JongChul Youn

The Domain-Specific, Stage-Limited Impact of the Apolipoprotein E Epsilon-4 Allele on Cognitive Functions in Alzheimer’s Disease

To examine the impact of the APOE Ε4 allele on the cognitive functions of Alzheimer’s disease (AD) patients, we administered the eight neuropsychological tests from the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery to 118 Korean AD patients. The impact of the APOE Ε4 allele was significant in the Word List Recall Test (WLRT) and the Word List Recognition Test (WLRcT) only, and its impact was confined to the very mild AD (VMAD) patients (F = 7.65, d.f. = 2, p < 0.01 for WLRT; F = 3.27, d.f. = 2, p = 0.04 for WLRcT). In the VMAD group, the performance on the two tests of the APOE-Ε4-positive patients was poorer than that of the APOE-Ε4-negative patients. Our findings suggest that the impact of the APOE Ε4 allele on cognitive functions in AD may be domain specific and confined to the early stage of AD.

Lack of Association Between Apolipoprotein E Polymorphism and Vascular Dementia in Koreans

To investigate an association of vascular dementia (VD) with the apolipoprotein E (APOE) polymorphism, the APOE polymorphism of 100 VD patients, 100 age- and gender-matched Alzheimer disease (AD) patients, and 200 age- and gender-matched nondemented control (NC) subjects was genotyped. The distribution of APOE polymorphism was compared. Neither the APOE ε4 allele nor the APOE ε2 allele was more prevalent in the VD patients compared with the NC subjects (P > .1 by the χ 2 test), which was the case when both men and women were analyzed separately (P > .1 by the χ2 test) and when young patients (75 years old or less) and old patients (more than 75 years old) were analyzed separately (P > .1 by the χ2 test). The estimated statistical power was over 0.80 when the odds ratios (OR) for VD conferred to the APOE ε4 are assumed to be higher than 2.2 and the type I error probability is set at 0.05, which is much higher than the power of the previous studies on the VD/APOE association. In conclusion, the results suggested that APOE ε4 allele does not confer the risk for VD, and even if it does, it does so very modestly.

Choline acetyltransferase G +4 A polymorphism confers a risk for Alzheimer’s disease in concert with Apolipoprotein E ε4

To examine whether the single nucleotide polymorphism at position +4 of the choline acetyltransferase (ChAT) confers a risk for Alzheimers disease (AD), we determined the ChAT and the Apolipoprotein (APOE) genotypes of the 246 AD patients and 561 non-demented controls. The ChAT AA genotype was found to confer the risk for AD in concert with the APOE epsilon4 by stochastic search variable selection (SSVS) approach. The odds of the ChAT AA for AD were 3.25 (95% CI = 1.17-9.03). The mean ages-at-onset of AD were lower in those carrying the ChAT AA than those carrying the ChAT AG or ChAT GG, regardless to the occurrence of the APOE epsilon4. The ChAT AA is a novel genetic risk factor AD, and the SSVS is a useful approach for analyzing association with multiple candidate genes simultaneously.

Neither the butyrylcholinesterase K variant nor transferrin C2 variant confers a risk for Alzheimer's disease in Koreans.

Summary. To investigate the possible involvement of the butyrylcholinesterase (BCHE) K variant and transferrin (TF) C2 variant in the manifestation of Alzheimers disease (AD), we analyzed the BCHE, TF and apolipoprotein E (APOE) genotypes of 164 sporadic AD patients and 239 normal elderly controls.The frequencies of the BCHE K and TF C2 did not differ between the AD patients and controls (P > 0.1). The occurrence of the APOE ε4 did not influence the distribution of the BCHE K and TF C2 variants (P > 0.1). No linkage disequilibrium between the BCHE K and TF C2 was observed either in both the AD patients and controls (P > 0.1).In conclusion, neither the BCHE K nor the TF C2 confers a risk for AD.

No association between alpha-1-antichymotrypsin polymorphism and Alzheimer's disease in Koreans.

To examine the possible involvement of the alpha-1-antichymotrypsin gene (ACT) polymorphism in the manifestation of Alzheimers disease (AD), we analyzed genotypes of the ACT and apolipoprotein E gene (APOE) among 110 Korean patients with probable AD and 209 nondemented controls. No significant difference was obtained in genotypic (chi(2)=1.98, df=2, P>0.1) and allelic frequencies (chi(2)=1.61, df=1, P>0.1) of ACT between the AD and control groups. No overexpression of the ACT A/A genotype and ACT A allele was found when we analyzed the late-onset AD patients and the early-onset AD patients, separately. Then we stratified the ACT genotypes based on the presence or absence of the APOE epsilon4 allele to evaluate the possible interaction between them. In the APOE epsilon4-negative subjects, although the ACT A allele tended to be overexpressed in the AD group, the differences in the frequencies of the ACT A allele (chi(2)=2.79, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.16, df=1, P>0.1) were not statistically significant. No significant overrepresentations of the ACT A allele (chi(2)=0.02, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.17, df=1, P>0.1) were found in the APOE epsilon4-positive subjects, either. In addition, the status of the ACT genotype did not influence the age-at-onset of AD (F=0.03, df=2, P>0.1). Therefore, the ACT polymorphism does not contribute to the development of AD independently or interactively with the APOE epsilon4 allele in Koreans.

