SERUM CLUSTERIN LEVELS AND THE RISK OF SERUM CLUSTERIN LEVELS AND THE RISK OF ALZHEIMER’S DISEASE IN CHINESE OLDER ALZHEIMER’S DISEASE IN CHINESE OLDER ADULTS WITH AMNESTIC MILD COGNITIVE ADULTS WITH AMNESTIC MILD COGNITIVE

IMPAIRMENTIMPAIRMENT A 3-YEAR PROSPECTIVE COHORT STUDYA 3-YEAR PROSPECTIVE COHORT STUDY

Prof. Leung-Wing ChuProf. Leung-Wing ChuMD, FRCP MD, FRCP (Lond., Edin. & Glas.)(Lond., Edin. & Glas.), FHKCP, FHKAM, FHKCP, FHKAM (Medicine) (Medicine)

Honorary Clinical Professor, and Honorary Clinical Professor, and

Associate Director, Centre on Ageing, andAssociate Director, Centre on Ageing, andChairman, HKU AD Research Network, SRT Healthy Chairman, HKU AD Research Network, SRT Healthy

Ageing,Ageing,The University of Hong KongThe University of Hong Kong

Chief, Division of Geriatrics, Queen Mary HospitalChief, Division of Geriatrics, Queen Mary Hospital

(Chu LW, Xu A, Zhou L, Wang Y, Chan SY, Ha CT, Yik PY, Chen LH, Song YQ, Lam KS)

OC 110

Conflict of InterestConflict of Interest

All authorsAll authors– Chu LW, Yik PY, Kwan F, Chan CSY , Chu LW, Yik PY, Kwan F, Chan CSY ,

Song YQSong YQ Has no real or apparent conflicts Has no real or apparent conflicts

of interest to reportof interest to report

BackgroundBackground

Genetic studies in late-onset Genetic studies in late-onset Alzheimer’s disease (LOAD) Alzheimer’s disease (LOAD) apart apart from APOE,from APOE,

recent Genome-Wide Association (GWA) recent Genome-Wide Association (GWA) studiesstudies– an association between LOAD and a single an association between LOAD and a single

nucloetide polymorphism of the CLU nucloetide polymorphism of the CLU (clusterin) gene(clusterin) gene1

– In Chinese, a similar association btw. AD & In Chinese, a similar association btw. AD & CLU found in our AD studyCLU found in our AD study

1Harold et al, Nat Genet 2009; Lambert et al, Nat Genet 2009; Seshadri et al, Harold et al, Nat Genet 2009; Lambert et al, Nat Genet 2009; Seshadri et al, JAMA, 2010JAMA, 2010

2 Chen LH & Chu LW et al, Neurobiol Aging 2012Chen LH & Chu LW et al, Neurobiol Aging 2012

BackgroundBackgroundClusterinClusterin

The CLU gene encodes the protein The CLU gene encodes the protein clusterin,clusterin,

Clusterin Clusterin – also known as apolipoprotein J, isalso known as apolipoprotein J, is

a disulfide-linked heterodimeric glycoproteina disulfide-linked heterodimeric glycoprotein widely ewidely expressed in tissues and xpressed in tissues and present in blood and all body fluidpresent in blood and all body fluid

In AD, clusterin bind to beta-amyloid and In AD, clusterin bind to beta-amyloid and enhances its clearance; reduces its enhances its clearance; reduces its depositsdeposits

Jenne et al, 1992; Poulakou et al, 2008

BackgroundBackgroundClusterin and ADClusterin and AD

In AD, clusterin may be related to its In AD, clusterin may be related to its pathogenesis pathogenesis

– Postmortem study: Clusterin found in cortex of the Postmortem study: Clusterin found in cortex of the frontal lobe and hippocampusfrontal lobe and hippocampus11

– In a csf study: clusterin increased in ADIn a csf study: clusterin increased in AD22

– Plasma clusterin associated w. brain atrophy Plasma clusterin associated w. brain atrophy (entorhinal cortex)(entorhinal cortex)33

