M. Styczyn´ska 1 , K. Jakubowska 3 , B. Peplon´ska 1 ,M. Chodakowska-Z˙ebrowska 4 , I. Przekop 1 , A. Slowik 5 , E. Golan´ska 6 , K. Hulas-Bigoszewska 6 ,D. Chlubek 3 , D. Religa 1 ; 7 , C. Z˙ekanowski 1 ; 2 , M. Barcikowska 1 ; 4 1 Department of Neurodegenerative Disorders, Medical Research Center, Polish Academy of Sciences, Warszawa, Poland 2 Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warszawa, Poland 3 Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland 4 Department of Neurology, MSWiA Hospital, Warszawa, Poland 5 Department of Neurology, Jagiellonian University, Krakow, Poland 6 Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland 7 Department of Neurotec, Section of Experimental Geriatrics, Karolinska Institutet, Stockholm, SwedenReceived: April 12, 2006  =  Accepted: June 18, 2006  =  Published online: August 8, 2006 # Springer-Verlag 2006 Summary  Prion protein gene polymorphism M129V represents a knownrisk factor for Creutzfeldt-Jakob disease. Recently, the meta-analysis re-vealed that homozygosity at codon 129 is connected with increased risk of Alzheimer’s disease (AD). To determine whether M129V polymorphismis a risk factor for AD we analyzed a group of early-onset, and late-onsetPolish AD patients. We observed that in LOAD patients there is a sta-tistically significant increase of MM (  p ¼ 0.0028) and decrease of MV(  p ¼ 0.0006) genotypefrequency,ascomparedtocontrols.Whenbothgroupswere stratified according to  APOE4  status, increase of MM and decreaseof MV genotype frequency were significant in the LOAD subgroup withno  APOE4  (  p ¼ 0.017, and  p ¼ 0.018, respectively). In the subgroup with  APOE4 allele, onlyMVgenotypefrequencywas significantlylower,ascom-pared to controls (  p ¼ 0.035). However, no interaction was found between  APOE4  status and M129V polymorphism. We conclude that MM geno-type increases LOAD risk in Polish population independently from the  APOE4  status. Keywords:  Prion protein gene, Alzheimer’s disease,  PRNP  polymor-phisms, M129V, promoter, APOE, risk factor Introduction The prion protein gene ( PRNP ) polymorphism at the codon129 (M129V) is a susceptibility factor for Creutzfeldt-JakobDisease (CJD) (Palmer etal.,1991).Homozygotes for methi-onine (M) and to some extent for valine (V) are associatedwith an increased risk for sporadic and variant CJD(Collinge, 1999). There are reports suggesting that homo-zygosity for codon 129 (M or V allele) is connected withearly-onset Alzheimer’s disease (EOAD), but not late-onsetAlzheimer’s disease (LOAD) (Combarros et al., 2000;Dermaut et al., 2003). In the German population MM geno-type confers EOAD risk, with decreasing age of onset, andindependently from the  APOE4  status (Riemenschneideret al., 2004). Results obtained for Italian population suggesta small, but significant acceleration in cognitive decline inLOADpatients homozygousfor valine (Casadeietal.,2001).Additionally, a link between V129V genotype and cognitiveimpairment in the elderly, as well as in young Down’s syn-drome patients was demonstrated (Berr et al., 1998; Del Boet al., 2003). Also epidemiological studies indicate familialclustering of sporadic CJD and Alzheimer’s disease (AD)(van Duijn et al., 1998).Codon 129 polymorphism is not a unique susceptibilityfactor for CJD, as 39% of population is homozygous for me-thionine, and 11% for valine (Alperovitch et al., 1999). It isspeculated that susceptibility determinants could be asso-ciated with 5 0 untranslated, regulatory regions (5 0 UTR) of the  PRNP  gene (McCormack et al., 2002). The  PRNP  genelocated on chromosome 20 consists of two exons: a shortuntranslated exon, and a larger one, enclosing open readingframe for the prion protein. Deletion analysis revealed the Correspondence: Cezary Z˙ekanowski PhD, Department of Neurodegenera-tive Disorders, Medical Research Center, Polish Academy of Sciences,02-106 Warszawa, ul. Pawinskiego 5, Polande-mail:  presence of regulatory regions upstream of the first exonand in the first intron.In the last years there has been an increasing interestin the role of M129V polymorphism in age-related neuro-degenerative processes and pathologies, like AD. Recentlyan association between M129M genotype and otherneurodegenerative condition, tremor-dominant idiopathicParkinson’s disease has been proposed (Gossrau et al.,2006). We decided to investigate a putative link between PRNP  gene polymorphism and AD, screening the entirecoding region and a part of 5 0 UTR of   PRNP  in a groupof Polish