Anna Frank

A polymorphism in the tau gene associated with risk for Alzheimer's disease.

Searching for tau genetic variations which could be associated with risk for Alzheimers disease (AD), we have performed a mutational analysis of a region containing the whole exon 11 of the tau gene, which encodes a microtubule binding region critical for tau self-assembly, and we have found a biallelic polymorphism at position +34 of intron 11 (IVS11 + 34G/A). We have analyzed the allelic frequencies of this polymorphism in a case-control sample (167 clinically diagnosed AD and 194 controls) and found that the presence of any G allele (genotypes AG + GG) is associated with a five-fold AD risk in individuals carrying the apolipoprotein E4 allele, strongly suggesting that the combined effect of tau and apoE is relevant in relation with AD pathogenesis.

Alzheimer's risk associated with human apolipoprotein E, alpha-2 macroglobulin and lipoprotein receptor related protein polymorphisms: absence of genetic interactions, and modulation by gender

Apolipoprotein E (apoE), the lipoprotein receptor related protein (LRP) and alpha-2 macroglobulin (alpha2M) have been proposed as a functional complex involved in amyloid clearance, a crucial event for Alzheimers disease development. In this work, we present an epidemiological approach aimed to study the interactions among these genes, age and gender. This approach did not reveal significant associations between the genes; however, the present study indicated that the risk associated with APOE promoter and LRP gene polymorphisms is modulated by gender.

Polymorphism in genes involved in adrenergic signaling associated with Alzheimer's.

To investigate the potential involvement of adrenergic signaling in Alzheimers disease (AD) pathogenesis, we performed genetic and functional studies of genes initiating the cascade. We chose two functional single-nucleotide polymorphisms (SNPs) in the beta1-adrenergic receptor (ADRB1) and the G protein beta3 subunit (GNB3) genes, respectively, and analyzed their allelic frequencies in a case-control sample of AD. We found that the GNB3 T allele produces a significant risk for AD in individuals homozygous for the ADRB1 C allele, suggesting that the combined effect of both polymorphisms influences AD susceptibility. Interestingly, the co-expression of GNB3 T and ADRB1 C alleles, compared with GNB3 C and ADRB1 G, produced increased cAMP levels and MAPK activation following adrenergic stimulation of transfected human cell lines. Furthermore, the co-expression of these alleles also produced increases in APP expression. These data strongly indicate that the combination of GNB3 and ADRB1 polymorphisms produces AD susceptibility by changing the cell responsiveness to adrenergic stimulation, pointing to the modulation of brain adrenergic receptors as a potential target for novel AD therapeutic strategies.

PHARMACODYNAMICS OF THE ORAL BACE INHIBITOR JNJ-54861911 IN EARLY ALZHEIMER'S DISEASE

cebo were studied. Comprehensive neuropathological assessments were performed ranging from 4 months to 14 years after the trial. Large coronal paraffin sections of cerebral hemisphere were immunostained for Ab, scanned, then (i) the entire neocortical ribbon was scored for plaques in a CERAD-like manner (frequent1⁄43, moderate1⁄42, sparse1⁄41, none1⁄40) and (ii) false coloured to permit visualisation of staining patterns at low power. Results: 16/21 had a distribution of tangles and at least some residual Ab pathology indicating the cause of dementia had been AD, whereas 5/21 had alternative causes for dementia (PSP1⁄41, DLB1⁄41, VaD1⁄41and FTDTDP431⁄42). 18/21 had received the active agent and 3/21 the placebo. Scanning and false colouration of large Ab immunostained sections generated images suitable for comparison with amyloid PET scans as used in current immunotherapy trials. 13/15 AD subjects receiving the active agent had evidence of plaque removal (almost complete removal1⁄45, extensive patches of removal1⁄44, small patches of removal1⁄44, no plaque removal1⁄42). In the immunised AD group the mean plaque score was 1.46 (range1⁄40.05-2.9) vs. 2.4 for the single placebo AD case. There was a significant inverse correlation between peripheral blood anti-Ab titres and plaque scores. Conclusions: AD patients actively immunised against Ab can remain virtually plaque–free for up to 14 years. Nearly a quarter of the patients examined in this study did not have neuropathologically verified AD. Neuropathology follow up of patients in therapeutic trials for AD provides valuable information on the cause of dementia and effects of treatment.

