Plasma Abeta42 Research Articles

Associations of smoking and biohazard exposure with Alzheimer’s disease brain and plasma biomarkers in early old age

AbstractBackgroundCigarette smoking and environmental exposure to other biohazardous chemicals and substances are associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Their associations with Alzheimer’s Disease (AD)‐related brain indicators of structural integrity and plasma biomarkers are less often examined.MethodAt average age 68 (range 61‐73), 1118 male participants in the Vietnam Era Twin Study of Aging (VETSA) self‐reported on cigarette smoking habits which we used to calculate pack years. Participants also self‐reported on prolonged or severe exposure to herbicides/pesticides, metal dust, Agent Orange, or other biochemical hazards. Using MRI data collected at average age 68 from approximately 470 participants, we examined a published an AD‐Brain signature based on thickness in 7 AD‐related cortical regions and hippocampal volume. We created a novel an AD‐Mean Diffusivity (AD‐MD) signature based on those same regions (higher AD‐MD scores being worse). We also examined a predicted brain age difference score (PBAD), an indicator of global accelerated brain aging. Plasma abeta42, abeta42/40 ratio, and total tau (t‐tau) were assayed using the Quanterix Simoa system. Multivariable analyses controlled for age, ethnicity, education, and the random effect of family (i.e., twin pairs).ResultsSmoking pack years at age 68 were negatively associated with AD‐Brain Signature (p<0.0001) and PBAD (p=0.0013). Pack years (p=0.0001) and Agent Orange (p=0.047) were positively associated with AD‐MD Signature. T‐tau was positively significantly associated with smoking (p=0.0039) and Agent Orange (p=0.004).ConclusionsHeavier lifetime smokers had brains more similar to brains of adults with AD, showed accelerated brain aging, and had higher levels of t‐tau in early old age. All of these are indicators of higher risk for AD. Exposure to Agent Orange, a toxic herbicide, was also related to poorer structural brain integrity and t‐tau. Smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority. The results suggest that more attention should be paid to potentially toxic environmental exposures that may increase risk for AD and other health conditions.

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes.

ObjectiveWe investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD).MethodsWe included 248 subjects with SCD (61 ± 9 years, 42% female, Mini‐Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models.ResultsFifty‐seven (23%) subjects were CSF‐amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF‐amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69–84%; plasma Abeta42: AUC = 66%, 95% CI: 58–74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77–89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4–2.3).InterpretationPlasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656–666

CSF AND PLASMA BIOMARKERS FOR DIAGNOSING DEMENTIA IN OUTPATIENT CLINIC

There is a great need for biomarkers that could diagnose Alzheimer’s disease (AD) early in the course of the disease. We accessed the usefulness of CSF and plasma biomarkers in outpatients. CSF Abeta40, Abeta42, total tau and plasma Abeta40, Abeta42 were measured in 239 outpatients attending the department of neurology at Hirosaki University hospital (37 AD, 14 MCI, 80 other dementia, 148 other neurological diseases, 12 normal controls). CSF Abeta40/42 ratio, CSF total tau, CSF AD index (CSF Abeta40/42 x CSF total tau), and plasma Abeta40/42 ratio were assessed. CSF Aß40/42 ratio, total tau, AD index were all increased significantly in AD and MCI patients. In AD patients, the specificity was around 82% in the all three indexes when the sensitivity was set at 90%. In AD patients, plasma Abeta40/Abeta42 ratio was significantly increased compared to normal control, however, the sensitivity and specificity was low. The specificity to diagnosis MCI was highest in CSF Abeta40/Abeta42, suggesting that the change of Abeta precedes that of tau. To predict the conversion of MCI to AD, CSF Abeta40/42 was useful. CSF Aß40/42, total tau, AD index were all useful for diagnosing AD. To diagnose MCI, CSF Abeta40/Abeta42 was useful.

