1. Factor analysis for the treatment response of Cholinesterase Inhibitors in Alzheimer’s disease
Li-Yu Tang1, Ta-Fu Chen1,2, Ming-Jang Chiu1,2*
1Taiwan Alzheimer’s Disease Association
2Department of Neurology, National Taiwan University Hospital
Correspondence to

2. Background
The deficiency in cholinergic neuro-transmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease.
The clinical benefits of these agents include improvement, stabilization or less than expected decline in cognition, function and behavior.
Cochrane Database Syst Rev Jan 25;(1)
Drugs Aging. 2004;21(7):453-78

3. Background
Between 40% and 60% of people with Alzheimer's disease benefit from cholinesterase inhibitor (ChEI) treatment.
However, it is not effective for everyone, and may improve symptoms only temporarily.
Therefore, we aim to explore possible factors that may influence the treatment response of ChEI.
Cochrane Database Syst Rev Jan 25;(1)
Drugs Aging. 2004;21(7):453-78

4. This study was using panel data from the Bureau of National Health Insurance (BNHI) of Taiwan from 2001 to Patients with mild or moderate AD were prescribed AChEI (donepezil, rivastigmine, or galantamine). By the regulation of BNHI, if the score of MMSE worsened by more than two points or CDR worsened by one or more grades in the follow-up every half year, the AChEI treatment would be terminated.
The average duration for AChEI therapy is around 14 months. The elderly are at high risk for treatment discontinuation.

5. Study Design Retrospective & prospective cohort study Subject:
Dementia subjects in NTUH memory clinic (hospital-based)
Mild to moderate AD
NINCDS-ADRDA CRITERIA
Initial MMSE scores 10-26; initial CDR 1 or 2
Under treatment with cholinesterase inhibitors
2000 ~ 2010 June (after biannual application approved)

6. Study Design (1) Obtained Information Demographic data
Age (onset &beginning to receive treatment), Gender, Education etc.
Cognitive & functional states
MMSE, CDR, Behave-AD
Lab exam
Vit.B12, Folic acid etc.
APOE polymorphism

7. Study Design (2) Obtained Information 4. Health condition
H/T, DM, Head injury, Heart dz, CVD, Hyperlipidemia
Gait problem, Swallowing difficulty, etc.
Insomnia, Parasomnia, etc.
5. Habits
Nutrition supplement, Vegetarian, Drinking, Smoking, Coffee, Tea
6. Activity
Religion , Exercise, Social activity, Leisure

8. Research Questions Duration of using ChEI?
Factors influencing the duration of using.
(To keep patients cognitive funciton within 2 points of MMSE decline)

9. Analysis - ChEI user ChEI users : 606 NHI supported only
Medication Condition
Continuous
Stop
Loss of follow up
Expired
Medication Duration
1 ~ 125M

10. Analysis - Definition
Cut point for responders and non-responders : 18months continuous use of ChEI (reapplication every 6 months successful for 3 times);
In total 422 subjects
Non-responders:
Those who could not apply for ChEI anymore (MMSE scores declined more than two points from baseline at 18 months).
Responders:
Continuous users of ChEI with the medication period longer than 18 months whose MMSE scores remained stable or declined within two points from baseline at 18 months or beyond.
Subjects lost of follow-up but already have had the medication longer than 18 months

11. Statistics Between group comparison Cox regression
Multi-variant regression
SAS software

12. Result – Demographic data 1
Number
(F/M)
Age-onset
Age-med
Education
MMSE
(baseline)
Non-Responder 51
(32/19)
73.6±11.0
75.5±11.2
7.2±5.4
18.1±4.3
Responder
371
(243/128)
72.8±9.0
74.6±8.7
7.8±4.9
19.1±4.4
Age-onset: Onset of Alzheimer’s disease
Age-med: Age when started to receive ChEI

13. Result – Functional status
ADL
IADL*
CDR***
Non-Responder
91.9±16.6
4.2±2.4
1.15
(0.5-3)
Responder
95.4±13.0
5.4±2.2
0.83
Cox regression: *:p<0.05; ***: p<0.0001, controlled with age and gender
CDR baseline

14. Result – Lab data APOe4 (+): 40.7% in AD APOe4 (-)/(+) (250) Vit. B12
(392)
Folic acid
(380)
Homocysteine
(271)
Non-Responder
11/7
519±235
11.7±9.6
10.8±3.3
Responder
130/102
588±268
13.1±6.9
12.0±9.3
APOe4 (+): 40.7% in AD

15. Result – Associated diseases1
(-)/(+)
Head injury
(297)
Ulcer HT
(405) DM
(410)
Stroke
(356)
Dyslipid
(398)
CAD
(353)
Non-Responder
(NR)
22/3
30/126
41/8
36/1
33/14
30/8
Responder
(R)
246/26
217/55
212/147
291/70
303/16
242/109
253/62

16. Result – Physical function2
(-)/(+)
Gait
(295)
Swallowing
Visual
Hearing
(294)
BMI
Non-Responder
18/6
20/4
21/3
19/5
22.6±3.7
Responder
209/62
225/46
229/42
230/40
22.6±3.6

17. Result – Sleep related disorders3
Treatment Response
Daytime Sleepiness
(294)
Insomnia
(291)
Severe snoring
(271)
RBD
(289)
Non-Responder
16/8
18/6
20/4
17/6
Responder
159/111
205/62
198/49
191/75

18. Result - Hobbies (-)/(+) Nutrition* Vegetarian (300) Drinking (354)
supplement (294)
Vegetarian
(300)
Drinking
(354)
Smoking
(359)
Coffee
(296)
Tea
(297)
Non-Responder
20/4
23/1
32/5
29/9
19/6
15/10
Responder
145/125
261/15
275/42
259/62
220/51
193/79
Cox regression: *: p<0.05, controlled with age and gender

19. Result – Life style (-)/(+) Religion (301) Exercise* (293) Leisure ±
(294)
Social activity **
Non-Responder
3/21
16/8
7/17
22/2
Responder
72/205
107/162
41/228
160/109
Cox regression: *: p<0.05, **: p<0.01, controlled with age and gender;
±: P=0.1~0.05

20. Result – Significant factors
Initial CDR
Hazard ratio: 5.27 (Chi-Square=23.93)
Nutrition supplement
Hazard ratio: 0.25 (Chi-Square=6.50)
Exercise
Hazard ratio: 0.36 (Chi-Square=5.65)
Social activity
Hazard ratio: 0.14 (Chi-Square=4.11)
(Uni-variant cox-regression, controlled with age and gender)

21. Result – Multi-variant regression
Factor
CDR
Nutrition supplement
Exercise
Social activity
Chi-Square
13.86
4.27
2.10
4.42 P
<
< 0.05
0.15
Hazard ratio
3.64
0.11 -
0.21
Controlled with age and gender; CDR: baseline CDR

22. Conclusion
AD patients get good response to cholinesterase inhibitor treatment when started early in their disease course.
AD patients participate in social activities (also as group habitual exercise) and probably take nutrition supplement would prolong their effect with cholinesterase inhibitors.
In our study the effect of exercise may be masked by the social activity (overlapped in the questionnaire, group exercise such as playing Tai-Chi 太極拳, Yuan-Chi Dancing 元極舞).

23. Thank you for your attention!
Correspondence to Dr. Ming-Jang Chiu,