The impact of social support on caregiver burden in dementia

79(8.5) years and MMSE was 14.6(6.8). GLM confirmed a significant association between dependence and ZBI score (P <0.0001), when controlling for patient age, and gender, caregiver age and gender, caregiver relationship to patient and patient accommodation status. Other significant predictors of ZBI score were patient accommodation (P <0.0001) and whether the caregiver was the patient’s child (i.e. son/daughter, P <0.05)).The model suggests that a one point increase in dependence is associated with 2.15 point increase in ZBI. In addition, if the patient is not in a nursing home/residential care facility, the ZBI score is expected to increase by 19 points. If the caregiver is a son/daughter of the patient, an increase of 9.2 points in ZBI is expected. For co-resident caregivers, the proportion of the time that patients can be left alone decreases as DS score increases. Conclusions: The results suggest that perceived caregiver burden increases with patient dependence on others and is higher when caregivers are the son/daughter of patient compared with spouse/partner caregivers. The decrease in perceived caregiver burden associated with a patient’s transition to nursing home care/residential care is not unexpected given the significant decrease in the time that co-residing caregivers can leave the patient alone as dependence increases.

EFFECT OF A POSITIVE INTERACTION, GROUP-BASED ACTIVITY PROGRAM (PIGAP) FOR DEMENTIA PATIENTS AND CAREGIVERS

capsule containing 28-mg memantine extended release (ER) and 10-mg donepezil was developed and tested for (1) bioequivalence with co-administered commercially available memantine ER (Namenda XR, 28 mg) and donepezil (Aricept, 10 mg), (2) bioavailability following food intake, and (3) bioavailability following sprinkling of the capsule contents on applesauce. Methods: Both studies were single-dose, randomized, open-label, and crossover (with 21-day washout periods between treatments), conducted in 18-45-year-old healthy individuals. In Study 1, fasting participants (N1⁄438) received Treatment A (co-administration of Namenda XR and Aricept) or Treatment B (FDC). In Study 2, participants (N1⁄436) received three treatments: Treatment A (intact FDC capsule, while fasting), Treatment B (intact FDC capsule, following a high-fat meal), and Treatment C (FDC contents sprinkled on applesauce, while fasting). In both studies, C max and AUC 0ˆ z for memantine and donepezil were compared using a linear mixed-effects model. Bioequivalence or no effect in the comparison of treatments was declared if the 90% confidence intervals (CI) of the least-squares geometric mean ratios of C max and AUC 0ˆ z were within the range of 80.00%-125.00%. T max values were compared using a Wilcoxon signed-rank test. Safety parameters were also evaluated. Results: CIs of all the comparisons were within 80.00%-125.00% window. The FDC capsule containing memantine ER and donepezil was bioequivalent to co-administered Namenda XR and Aricept. There was no significant food effect on the bioavailability of the FDC capsule. The intact FDC capsule and capsule contents sprinkled on applesauce were bioequivalent. There were no clinically relevant differences in T max across treatments. Safety profiles were also similar across treatments. Conclusions: A FDC capsule containing 28-mg memantine ER and 10-mg donepezil is bioequivalent to co-administered commercially available memantine ER and donepezil. In addition to ingestion by swallowing with or without food, the formulation allows for sprinkling of the capsule contents on applesauce, making ingestion and administration easier for patients and caregivers, respectively. Sponsorship: Forest Research Institute.

EFFECTS OF A PERSON-CENTERED ACTIVITY PROGRAM (PAP) ON THE MANAGEMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD) OF COMMUNITY-RESIDING PATIENTS WITH ALZHEIMER'S DISEASE AND ON CAREGIVER BURDEN

P1-392 DRUG DEVELOPMENT FOR AGITATION AND AGGRESSION IN ALZHEIMER’S DISEASE (AD): STUDY DESIGN AND OUTCOME MEASURES IN PHASE 2 STUDYOF SCYLLO-INOSITOL (ELND005 STUDYAG201) Susan R. Abushakra, Patrick Kesslak, Matthias Kurth, Frank Fan, Menghis Bairu, David S. Miller, Constantine Lyketsos, Elan Pharmaceutical, Cambridge, Massachusetts, United States; Bracket Global, Wayne, Pennsylvania, United States; Johns Hopkins University, Baltimore, Maryland, United States. Contact e-mail: susan.abushakra@ elan.com