Clinical studies in Caucasian populationsClinical studies in Caucasian populations Plasma or serum clusterin associated w. Plasma or serum clusterin associated w.

baseline severity of ADbaseline severity of AD4,54,5, but, but– not incidence of AD in not incidence of AD in non-demented oldernon-demented older adults adults5,65,6

1Lidstrom, 1998; 2Sihlbom, 2008; 3Thambisetty, 2010; 4Thambisetty, 2010; 5Schrijvers, 2011; 6Ijsselstijn, 2011

BackgroundBackgroundClusterinClusterin

So far, no published data on mild So far, no published data on mild cognitive impairment cognitive impairment – the plasma or serum clusterin level the plasma or serum clusterin level

is is

a predictor of the progression of a predictor of the progression of amnestic mild cognitive impairment amnestic mild cognitive impairment (aMCI) to dementia and AD(aMCI) to dementia and AD

Objectives of the studyObjectives of the study

The objective of the present prospective The objective of the present prospective study was study was

to investigate the serum clusterin levels to investigate the serum clusterin levels as a predictor of progression from as a predictor of progression from amnestic mild cognitive impairment amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD)(aMCI) to Alzheimer’s disease (AD)

in a 3-year cohort study among Chinese in a 3-year cohort study among Chinese older adults (Southern Chinese)older adults (Southern Chinese)

MethodsMethods

Design:Design: A 3-year cohort studyA 3-year cohort study Setting:Setting: Ambulatory setting Ambulatory setting Subjects:Subjects: Chinese older adults, aged 55 to 93 Chinese older adults, aged 55 to 93

years old, with aMCI criteria modified from years old, with aMCI criteria modified from the Petersen’s criteria. the Petersen’s criteria.

Measurements:Measurements: – Baseline socio-demographic, Baseline socio-demographic, – co-morbid diseases, co-morbid diseases, – cognitive tests including MMSE, ADAS-cog cognitive tests including MMSE, ADAS-cog – neuropsychological tests, and neuropsychological tests, and – apolipoprotein E genotype (APOE) apolipoprotein E genotype (APOE) – Serum clusterin level (by ELISA)Serum clusterin level (by ELISA)

aMCI criteria- Modified from Petersen et al (1999) the presence of memory

complaint (corroborated by an informant),

impaired memory function for age and education (< 1SD verbal memory recall test)*

intact activities of daily living and no dementia (by DSM-IV criteria) *Note: 1SD better Sens. & spec. than 1.5 SD in predicting dementia (Busse A et

al, 2006)(delayed word recall score < 1 SD below normal age-and education-matched

mean for Chinese older adults)

MethodsMethods

Follow-up: Follow-up: All subjects were followed All subjects were followed up for three years up for three years

Outcome: Outcome: – Dementia by DSM-IV criteria & Dementia by DSM-IV criteria & – AD was diagnosed by the NINCDS-AD was diagnosed by the NINCDS-

ADRDA criteria for ADRDA criteria for probable ADprobable AD

ResultsResults

N= 139 Chinese older adults w. N= 139 Chinese older adults w. aMCIaMCI

Mean age =75.4 (SD 6.6) years Mean age =75.4 (SD 6.6) years Females = 75.5%Females = 75.5% Mean MMSE score = 23.4 (SD 3.9)Mean MMSE score = 23.4 (SD 3.9) Mean ADAS-cog score = 14.29 Mean ADAS-cog score = 14.29

(SD 5.58)(SD 5.58)

ResultsResults

3-year follow-up, 25.2% (n=35)* 3-year follow-up, 25.2% (n=35)* developed dementia developed dementia (by DSM-IV (by DSM-IV criteria)criteria)

– All having Alzheimer’s disease (by All having Alzheimer’s disease (by NINCDS-ADRDA criteria)NINCDS-ADRDA criteria)

*versus 0.6% (n= 359) over 3-year follow-up in another cohort of cognitively normal Chinese older adults in HK

Bivariate analyses of Bivariate analyses of predictors of aMCI predictors of aMCI progression to ADprogression to AD(Cognitive, neuropsychological tests) (Cognitive, neuropsychological tests)

