GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.

Impact of apolipoprotein E4-cerebrospinal fluid ß-amyloid interaction on hippocampal volume loss over 1 year in mild cognitive impairment.

BACKGROUND: The majority of studies relating amyloid pathology with brain volumes have been cross-sectional. Apolipoprotein ɛ4 (APOE ɛ4), a genetic risk factor for Alzheimer's disease, is also known to be associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE ɛ4 together on longitudinal volume loss. METHODS: We evaluated whether an abnormal level of cerebrospinal fluid beta-amyloid (CSF Aß) and APOE ɛ4 carrier status were independently associated with greater hippocampal volume loss over 1 year. We then assessed whether APOE ɛ4 status and CSF Aß acted synergistically, testing the significance of an interaction term in the regression analysis. We included 297 participants: 77 cognitively normal, 144 with mild cognitive impairment (MCI), and 76 with Alzheimer's disease. RESULTS: An abnormal CSF Aß level was found to be associated with greater hippocampal volume loss over 1 year in each group. APOE ɛ4 was associated with hippocampal volume loss only in the cognitively normal and MCI groups. APOE ɛ4 carriers with abnormal CSF Aß in the MCI group acted synergistically to produce disproportionately greater volume loss than noncarriers. CONCLUSION: Baseline CSF Aß predicts progression of hippocampal volume loss. APOE ɛ4 carrier status amplifies the degree of neurodegeneration in MCI. Understanding the effect of interactions between genetic risk and amyloid pathology will be important in clinical trials and our understanding of the disease process.

National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.

BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis.

For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.

Evidence for an association between KIBRA and late-onset Alzheimer's disease.

We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.

Subtype of mild cognitive impairment and progression to dementia and death.

BACKGROUND: Mild cognitive impairment (MCI) represents a common cognitive state between normal cognitive aging and dementia. There is limited information about the heterogeneity of MCI and how this heterogeneity may influence the clinical course of MCI. We determined the longitudinal course of subtypes of MCI and assessed the rate of progression to dementia and to death. METHODS: As part of the Alzheimer's Disease Research Centers of California, we studied 327 patients with MCI (250 with amnestic MCI, 34 with single nonmemory MCI, and 43 with multiple domain MCI) who were followed longitudinally. We determined if subtype of MCI was independently associated with time to dementia diagnosis and time to death using Cox proportional hazard models, and type of dementia using Fisher's exact test. RESULTS: Mean age of the patients with MCI was 72.9 +/- 9.3 years and mean Mini-Mental State Examination score was 25.7 +/- 4.3. After a mean follow-up of 3.1 years, 199 (65%) progressed to dementia and 80 (24%) died. After multivariate adjustment, compared to those with amnestic MCI, patients with single nonmemory or multiple subtype MCI were less likely to receive a diagnosis of dementia (HR = 0.60; 95% CI 0.35-1.05 and HR = 0.71; 95% CI 0.44-1.14) but more likely to die (HR = 2.57; 95% CI 1.13-5.84 and HR = 1.73; 95% CI 0.72-4.18), but these results were of borderline statistical significance. There were significant differences in the type of dementia diagnosed across MCI subtypes (p = 0.006). Among the patients who progressed to Alzheimer's disease, 76% had prior amnestic MCI; of the patients who progressed to vascular dementia, 50% had prior amnestic MCI; all patients who progressed to a frontal dementia syndrome had single nonmemory MCI previously. CONCLUSIONS: The majority of patients with MCI progressed to dementia and a significant proportion died. Subtype of MCI may influence rates of progression to death and to dementia and has a major influence on subsequent type of dementia diagnosis.