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

1. Clinical, cognitive and genetic predictors of conversion from amnestic mild cognitive impairment to Alzheimer’s disease in Chinese older adults (Chu LW, Mok W, Chung CP, Chan M, Yik PY, Kwan F, Chan CSY , Song YQ, Lee P) Prof. Leung-Wing ChuMD, FRCP (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 • *OC126 • March 29, 2011

2. Conflict of Interest • All authors • Chu LW, Mok W, Chung CP, Chan M, Yik PY, Kwan F, Chan CSY , Song YQ, Lee P • Has no real or apparent conflicts of interest to report • *ADI2011-1083 • OC126

3. Prevalence of AD in Chinese (Systematic analysis of 1980-2004 25 studies in China*) *Dong et al, 2007 Lower Prevalence In Men %

4. Prevalence of Very Mild & Mild Dementia in Hong Kong • Older people 60+ • Prevalence of dementia =11.4% • Very mild (CDR 0.5) = 5.8% • Mild (CDR 1.0) = 5.4 • Subtypes • 73.5% possible AD • 22.4% possible VaD • 3.9% PD dementia or LBD (Lam L et al, 2008)

5. Delay in Diagnosis in ADSymptom onset and 1st consultation • Mean Delay -- 3.1 years in AD patients1 Symptoms ignored as “normal ageing!” 1Chiu KC et al, 2002 • (More than 2 times that of Caucasian AD patients (i.e. 1.2 years in Caucasian dementia patients2 ). 2Cattel C et al, J Gerontol: Med Sci 2000; M98)

6. Undiagnosed Dementia in the HK Community • Prevalence of previously diagnosed dementia • 1.7% (including old age homes)1 • 0.33%(excluding old age homes) 2 • Undiagnosed dementia: Estimated prevalence – 9.7% to 11.1% 1Chu LW et al, 1998; 2Chu LW et al, 2005

7. Mild cognitive Impairment (MCI) • Mild cognitive impairment (MCI) is a clinical syndrome defined as • cognitive decline greater than that expected for a person’s age and education level • but does not affect notably with activities of daily life (Gauthier S et al, Lancet 2006) • MCI refers to • a transitional cognitive phase between cognition of normal aging and mild dementia & • may precede the onset of dementia or AD (Petersen et al, 1999 & 2001)

8. MCI Subtypes • Amnestic MCI (aMCI) 1. MCI (Amnestic)(Single memory domain) • Alzheimer’s disease (AD) 2. MCI (Multiple domains slightly impaired)  Alzheimer’s disease; Vascular Dementia • Non-amnestic MCI (naMCI) 3. MCI (Single Non-memory Domain)  Fronto temporal Dementia; Lewy Body Dementia; Vascular Dementia; Primary Progressive Aphasia; Parkinson’s Disease; Alzheimer's Disease

9. Progression of MCI Conversion rate and Predictors • Progression of aMCI to dementia 12% per year; 80%/6 years (Petersen, 1999 & 2001) • Clinical, neuropsychological, genetic predictors of conversion or progression to dementia / AD • Neuropsych. Tests, particularly delayed recall memory test, APOE4 (Petersen 1999, Fleisher 2006) • Other predictors: Imaging (MRI, PET), csf biomarkers

10. Predictors of amnestic Mild Cognitive Impairment (aMCI) conversion to dementia • Clinical predictor: Body Mass Index (BMI) as a predictor has not been studied fully • Non-demented older adults –low BMI predicts dementia/AD in several studies • MCI: Low BMI  more cognitive decline but not dementia conversion in 1 study (Cronk et al, 2010) • Limited Chinese data on MCI on • The clinical, genetic & cognitive predictors of conversion of MCI to dementia, • Wang et al, 58 MCI subjects 32.7% AD over 3 years • Only cognitive performance independent predictor (APOE & hippocampal volume – NS)

11. Objectives of the study • To investigate the conversion rate of aMCI to AD/dementia in aMCIin Chinese older adults (Southern Chinese) • To investigate the clinical, genetic & cognitive predictors of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) • Particularly, to study if BMI predicts conversion of aMCI to AD* in Chinese older adults (Southern Chinese) *In our previous cross-sectional study, AD & aMCI lower BMI than cognitively normal older adults

12. Methods • Design:A one-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 demographic, • BMI, • co-morbid diseases, • cognitive including MMSE, ADAS-cog • neuropsychological tests, and • apolipoprotein E genotype (APOE)

13. 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)

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

15. Results • 243 Chinese older adults with aMCI were recruited from Jan. 2001 to Nov. 2009 • One year follow-up, 16.5% (n=40) developed dementia (by DSM-IV criteria)* • All having Alzheimer’s disease (by NINCDS-ADRDA criteria) *versus 0.5% (2 out of 444) in another cohort of cognitively normal Chinese older adults in HK

16. Bivariate analyses of predictors of aMCI conversion to AD • Bivariate analyses showed that • advanced age, low body mass index (BMI), APOE4+ (1 or 2 copies), low MMSE, DWRT, ADAS-cog and neuropsychological assessment tests’ scores increased the risk of conversion to AD significantly • Arthritis & CHD showed only non-significant trends

17. Bivariate analyses of predictors of aMCI conversion to AD(Demographic, co-morbid ds.) Note: Mean ± SD, or %; CHD=coro heart ds

18. Bivariate analyses of predictors of aMCI conversion to AD(Co-morbid ds., genetic) Note: %

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

20. Logistic regression analyses: Independent predictors of aMCI conversion to AD

21. Logistic regression analyses: Independent predictors of aMCI conversion to AD • After adjustment for confounders, logistic regression analyses showed that • APOE4+ (vs. 4-) (RR=2.70), • BMI (RR=0.84), • Verbal memory test: 30-minute recall of the selective reminding test (RR=0.75) • Visual memory test: delayed recall score in visual reproduction test (RR=0.79), and weresignificant independent predictors for conversion to AD. • Age, arthritis, CHD were non-significant & • MMSE, DWRT, ADAS-cog were not independent predictors because of SRT-30 & VR-delayed w

22. Discussion • Similar to previous studies, we found • APOE4, low cognitive / neurpsych memory test predicts conversion of aMCI to dementia/AD in (Southern) Chinese older adults (with aMCI ) • However, to our knowledge, this is the 1st study • BMI predicts future risk of aMCI to dementia/AD • Low BMI increases the risk • One kg/m2 less in BMI increases the risk of aMCI to dementia (AD) by 16%

23. Discussion • In our previous cross-sectional study on 3 groups of older adults • Significant progressive decline in BMI reported from NaMCIAD (Chu LW et al JAD, 2009) • Low BMI can either be a risk factor or preclinical symptom/sign of aMCI conversion to AD

24. Conclusions • In Chinese older adults, • low BMI, as well as • the presence of apolipoprotein epsilon 4, and • poor performance in delayed recall tests in verbal and visual memory tests predict increased risks of aMCI conversion to AD in this 1-year cohort study. • Future studies needed.

25. Acknowledgement Co-investigators: Mok W, Chung CP, Chan M, Song YQ, Lee P Research staff: Yik PY, Kwan F, Chan CSY Research grant support: SK Yee Medical Foundation, Hong Kong SRT Healthy Aging, the University of Hong Kong: Alzheimer’s Disease Research Network

26. Thank you