patients with late-onset AD, early-onset AD, andin a control group. Patients and methods  Materials and methods The study group consisted of 166 unrelated AD patients, which included 53patients with clinically diagnosed EOAD (mean age of onset: 52.4  9.2years; 64.2% women) and 113 LOAD patients (mean age of onset:71.6  4.2 years; 64.6% women). The control group consisted of 194 non-demented subjects (mean age 73.2  5.5; 75.3% women). Both AD andcontrols were Caucasians (Table 1).The patients were diagnosed in the Outpatient Clinic of the Departmentof Neurodegenerative Disorders of Medical Research Center of the PolishAcademy of Sciences in Warsaw. They were examined by a neurologist,neuropsychologist (evaluation in MMSE, Global Deterioration Scale,Alzheimer’s Disease Assessment Scale-cognitive subscale [ADAS-cog]and Blessed Dementia Rating Scale), psychiatrist and obtained a CT scanof the brain (Styczynska et al., 2003). The diagnosis of probable AD wasconfirmed using a standardized protocol according to the National Instituteof Neurological and Communicative Disorders and Stroke – Alzheimer’sDisease and Related Disorders Association (NINCDS-ADRDA) criteriaof AD. Early-onset AD was diagnosed if the age of onset was less than65 years.The control subjects were volunteers over 65 years old recruited from theDepartment of Internal and Surgery Medicine and The Third Age Univer-sity. All subjects were screened on cognitive function and none of thempresented symptoms of dementia or any movement disorders (The meanvalue of the MMSE was 29   1 for the control group). PRNP  coding sequence was amplified in two overlapping fragmentsand screened using SSCA (single strand conformation analysis) withMDE (Mutation Detection Enhancement) gel (BMA) in room tempera-ture, as described previously (Petraroli et al., 2000; Zekanowski et al.,2003). The 5 0 UTR region of   PRNP  screening (positions:   290,  þ 120)was performed using dHPLC (denaturing high-performance liquid chroma-tography) as described previously (Kurzawski et al., 2002; Zekanowskiet al., 2005). DNA samples with aberrant SSCA patterns or chromato-graphic elution profiles were sequenced using fluorescent, direct sequencingmethod.Allele and genotype distributions in the studied groups and in the controlswere compared using Fisher exact test (for 2  2 tables) or the chi-squaretest. Statistical analysis of genotype distribution, test for deviation of Hardy-Weinberg equilibrium and two-point test for association, was performedusing tests according to Sasieni (Sasieni, 1997). Univariate and multivariatelogistic regression was used to study the associations between genotypesand the presence of AD. The calculations were performed using Statistica6.0 software and online resource at the Institute for Human Genetics,Munich, Germany (http: == and Vassar College, USA (http: == = lowry = VassarStats.html).The study was approved by the Ethics Committee of the MSWiA Hospi-tal. A consent was obtained from all participants or their relatives after thestudy had been fully explained. Results SSCA screening of the entire coding PRNP region revealedin the studied group five common polymorphisms A117A(c.351A- > G),G124G(c.372C- > G),M129V(c.385A- > G)and octapeptide repeat region deletions R2, and R3. DelR2and delR3 were observed only in heterozygous state. DelR2was observed on V allele only, whereas delR3 was con-nected with M allele exclusively. There are no significantdifferences in the distribution of the four of the identifiedalleles in LOAD, or EOAD as compared to controls: A117A(0.9,3,and4%respectively),G124G(0,0,and0.5%),delR2(0.9, 2, and 0%), and del R3 (0, 1, and 0%).dHPLC analysis of the 5 0 regulatory region upstream thefirst exon of the  PRNP  gene revealed a common polymor-phism   102c = g. In one control subject a novel polymor-phism  þ 113c = a in one allele was identified.There is a slight deviation from Hardy-Weinberg equi-librium for M129V polymorphism in the control group(  p ¼ 0.042) and LOAD group (  p ¼ 0.059). M129V hetero-zygotes were over-represented in the controls and under-represented in LOAD group.When M129V genotype frequencies were compared bythe chi-square test, significant differences between EOAD,LOAD and controls were found (  p ¼ 0.0092).In LOAD patients there is statistically significant increaseofMManddecreaseofMVgenotypefrequency(  p ¼ 0.0028,and 0.0006, respectively) in relation to the controls (Table 2).Risk estimation for MV compared to MM, shows that MVgenotype is protective against LOAD. This effect was alsoseen for carriers of V allele (MV þ VV) compared to MMhomozygotes. No significant difference in the LOAD risk of VV homozygotes versus MM homozygotes or versusMV heterozygotes was observed (Table 3). Table 1.  