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 mjchiu@ntu.edu.tw

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. 2006 Jan 25;(1) Drugs Aging. 2004;21(7):453-78

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. 2006 Jan 25;(1) Drugs Aging. 2004;21(7):453-78

This study was using panel data from the Bureau of National Health Insurance (BNHI) of Taiwan from 2001 to 2004. 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.

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

Result – Multi-variant regression Factor CDR Nutrition supplement Exercise Social activity Chi-Square 13.86 4.27 2.10 4.42 P < 0.0005 < 0.05 0.15 Hazard ratio 3.64 0.11 - 0.21 Controlled with age and gender; CDR: baseline CDR

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).

Thank you for your attention! Correspondence to Dr. Ming-Jang Chiu, mjchiu@ntu.edu.tw