SERUM CLUSTERIN LEVELS AND THE RISK OF
ALZHEIMER’S DISEASE IN CHINESE OLDER
ADULTS WITH AMNESTIC MILD COGNITIVE
IMPAIRMENT
A 3-YEAR PROSPECTIVE COHORT STUDY
(Chu LW, Xu A, Zhou L, Wang Y, Chan SY, Ha CT, Yik PY, Chen LH, Song YQ, Lam KS)
MD, FRCP
Prof. Leung-Wing Chu
(Lond., Edin. & Glas.),
FHKCP, FHKAM (Medicine)
Honorary Clinical Professor, and
Associate Director, Centre on Ageing, and
Chairman, HKU AD Research Network, SRT Healthy Ageing,
The University of Hong Kong
Chief, Division of Geriatrics, Queen Mary Hospital
OC 110
Conflict of Interest

All authors
– Chu LW, Yik PY, Kwan F, Chan CSY ,
Song YQ

Has no real or apparent conflicts of
interest to report
Background

Genetic studies in late-onset Alzheimer’s
disease (LOAD)  apart from APOE,
recent Genome-Wide Association (GWA)
studies
– an association between LOAD and a single
nucloetide polymorphism of the CLU
(clusterin) gene1
– In Chinese, a similar association btw. AD &
CLU found in our AD study
1Harold
et al, Nat Genet 2009; Lambert et al, Nat Genet 2009; Seshadri et al, JAMA, 2010
2 Chen LH & Chu LW et al, Neurobiol Aging 2012
Background
Clusterin


The CLU gene encodes the protein clusterin,
Clusterin
– also known as apolipoprotein J, is
a disulfide-linked heterodimeric glycoprotein
 widely expressed in tissues and



present in blood and all body fluid
In AD, clusterin bind to beta-amyloid and
enhances its clearance; reduces its deposits
Jenne et al, 1992; Poulakou et al, 2008
Background
Clusterin and AD

In AD, clusterin may be related to its
pathogenesis
– Postmortem study: Clusterin found in cortex of the
frontal lobe and hippocampus1
– In a csf study: clusterin increased in AD2
– Plasma clusterin associated w. brain atrophy (entorhinal
cortex)3

Clinical studies in Caucasian populations

Plasma or serum clusterin associated w. baseline
severity of AD4,5, but
– not incidence of AD in non-demented older adults5,6
1Lidstrom,
1998; 2Sihlbom, 2008; 3Thambisetty, 2010; 4Thambisetty, 2010; 5Schrijvers, 2011; 6Ijsselstijn, 2011
Background
Clusterin

So far, no published data on mild
cognitive impairment
– the plasma or serum clusterin level is
a predictor of the progression of
amnestic mild cognitive impairment
(aMCI) to dementia and AD
Objectives of the study
The objective of the present prospective study
was
 to investigate the serum clusterin levels as a
predictor of progression from amnestic mild
cognitive impairment (aMCI) to Alzheimer’s
disease (AD)
in a 3-year cohort study among Chinese older
adults (Southern Chinese)
Methods

Design: A 3-year cohort study
Setting: Ambulatory setting
Subjects: Chinese older adults, aged 55 to 93 years

Measurements:


old, with aMCI criteria modified from the Petersen’s
criteria.
–
–
–
–
–
–
Baseline socio-demographic,
co-morbid diseases,
cognitive tests including MMSE, ADAS-cog
neuropsychological tests, and
apolipoprotein E genotype (APOE)
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)
Methods

Follow-up: All subjects were followed up for

Outcome:
three years
– Dementia by DSM-IV criteria &
– AD was diagnosed by the NINCDSADRDA criteria for probable AD
Results





N= 139 Chinese older adults w. aMCI
Mean age =75.4 (SD 6.6) years
Females = 75.5%
Mean MMSE score = 23.4 (SD 3.9)
Mean ADAS-cog score = 14.29 (SD
5.58)
Results