General characteristics of the LOAD, EOAD patients and controls Group LOAD EOAD ControlsNo. of subjects 113 53 194Mean age at onset(LOAD, EOAD) orexamination (controls)71.6  4.2years52.4  9.2years73.2  5.5yearsNumber of females (%) 73 (64.6)  34 (64.2)  146 (75.3)Familial AD (%) n.a. 29 (54.7) n.a.AD causative mutationsidentified (%)n.a. 6 (11.3) n.a. n.a.  Not applicable;    p ¼ 0.051;    p ¼ 0.12 in relation to controls. 1748  M. Gacia et al.  There is a slight difference in the frequency of M129Valleles inLOAD,ascomparedtocontrols(  p ¼ 0.050).Logis-tic regression calculation for V and M alleles indicated thatpresence of Vallele could slightly decrease the LOAD risk.In EOAD patients M129V genotype frequencies are notsignificantly different from controls (  p ¼ 0.14, chi-squaretest). Only MV heterozygotes are slightly less frequent, butwithout statistical significance (  p ¼ 0.062). No differencesbetween EOAD patients without a family history (defined asat least one family member with presenile dementia,  n ¼ 24)or without a causative mutation identified ( n ¼ 47), andall EOAD patients or controls were found (  p ¼ 0.69 and  p ¼ 0.075 respectively, for the EOAD subgroup withoutmutation). M129V genotype frequencies were not differentin EOAD and LOAD patients (  p ¼ 0.72, chi-square test).To test possible interaction between M129V and  APOE  polymorphism, we stratified LOAD patients and controlsfor the presence of an  APOE4  allele (Table 4). The M129Vgenotype distribution in  APOE4 þ and  APOE4  subgroupsmet Hardy-Weinberg expectations for LOAD (  p ¼ 0.14 and  p ¼ 0.26, respectively) and controls (  p ¼ 0.20 and  p ¼ 0.15,respectively).In the LOAD group the statistically significant increase of MM and decrease of MV genotypes frequency in relation tothe controls was observed only for subgroup without  APOE4 allele(  p ¼ 0.017and  p ¼ 0.018,respectively).Lesssignificantdecrease of MV genotype frequency was observed for thesubgroup with  APOE4  allele (  p ¼ 0.035). Risk estimationfor MV compared to MM in the  APOE4   subgroup shows Table 2.  PRNP M129V and    102c = g allele and genotype frequencies in LOAD and EOAD patients and controls M129V   102c = gGroup Controls LOAD EOAD Group Controls LOAD EOAD n  %  n  %  n  %  n  %  n  %  n  %Allele AlleleM 249 64.2 163 72.1 a 72 67.9 C 346 89.2 201 88.9 92 86.8V 139 35.8 63 27.9 34 32.1 G 42 10.8 25 11.1 14 13.2Total 388 100 226 100 106 100 Total 388 100 226 100 106 100Genotype GenotypeMM 73 37.6 63 55.7 b 26 49.1 CC 152 78.4 88 77.9 39 73.6MV 103 53.1 37 32.7 c 20 37.7 CG 42 21.6 25 22.1 14 26.4VV 18 9.3 13 11.5 7 13.2 GG 0 0 0 0 0 0Total 194 100 113 100 53 100 Total 194 100 113 100 53 100 a Higher frequency than controls,  p ¼ 0.050;  b higher frequency than controls,  p ¼ 0.0028;  c lower frequency than controls,  p ¼ 0.0006.Table3.  OddsratiosforPRNPM129Vgenotypesandallelesasriskfactorsof LOAD in relation to the controls Compared M129Vgenotypes or allelesOR 95% C.I.  p MV vs MM 0.416 0.251–0.689 0.00059MV þ VV vs MM 0.479 0.299–0.767 0.0020VV vs MM 0.837 0.380–1.842 0.66VV vs MV 2.011 0.898–4.503 0.086Allele V vs M 0.692 0.484–0.990 0.043Table 4.  PRNP M129V genotypes stratified with APOE4 status Group APOE4statusM129V TotalMM MV VV n  %  n  %  n  %  n Controls APOE4 þ  19 39.6 26 54.2 3 6.2 48APOE4   54 37.0 77 52.7 15 10.3 146LOAD APOE4 þ  36 54.6 22 33.3 c 8 12.1 66APOE4   27 57.4 a 15 32.0 b 5 10.6 47 a Higher frequency than APOE4  controls,  p ¼ 0.017;  b lower frequencythan APOE4  controls,  p ¼ 0.018;  c lower frequency than APOE4 þ con-trols,  p ¼ 0.035.Table5.  OddsratiosforPRNPM129Vgenotypesandallelesasriskfactorsof LOAD in relation to the controls for the subgroups stratified according to APOE4 status APOE4statusCompared M129Vgenotypes or allelesOR 95% C.I.  p APOE4 þ  MV vs MM 0.447 0.202–0.988 0.045MV þ VV vs MM 0.546 0.257–1.161 0.11Allele V vs M 0.809 0.458–1.426 0.46APOE4   MV vs MM 0.390 0.190–0.801 0.0091MV þ VV vs MM 0.435 0.223–0.849 0.013Allele V vs M 0.626 0.374–1.049 0.074Prion protein gene M129 allele is a risk factor for Alzheimer’s disease  1749  that MV is a protective genotype (Table 5). Protective effectwas also seen when MV þ VV genotypes were compared toMM genotype. In  APOE4 þ  group there is only a slightlylower