PredictorPredictor

at baseline (Mean ± SD)at baseline (Mean ± SD)Progress to ADProgress to AD

(n = 35) Stable Stable

(n = 104) p

MMSE MMSE 22.0 ± 4.0 22.0 ± 4.0 23.8 ± 3.8 23.8 ± 3.8 0.0150.015

ADAS-cog ADAS-cog 16.8 ± 6.0 16.8 ± 6.0 13.5 ± 5.2 13.5 ± 5.2 0.0020.002

DWRT,10-word DWRT,10-word 1.22 ± 1.19 1.22 ± 1.19 2.74 ± 2.74 ± 1.70 1.70

<0.00<0.0011

Selective Reminding Test Selective Reminding Test

30-min recall 30-min recall 0.97 ± 2.060.97 ± 2.06 3.46 ± 3.46 ±

2.852.85<0.001<0.001

Visual reproduction-Visual reproduction-delayed recalldelayed recall

1.26 ± 2.68 1.26 ± 2.68 7.98 ± 7.98 ± 8.25 8.25

<0.001<0.001

Logical memory-delayed Logical memory-delayed recallrecall

1.34 ± 3.04 1.34 ± 3.04 5.70 ± 5.70 ± 5.76 5.76

<0.001<0.001

(Most cognitive, neuropsychological tests p<0.05)(Most cognitive, neuropsychological tests p<0.05)

Results: Bivariate analyses Results: Bivariate analyses

Predictor Predictor at baselineat baseline

Progress Progress to ADto AD (n = 35)

Stable Stable (n = 104)

p

Gender (F),% Gender (F),% 71.4 76.9 0.510.51

Age, yrs. Age, yrs. 77.7 ± 5.577.7 ± 5.5 74.7 ± 6.7 74.7 ± 6.7 0.0180.018

Education level, yrsEducation level, yrs 2.66 ± 4.472.66 ± 4.47 2.50 ± 4.00 2.50 ± 4.00 0.850.85

APOE4+ (versus 4-) , APOE4+ (versus 4-) , % %

20.620.6 14.414.4 0.390.39

Serum clusterin level Serum clusterin level , ug/ml , ug/ml

32.4 ± 11.432.4 ± 11.4 35.0 ± 15.035.0 ± 15.0 0.340.34

Note: Mean ± SD, or %; All comorbid diseases are NS

Multivariate logistic Multivariate logistic regression analysesregression analyses

Note: adjusted for gender, age and apolipoprotein E genotype; Age but not apolipoprotein E genotype also increased the risk

Predictor of Predictor of progression to progression to ADAD

Relative Relative Risk Risk (RR) (RR)

95% CI 95% CI

RRRRp

Gender ( F vs. M)Gender ( F vs. M) 0.72 0.29, 1.76 0.460.46

Age, yrs. Age, yrs. 1.091.09 1.02, 1.161.02, 1.16 0.0150.015

APOE4+ (versus 4-) APOE4+ (versus 4-) 1.711.71 0.61, 4.80.61, 4.8 0.310.31

Serum clusterin Serum clusterin level , ug/ml level , ug/ml

0.990.99 0.96, 1.030.96, 1.03 0.720.72

DiscussionDiscussion

There is limited published data on the There is limited published data on the clinical relevance of clusterin to the clinical relevance of clusterin to the risk of AD development*risk of AD development*

Is the blood clusterin level a biomarker Is the blood clusterin level a biomarker to predict AD ?to predict AD ?