3-year follow-up, 25.2% (n=35)*
developed dementia (by DSM-IV criteria)
– All having Alzheimer’s disease (by
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 predictors
of aMCI progression to AD
(Cognitive, neuropsychological tests)
Progress to AD
(n = 35)
Stable
(n = 104)
p
MMSE
22.0 ± 4.0
23.8 ± 3.8
0.015
ADAS-cog
16.8 ± 6.0
13.5 ± 5.2
0.002
DWRT,10-word
1.22 ± 1.19
2.74 ± 1.70
<0.001
Selective Reminding Test
30-min recall
0.97 ± 2.06
3.46 ± 2.85 <0.001
Visual reproduction-delayed
recall
1.26 ± 2.68
7.98 ± 8.25
Logical memory-delayed
recall
1.34 ± 3.04
5.70 ± 5.76 <0.001
Predictor
at baseline (Mean ± SD)
(Most cognitive, neuropsychological tests p<0.05)
<0.001
Results: Bivariate analyses
Predictor
at baseline
Progress to
AD
Stable
p
(n = 104)
(n = 35)
Gender (F),%
Age, yrs.
Education level, yrs
APOE4+ (versus 4-) , %
Serum clusterin level ,
ug/ml
71.4
76.9
0.51
77.7 ± 5.5
74.7 ± 6.7
0.018
2.66 ± 4.47
2.50 ± 4.00
0.85
20.6
14.4
0.39
32.4 ± 11.4
35.0 ± 15.0
0.34
Note: Mean ± SD, or %; All comorbid diseases are NS
Multivariate logistic regression
analyses
Relative
Risk (RR)
95% CI
RR
p
Gender ( F vs. M)
0.72
0.29, 1.76
0.46
Age, yrs.
1.09
1.02, 1.16
0.015
APOE4+ (versus 4-)
1.71
0.61, 4.8
0.31
Serum clusterin level ,
ug/ml
0.99
0.96, 1.03
0.72
Predictor of
progression to
AD
Note: adjusted for gender, age and apolipoprotein E genotype;
Age but not apolipoprotein E genotype also increased the risk
Discussion


There is limited published data on the
clinical relevance of clusterin to the risk of
AD development*
Is the blood clusterin level a biomarker to
predict AD ?
*despite previous positive studies of the genetic association of 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)
Discussion



Our study is one of the three studies in the
investigation of blood clusterin levels & the
risk of AD development
The aMCI popultaion is an at risk group for
future AD development
In the present 3-year cohort studies among
Chinese older adults with aMCI,
– the serum clusterin level did not predict the
progression of amnestic mild cognitive
impairment (aMCI) to dementia and AD
Discussion
Together with 2 previous Caucasian
studies in non-demented older
adults*
 Both are –ve studies reported in
Caucasian subjects, showing
in non-demented older adults

– Plasma clusterin levels – no effect on
the incidence of AD
*Rotterdam Study (Schrijvers et al, 2011)
Rotterdam Scan Study (Ijsselstijn et al, 2011),
Discussion
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 4% (n=43)
n=61)
Serum clusterin level,
mean(SD)
-Not associated with
incident AD*
*Associated w prevalent AD
No difference
AD =62.7 (13.9) mg/L
Control= 61.0 (11.4)
mg/L
Conclusion
In Chinese older adults with aMCI,
the serum clusterin level is not a
predictor of progression to AD.
 Together with 2 previous Caucasian
studies in non-demented older
adults*, we conclude that

– the blood clusterin level is not a
biomarkers of AD for both MCI and
cognitively normal older adults.
Acknowledgement

Co-investigators:
– Xu A, Zhou L, Wang Y, Chen LH, Song YQ, Lam KS

Research staff:
– Chan SY, Ha CT, Yik PY

Research grant support:
– SK Yee Medical Foundation, Hong Kong
– SRT Healthy Aging, the University of Hong Kong:

Alzheimer’s Disease Research Network
Thank
you
Bivariate analyses of predictors
of aMCI progression to AD
(Co-morbid ds., genetic)
Predictor
at baseline
Progress to AD
(n = 35)
Stable
p
(n = 104)
HT, %
48.9
52.9
0.66
DM, %
22.9
20.2
0.74
Depression
(treated), %
5.7
6.7
0.83
Hyperlipidemia , %
74.3
68.3
0.50
Chronic Obstructive P. ds
2.9
1.0
0.45
Osteoporosis, %
17.1
8.7
0.18
APOE4+ (versus 4-) , %
20.6
14.4
0.39