Identification of misdiagnosed fronto-temporal dementia using APOE genotype and phenotype-genotype correlation analyses.

OBJECTIVE: Postmortem and genetic studies of clinically diagnosed Frontotemporal dementia (FTD) patients suggest that a number of clinically diagnosed FTD patients are actually "frontal variants" of Alzheimer's disease (fvAD). The purpose of this study was to evaluate this hypothesis by combining neuropathological data, genetic association studies of APOE, phenotype-APOE genotype correlations and discriminant analysis techniques. METHODS: Neuropathological information on 24 FTD cases, genetic association studies of APOE (168 FTD, 3083 controls and 2528 AD), phenotypegenotype correlations and discriminant techniques (LDA, logistic regression and decision trees) were combined to identify fvAD patients within a clinical FTD series. RESULTS: Four of 24 FTLD patients (16.6%) met criteria for definite AD. By comparing allele and genotype frequencies of APOE in controls, FTD and AD groups and by applying the Hardy- Weinberg equilibrium law (HWE), we inferred a consistent (17.2%) degree of AD contamination in clinical FTD. A penetrance analysis for APOE ε4 genotype in the FTD series identified 14 features for discrimination analysis. These features were compared between clinical AD (n=332) and clinical FTD series (n=168) and classifiers were constructed usinglinear discriminant analysis logistic regression or decision tree techniques. The classifier had 92.8% sensitivity to FTD and 93.4% sensitivity to AD relative to neuropathology (global AUC=0.939, p<<0.001). We identified 30 potential fvAD cases (17.85%) in the clinical FTD sample. CONCLUSION: The APOE locus association in clinical FTD might be entirely explained by the existence of "hidden" fvAD cases within an FTD sample. The degree of fvAD contamination can be inferred from APOE genotypes.

The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease.

BACKGROUND: In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genome-wide association study (GWAS) in the Spanish population. METHODS: We genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings. RESULTS: Meta-analysis of our data and independent replication datasets allowed us to confirm a novel genome-wide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls). CONCLUSIONS: Our results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases.

Ecological assessment of executive functions in mild cognitive impairment and mild Alzheimer's disease.

Although memory deficits are typically the earliest and most profound symptoms of Alzheimer's disease (AD) and mild cognitive impairment (MCI), there is increasing recognition of subtle executive dysfunctions in these patients. The purpose of the present study was to determine the sensitivity of the Behavioral Assessment of the Dysexecutive Syndrome (BADS), and to detect early specific signs of the dysexecutive syndrome in the transition from normal cognition to dementia. The BADS was administered to 50 MCI subjects, 50 mild AD patients, and 50 normal controls. Statistically significant differences were found among the three groups with the AD patients performing most poorly, and the MCI subjects performing between controls and AD patients. The Rule Shift Cards and the Action Program subtests were the most highly discriminative between MCI and controls; the Zoo Map and Modified Six Elements between MCI and AD; and the Action Program, Zoo Map, and Modified Six Elements between AD and controls. These results demonstrate that the BADS is clinically useful in discriminating between normal cognition and progressive neurodegenerative conditions. Furthermore, these data confirm the presence of a dysexecutive syndrome even in mildly impaired elderly subjects.