SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians.

To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

Wandering and fecal smearing in people with dementia.

BACKGROUND: Wandering and fecal smearing (scatolia) are among the problematic behaviors in dementia, and many caregivers are troubled by these behaviors. The purpose of this study was to clarify the clinical characteristics of patients with these symptoms. METHODS: We performed a questionnaire survey. The questionnaire items were the age, sex, living environment, diagnosis, cognitive function, and activities of daily living. Other clinical characteristics were evaluated using the quality of life (QOL) questionnaire for dementia. RESULTS: A total of 246 patients with dementia were rated. Wandering was observed frequently in 23%, sometimes in 12%, rarely in 14%, and never in 51% of the patients; scatolia was observed frequently in 2%, sometimes in 8%, rarely in 15%, and never in 75%. Wanderers were more frequent among those with severe dementia. They displayed more restlessness, positive affect and attachment to others with respect to QOL. The patients with scatolia tended to get lower scores in tests of cognitive function and displayed more negative affect/actions with respect to QOL. Both wanderers and patients with scatolia suffered from insomnia more frequently. CONCLUSIONS: These results suggest that both wandering and scatolia are behavioral symptoms intimately associated with cognitive dysfunction and insomnia.

Japanese version of the Frontal Assessment Battery for dementia.

The Frontal Assessment Battery (FAB) was developed as a short bedside cognitive and behavioral battery to assess frontal lobe functions. The purpose of this study was to evaluate the validity and reliability of a Japanese version of the FAB to measure cognitive dysfunction in patients with dementia. We studied 25 normal subjects and 105 patients with Alzheimer's disease, n=58, vascular dementia, n=24, and frontotemporal dementia, n=23. The neuropsychological test battery included the FAB, the Mini Mental State Examination (MMSE), a memory test, and the Wisconsin Card Sorting Test (Keio version: KWCST). Patients with dementia performed significantly more poorly than controls on all tests. The FAB showed a good correlation with other cognitive measures: MMSE (r=0.725), KWCST number of categories completed (r=0.654), KWCST number of perseveration errors (r=-0.484), and memory test (r=0.643). Patients with more severe Clinical Dementia Rating scores showed lower scores on the FAB. There was good inter-rater reliability (r=0.972), test-retest reliability (r=0.769), and internal consistency (Cronbach's coefficient alpha=0.715). The FAB is a valid and reliable screening test to evaluate cognitive dysfunction among patients with dementia.

A variant of the sigma receptor type-1 gene is a protective factor for Alzheimer disease.

OBJECTIVE: Some preclinical evidence suggests that the sigma receptor type 1, which plays several roles in learning and memory, may also be involved in the pathogenesis of Alzheimer disease (AD). The authors provide here genetic evidence that the sigma receptor type 1 (SIGMAR1) gene is involved in susceptibility to AD. METHODS: Two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Q2P, were analyzed in a Japanese sample of 239 patients with AD and 227 comparisons subjects. These two polymorphisms were in complete linkage disequilibrium with each other, resulting in only two haplotypes, GC-241-240Q2 and TT-241-240P2. RESULTS: There was a significant association between AD and the TT-241-240P2 haplotype of the SIGMAR1 gene and its homozygote, found with late-onset, but not early-onset AD. After stratification by epsilon4 allele status of the apolipoprotein E gene, TT-241-240P2 homozygosity of the SIGMAR1 gene reduced the risk of AD in epsilon4 allele carriers by three-fourths. CONCLUSION: The present study suggests that the TT-241-240P2 haplotype of the SIGMAR1 gene, which decreases expression of the gene, may have a protective role against susceptibility to AD.

Delusion of theft and phantom intruder delusion in demented elderly patients in Japan.

Delusion of theft and phantom intruder delusion are among the most frequent delusions in dementia. The purpose of this study was to clarify the clinical characteristics of patients with these symptoms. The authors conducted a questionnaire survey; items included age, gender, dementia diagnosis, cognitive function, and activities of daily living. Other clinical characteristics were evaluated using the quality of life questionnaire for dementia. A total of 217 patients with dementia were rated. Frequencies of delusion of theft were as follows: frequent, 7%; sometimes, 11%; rare, 16%; and none, 66%. Frequencies of phantom intruder delusion were as follows: frequent, 4%; sometimes, 10%; rare, 9%; and none, 77%. Comparison between positive and negative groups with these symptoms revealed that positive groups had higher scores in 2 of 6 domains of the quality of life questionnaire for dementia, namely, negative affect and actions, and restlessness. The positive group with delusion of theft had higher scores in cognitive function and activities of daily living than did the negative group. These results suggest that negative affect and action and restlessness might be related to delusion of theft or phantom intruder delusion and that delusion of theft frequently occurs in the early stage of dementia.

No association between the insulin degrading enzyme gene and Alzheimer's disease in a Japanese population.

Susceptibility to Alzheimer's disease (AD) is thought to be regulated by multiple genetic factors. Recently, three independent studies have reported that loci on chromosome 10q are linked with AD, and the insulin degrading enzyme (IDE; MIM 146680) gene located on chromosome 10q23-q25; IDE is located close to the maker D10S583, which exhibits a maximum LOD score for late-onset AD. We examined seven polymorphisms in the IDE gene, the marker D10S583 in the 5' flanking region, and SNPs in introns 1, 3, 11, 20, 21, and 22 (rs#1999764, 1855915, 1970244, 538469, 551266, and 489517, respectively). Four SNPs in introns 3, 11, 20, and 22 did not exhibit any polymorphisms in the Japanese population that was studied. D10S583 and two SNPs in introns 1 and 21 did not exhibit a significant association with early- or late-onset AD. In addition, no associations were observed for subgroups of AD grouped according to APOE status. The present study indicates that the IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population.

Association of the Neprilysin gene with susceptibility to late-onset Alzheimer's disease.

Neprilysin (NEP), also known as neutral endopeptidase, enkephalinase, CD 10, and common acute lymphoblastic leukemia antigen, is a 97-kD protein. NEP can degrade amyloid beta peptides, and its mRNA and protein levels are known to be reduced in the brains of patients with Alzheimer's disease (AD), making the NEP gene a substantial candidate for an AD risk factor. We examined the genetic association of three NEP polymorphisms, a GT-repeat polymorphism and two single nucleotide polymorphisms (SNPs, -1075A>G and -1284G>C) in its promoter region, with AD in a Japanese case-control sample (240 patients and 163 controls). The GT-repeat polymorphism, but not the SNPs, was significantly associated with late-onset AD (p = 0.0007). Our findings suggest that the GT-repeat polymorphism in the promoter region of the NEP gene or some other unknown polymorphisms, which are in a linkage disequilibrium, confer a susceptibility to late-onset AD.

Development and evaluation of a health-related quality of life questionnaire for the elderly with dementia in Japan.

OBJECTIVES: The purpose of this study was the development of the quality of life (QOL) questionnaire for dementia (QOL-D) in Japan. METHODS: We performed a questionnaire survey of QOL assessment in elderly patients with dementia in Japan, and developed QOL-D. RESULTS: The final version consists of only 31 items grouped into six response sets, each with its own scale. Reliability is good to excellent, and validity is, to some extent, established. The six domains of health-related QOL are divided into two groups. One is the positive and the other is the negative aspects of health-related QOL. The positive aspects have been shown to correlate positively with cognitive function and activities of daily living (ADL) score, whereas the negative aspects have not. The concept of QOL for elderly patients with dementia in Japan is similar to that in Western countries. CONCLUSION: We demonstrated that QOL-D is a reliable and valid instrument for QOL assessment in elderly patients with dementia in Japan.