*despite previous positive studies of the genetic association of *despite previous positive studies of the genetic association of LOAD with CLU gene ( LOAD with CLU gene ( Harold et al, Nat Genet 2009; Lambert et al, Nat Genet 2009; Seshadri et al, JAMA, 2010; Chen LH & Chu

LW et al, Neurobiol Aging 2012)

DiscussionDiscussion

Our study is one of the three studies in Our study is one of the three studies in the investigation of blood clusterin the investigation of blood clusterin levels & the risk of AD developmentlevels & the risk of AD development

The aMCI popultaion is an at risk group The aMCI popultaion is an at risk group for future AD developmentfor future AD development

In the present 3-year cohort studies In the present 3-year cohort studies among Chinese older adults with aMCI, among Chinese older adults with aMCI, – the serum clusterin level did not predict the serum clusterin level did not predict

the progression of amnestic mild cognitive the progression of amnestic mild cognitive impairment (aMCI) to dementia and ADimpairment (aMCI) to dementia and AD

DiscussionDiscussion

Together with 2 previous Together with 2 previous Caucasian studies in non-Caucasian studies in non-demented older adults*demented older adults*

Both are –ve studies reported in Both are –ve studies reported in Caucasian subjects, showingCaucasian subjects, showing

in non-demented older adultsin non-demented older adults Plasma clusterin levels – no effect Plasma clusterin levels – no effect

on the incidence of ADon the incidence of AD*Rotterdam Study (Schrijvers et al, 2011) *Rotterdam Study (Schrijvers et al, 2011)

Rotterdam Scan Study (Ijsselstijn et al, 2011), Rotterdam Scan Study (Ijsselstijn et al, 2011),

DiscussionDiscussion

Rotterdam Study (Schrijvers et al, JAMA, 2011)

Rotterdam Scan Study (Ijsselstijn et al, J Proteome Res, 2011)Nested case-control

Non-demented older adults

Subcohort 926 Case=43; control=43

Age, years 72.8(7.3) 60-90

FU, year; mean(SD) 7.2 (2.3) 4.2 (2.6)

Outcome =AD 5.6% (n=52) (dementia n=61)

4% (n=43)

Serum clusterin level, mean(SD)

-Not associated with incident AD*

No differenceAD =62.7 (13.9) mg/LControl= 61.0 (11.4) mg/L

*Associated w prevalent AD

ConclusionConclusion

In Chinese older adults with aMCI, In Chinese older adults with aMCI,

the serum clusterin level is not a the serum clusterin level is not a predictor of progression to AD. predictor of progression to AD.

Together with 2 previous Caucasian Together with 2 previous Caucasian studies in non-demented older studies in non-demented older adults*, we conclude thatadults*, we conclude that– the blood clusterin level is not a the blood clusterin level is not a

biomarkers of AD for both MCI and biomarkers of AD for both MCI and cognitively normal older adults. cognitively normal older adults.

AcknowledgementAcknowledgement

Co-investigators: Co-investigators: – Xu A, Zhou L, Wang Y, Chen LH, Song YQ, Lam KS Xu A, Zhou L, Wang Y, Chen LH, Song YQ, Lam KS

Research staff:Research staff:– Chan SY, Ha CT, Yik PY Chan SY, Ha CT, Yik PY

Research grant support:Research grant support:– SK Yee Medical Foundation, Hong KongSK Yee Medical Foundation, Hong Kong– SRT Healthy Aging, the University of Hong SRT Healthy Aging, the University of Hong

Kong: Kong: Alzheimer’s Disease Research NetworkAlzheimer’s Disease Research Network

Thank Thank youyou

Bivariate analyses of Bivariate analyses of predictors of aMCI predictors of aMCI progression to ADprogression to AD (Co-morbid ds., genetic) (Co-morbid ds., genetic)

PredictorPredictorat baselineat baseline

Progress to ADProgress to AD (n = 35)

Stable Stable (n =

104)

p

HT, % HT, % 48.948.9 52.952.9 0.660.66

DM, % DM, % 22.922.9 20.220.2 0.740.74

Depression Depression

(treated), % (treated), % 5.75.7 6.76.7 0.830.83

Hyperlipidemia , % Hyperlipidemia , % 74.374.3 68.368.3 0.500.50

Chronic Obstructive Chronic Obstructive P. dsP. ds

2.92.9 1.01.0 0.450.45

Osteoporosis, % Osteoporosis, % 17.117.1 8.78.7 0.180.18

APOE4+ (versus 4-) , APOE4+ (versus 4-) , % %

20.620.6 14.414.4 0.390.39