TOWARD HARMONISATION OF NEUROPSYCHOLOGICAL ASSESSMENT OF ALZHEIMER’S DISEASE IN EUROPE: EVIDENCE FROM NOVEL COGNITIVE MAKERS

Background: Prior research links vascular risk factors and depression to cognitive functioning; however, few studies have examined this phenomenon in Mexican Americans. Mexican Americans report higher rates of depression symptomology and prevalence of cardiovascular risk factors, both of which put them at risk for cognitive impairment in later life. The goal of this study was to examine the relationship between vascular risk and depression on executive functioning among Mexican American adults and elders. Methods:Data was analyzed from 352 Mexican American women (NC1⁄4289; MCI1⁄449), enrolled in the Health and Aging Brain among Latino Elders (HABLE) study. The HABLE study is an epidemiological study of cognitive aging among Mexican Americans. Participants underwent an interview, neuropsychological testing, blood draw, medical examination, and informant interviews. Cognitive diagnosis were assigned via consensus review using standard published criteria. Vascular risk (BMI-Framingham 10 year Cardiovascular Risk Scores) and depression (Geriatric Depression Scale) were entered into the model as predictors. Executive function was assessed via Trails B scaled scores, and the EXIT. Linear regression analyses were split by cognitive status. Follow up logistic regression analyses were carried out to examine the relationship between vascular risk and depression on MCI diagnosis. Results: For normal control women, the average age was 58.0(SD1⁄4 5.9) and the BMI-Framingham risk score was 17.0 (SD1⁄49.2). For MCI women, the average age was 61.4 (SD1⁄46.8), and Framingham risk score was 20.6(SD1⁄48.2). Among normal controls, higher depression (p1⁄4.003) and higher vascular risk (p1⁄4.002) were significantly associated with low Trails B scaled scores. High vascular risk (p1⁄4.010) and GDS (p1⁄4.011) scores were significantly associated with higher EXIT scores. For MCI, there were no significant findings for Trails B or Exit. Higher GDS scores (OR1⁄41.10; 95% CI 1⁄41.030-1.115, p1⁄4 .001), and higher vascular risk scores (OR1⁄41.04; 95%CI1⁄41.01-1.10, p1⁄4.020) significantly predicted MCI status in Mexican American women. Conclusions: Vascular risk and depression were significantly associated with poorer executive dysfunction, and increased risk for MCI in Mexican American women. These findings suggest a vascular depression may contribute to cognitive dysfunction among in Mexican Americans.

AMYLOID-β42 (Aβ42) DIFFERENTIALLY CORRELATES WITH CSF TOTAL AND HYPERPHOSPHORYLATED TAU IN AN AMYLOID-POSITIVE VERSUS AMYLOID-NEGATIVE EARLY PRODROMAL AND ASYMPTOMATIC AT-RISK FOR AD POPULATION

the sets of biomarkers and clinical/cognitive outcomes including EYO itself and a global cognitive composite from 22 tests, and compared the matrix from the two EYO sub-intervals. If the correlation matrices were different, we repeated the procedure to each EYO sub-interval until no further dichotomization led to different correlation matrices. A canonical correlation analysis was subsequently performed to MCs in each EYO sub-interval to derive the optimum correlation between the two sets of markers and the optimum weighted canonical variates of biomarkers. Similar analyses were repeated to Non-MCs. Results: The correlation structure from 101 asymptomatic MCs between the sets of biomarkers and clinical/cognitive outcomes was significantly different with EYO dichotomized at -7 years (p<0.0001). Further dichotomization led to a statistical trend, suggesting another possible cutoff of EYO1⁄419yr. For MCs at least 19 years prior to symptom onset (EY)<1⁄419yr), the canonical variate of biomarkers had large weights on CSF Ab42 and PET PIB cortical uptake but almost 0 weights on CSF tau, MRI cortical thickness(precuneus), and PET FDG mean cortical uptake. In contrast, the canonical variate of biomarkers within 7 years of symptom onset(EYO>-7yr) had large weights on MRI cortical thickness, hippocampal volume, and PET FDG uptake. Finally, the canonical variate of biomarkers with EYO from -19 to -7 years weighed largely on CSF Tau and Ab42. Interestingly, the weight on MRI hippocampal volume was large even in the earliest preclinical stage(EYO<1⁄4-19yr). Analyses on 95 asymptomatic Non-MCs revealed no significant difference on correlation structures between biomarkers and clinical/cognitive outcomes as a function of EYO. Conclusions:Results support the hypothesized biomarker orderings and NIA-AA preclinical stages of AD, but the role of hippocampal volume mandates further investigation.