risk for MV compared to MM genotype. However,the lack of highly significant differences for  APOE4 þ  sub-groupcouldbecausedbylowernumberof   APOE4 þ controls.When multivariate logistic regression was used to studythe combined influence of   APOE   and M129V polymor-phisms on LOAD risk, no significant interaction betweenthe polymorphisms was found (  p ¼ 0.66). They affect LOADrisk independently: the presence of   APOE4 þ  is a risk fac-tor [OR 4.264, 95% C.I. ¼ 2.570–7.076,  p < 0.000001] andthe presence of V allele (MV þ VV) is a protective factor[OR 0.480, 95% C.I. ¼ 0.291–0.794,  p ¼ 0.0041].No statistically significant differences were found be-tween both AD groups and controls for the promoter regionpolymorphism distribution. The genotype frequencies werein Hardy-Weinberg equilibrium (  p ¼ 0.136 for controls,  p ¼ 0.35 for LOAD, and  p ¼ 0.58 for EOAD). The commonpromoter polymorphism,   102c = g, is not in linkage dis-equilibrium with any of the polymorphisms identified inthe coding region. Discussion Previous reports concerning M129V polymorphism suggestanassociationbetweenVorMhomozygosityandtheriskforEOAD, independent of the  APOE   genotype. Other studiesshow a link between cognitive decline of AD patients andat least one Vallele. We observed a statistically significantassociation between M129V genotypes and LOAD. WhenLOAD group was stratified according to the  APOE4  status,this association was highly significant in the subgroup withno  APOE4  allele, but the significance of the association inthesubgroupwith  APOE4 wasborderline.Similareffectwasseen in the German EOAD population (Riemenschneideret al., 2004). However, our sample size was limited and theresultsshouldbeinterpretedwithcaution.Multivariateanal-ysis did not reveal significant interaction between M129Vand the  APOE4  status. There was no statistically signifi-cant difference in the age at LOAD onset between M129Vpolymorphism genotypes. We also observed no statisticallysignificant association of M129V polymorphism and EOAD.There was also no association between  PRNP  promoterpolymorphism and EOAD, or LOAD.A slight deviation from Hardy-Weinberg equilibriumresulting from an over-representation of M129V hetero-zygotes in the control group could be due to the CJD pro-tective effect exerted by the M129V polymorphism (Meadet al., 2003). It was proposed that a subtly modified prionproteins act as a decoy by binding pathological PrP andpreventing its further replication (Petchanikow et al., 2001;Aguzzietal.,2004).Thiseffectisstrongenough tobea basisfor a selective evolutionary pressure, influencing the M129Vfrequency as a result. Alternatively, the deviation could beexplained as a result of the control group selection criteria,including no cognitive impairment. As reported previouslyV129V homozygotes are associated with reduced cognitiveabilities in the elderly (Berr et al., 1998). However it isunlikely, that population admixture could explain the de-viation, asthere are no great differences inage,and few othergeneticmarkersbetweencontrolsorLOADpatientsincludedin the study (data not shown). Additionally, a statisticallysignificant increase of MM and decrease of MV genotypefrequency were also observed in a previously publishedstudy of another Polish AD cohort (Golanska et al., 2004).It remains still unclear how  PRNP  polymorphic variantscould contribute to the AD pathology. It has been recentlyproposed that M129 protein oligomerizes more rapidlythan V129 one, which explains the higher susceptibilityof homozygotic M129M individuals to sporadic and variantCJD (Tahiri-Alaoui et al., 2004). On the other hand, V129protein prevents transmission of BSE-like prions on sub-passage, and was reported to result in subclinical and atyp-ical vCJD infection (Wadsworth et al., 2004).PrP deposits are not frequently found in AD patients,however PrP is localized to the senile plaques (Ferrer et al.,2001). Recently, it has been proposed that prion protein pro-motes plaque formation, presumably increasing amyloid- b aggregation under pathological conditions (Schwarze-Eickeret al., 2005). A complementary mechanism of   PRNP  in-fluence on AD could be connected with the role of PrP inphysiological neuronal functioning, like protection againstoxidative stress and apoptosis (Kim et al., 2004; Sakudoet al., 2005). Our results support recent meta-analysis, show-ing that MM genotype and M allele represent a risk factorfor AD (Del Bo et al., 2005). 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