Development and validation of a screening algorithm for Alzheimer's disease using the categorical fluency test

Methods: After translating into Spanish and adapting to Chilean population, the TYM-S was developed and administered to 30 dementia patients, 14 mild cognitive impairment (MCI) subjects and 30 controls in addition to MMSE and ACE-R-Ch for assessing global cognitive efficiency. Caregivers of dementia patients and collateral sources of MCI and control subjects were interviewed with measures of dementia severity, functional status in activities of daily living and cognitive changes. Convergent validity, internal consistency reliability, cut-off points, sensitivity and specificity for the TYM-S were estimated. Results: Table 1 summarizes the demographic characteristics and clinical profiles of the sample. Regarding convergent validity, the TYM-S showed significant correlations (p<0.001) with other cognitive measures (r1⁄40.902 with MMSE; r1⁄40.922 with ACER-Ch; r1⁄40.923 with MoCA and r1⁄40.862 with FAB), a rating for dementia severity (r1⁄4-0.757 with CDR), functional capacity assessments (r1⁄4-0.864

Norms for total scores on the CERAD Neuropsychological Assessment Battery in an educationally diverse elderly population

Demographic data Age 70.18 5.01 69.00 4.75 69.96 5.49 0.491 .614 none Education year 1.06 1.68 4.00 0.00 14.21 3.16 354.173 <.001 E1 < E2 < E3 TGDS 4.85 3.00 3.88 2.30 2.57 2.71 5.440 .006 E1 < E3 MMSE 21.30 3.26 26.50 1.81 28.00 2.02 45.010 <.001 E1 < E2 < E3 MoCA sub-items Trail B 0.06 0.24 0.62 0.49 0.89 0.32 68.918 <.001 E1 < E2 < E3 Cube 0.00 0.00 0.19 0.40 0.89 0.32 78.121 <.001 E1 < E2 < E3 CDT 1.42 0.97 2.25 0.67 2.82 0.39 31.651 <.001 E1 < E2 < E3 circle 0.85 0.36 1.00 0.00 0.96 0.19 3.511 .034 E1 < E2 number 0.36 0.49 0.75 0.44 1.00 0.00 20.858 <.001 E1 < E2 < E3 hands 0.21 0.42 0.50 0.51 0.86 0.36 21.238 <.001 E1 < E2 < E3 Naming 2.27 0.94 2.94 0.25 2.96 0.19 8.350 .001 E1< E2, E3 lion 0.88 0.33 1.00 0.00 1.00 0.00 4.004 .022 E1< E2 rhinoceros 0.70 0.47 0.94 0.25 0.96 0.19 4.530 .015 E1 < E2, E3 camel 0.70 0.47 1.00 0.00 1.00 0.00 12.623 <.001 E1 < E2, E3 Digit forward 0.55 0.51 0.91 0.30 0.89 0.32 6.716 .002 E1< E2, E3 Digit backward 0.58 0.50 0.81 0.40 0.93 0.26 6.165 .004 E1< E3 Vigilance test 0.88 0.33 1.00 0.00 1.00 0.00 4.004 .022 E1 < E2 Serial-7 1.70 0.88 2.28 0.73 2.61 0.74 10.529 <.001 E1 < E2, E3 Repetition 0.12 0.33 0.38 0.55 1.61 0.69 54.232 <.001 E1, E2 < E3 Letter fluency 0.00 0.00 0.25 0.44 0.75 0.44 34.828 <.001 E1 < E2 < E3 Abstraction 0.24 0.44 0.75 0.72 1.54 0.69 36.908 <.001 E1 < E2 < E3 Recall 1.21 1.47 2.34 1.66 3.39 1.31 16.174 <.001 E1 < E2 < E3 Orientation 5.06 0.90 5.88 0.34 5.93 0.26 13.863 <.001 E1 < E2, E3 date 0.73 0.45 0.91 0.30 0.96 0.19 3.755 .029 E1 < E3 month 0.88 0.33 1.00 0.00 1.00 0.00 4.004 .022 E1 < E2 year 0.55 0.51 0.97 0.18 1.00 0.00 20.147 <.001 E1 < E2,E3 day 0.91 0.29 1.00 0.00 0.96 0.19 1.663 .195 None place 1.00 0.00 1.00 0.00 1.00 0.00 NA None province 1.00 0.00 1.00 0.00 1.00 0.00 NA None Total scores 14.09 3.74 20.59 2.85 26.21 2.15 129.791 <.001 E1 < E2 < E3