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

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).

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

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  1. SERUM CLUSTERIN LEVELS AND THE RISK OF ALZHEIMER’S DISEASE IN CHINESE OLDER ADULTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENTA 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) Prof. Leung-Wing ChuMD, FRCP (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

  2. 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

  3. Background • Genetic studies in late-onset Alzheimer’s disease (LOAD) apart from APOE, recent Genome-Wide Association (GWA) studies • an association betweenLOAD 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 • 2Chen LH & Chu LW et al, Neurobiol Aging 2012

  4. BackgroundClusterin • 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

  5. BackgroundClusterin 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

  6. BackgroundClusterin • 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

  7. 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)

  8. Methods • Design:A 3-year cohort study • Setting: Ambulatory setting • Subjects: Chinese older adults, aged 55 to 93 years old, with aMCI criteria modified from the Petersen’s criteria. • Measurements: • Baseline socio-demographic, • co-morbid diseases, • cognitive tests including MMSE, ADAS-cog • neuropsychological tests, and • apolipoprotein E genotype (APOE) • Serum clusterin level (by ELISA)

  9. 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)

  10. Methods • Follow-up: All subjects were followed up for three years • Outcome: • Dementia by DSM-IV criteria & • AD was diagnosed by the NINCDS- ADRDA criteria for probable AD

  11. 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)

  12. 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

  13. Bivariate analyses of predictors of aMCI progression to AD(Cognitive, neuropsychological tests) (Most cognitive, neuropsychological tests p<0.05)

  14. Results: Bivariate analyses Note: Mean ± SD, or %; All comorbid diseases are NS

  15. Multivariate logistic regression analyses • Note: adjusted for gender, age and apolipoprotein E genotype; • Age but not apolipoprotein E genotype also increased the risk

  16. 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)

  17. Discussion • Our study is one of the three studies in the investigation of blood clusterin levels & the risk of AD development • The aMCIpopultaion 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

  18. 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),

  19. Discussion *Associated w prevalent AD

  20. 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.

  21. 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

  22. Thank you

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

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