Plasma and Cerebrospinal fluid (CSF) Abeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting

Background Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. Objectives To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. Search methods We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. Selection criteria We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. Data collection and analysis Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. Main results We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. Authors' conclusions Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

Quantitation of plasma Abeta40 and Abeta42 levels using rabbit monoclonal antibodies

Previously we quantitated plasma Abeta40 and Abeta42 levels using a combination of mouse monoclonal antibody 6E10 as a capture antibody and rabbit polyclonal antibodies specific to Abeta as detection antibodies. Recently, we have produced rabbit monoclonal antibodies (Rabmab) to Abeta40 and Abeta42. Currently there is a great interest in the measurement of plasma Abeta levels at intervals in AD and elderly non-demented controls. Reports showed conflicting data and the reason is not known. We hypothesize that differences in antibody epitopes and affinity may have contributed to the variable findings. We examined 40 AD or control plasma samples using 1) a combination of Rabmab to Abeta as capture antibodies and 4G8 mouse monoclonal antibody as detecting antibody; and 2) mouse monoclonal antibody 6E10 as a capture antibody and Rabmab to Abeta as detecting antibodies in sandwich ELISA. There was a significant relation between Abeta40 levels of Rabmab to Abeta40 and rabbit polyclonal antibody to Abeta40 using 4G8 as detecting antibody (r = .67; p < 0.001), and Rabmab to Abeta42 and rabbit polyclonal antibody to Abeta42 using 4G8 as detecting antibody (r = .97; p < 0.001). Similarly there was a relation between Abeta levels using mouse monoclonal antibody 6E10 as capture antibody and Rabmab or polyclonal antibody as detecting antibodies. When the relationship between the levels using 4G8 and 6E10 were compared, there was a significant relation in Abeta40 levels (r = .63; p < .001) but not in Abeta42 levels (r = .19; p < .24). The data show that differences in capture or detecting antibodies may contribute to different findings among published studies.

APOE Genotype Results in Differential Effects on the Peripheral Clearance of Amyloid-β42 in APOE Knock-in and Knock-out Mice

The epsilon4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-beta (Abeta) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE-/- mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Abeta42 in APOE epsilon2, epsilon3, and epsilon4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the rate at which the mice are able to clear Abeta42 from their bloodstream. Both APOE epsilon4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Abeta42 over time compared to APOE epsilon2/APOE knock-out rE2 and APOE epsilon3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Abeta42 is significantly altered by APOE genotype. Given that APOE epsilon4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Abeta which may impact on clearance from the brain.

Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, Aß, and Alzheimer's Disease

BackgroundThe insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).Methodology/Principal FindingsWe examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5×10−8, fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Aβ40 levels (ß = −0.124, p = 0.011) and total measured plasma Aβ levels (b = −0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association.ConclusionsThus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Aß40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

Reduction of Aβ42 in brains of transgenic APPswe mice by 2‐3‐chlorophenylaminophenylacetate

1. Imbalanced generation of the Abeta42 peptide from the amyloid beta protein precursor (APP) is implicated in the pathogenesis of Alzheimer's disease. 2. The present study is the first to evaluate the ability of 2-[3-chlorophenylamino]phenylacetic acid (GLY-230), a new drug in clinical development for the treatment of vascular complications of diabetes, to modulate Abeta42 levels in transgenic mice expressing APP. 3. Oral administration of 7.5 mg/kg GLY-230 twice a day for 14 days to APPswe transgenic mice aged 3 months significantly reduced brain Abeta42 and increased plasma Abeta42 levels by 50 and 20%, respectively. 4. GLY-230 readily entered the brain after administration of a dose (7.5 mg/kg) that decreased brain Abeta42. 5. These results are the first to demonstrate that GLY-230, which exhibits antiglycation but no cyclo-oxygenase inhibitory properties, lowers brain Abeta42 levels in this experimental model of Alzheimer's disease.

Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).

Depression and Plasma Amyloid β Peptides in the Elderly With and Without the Apolipoprotein E4 Allele

Depression associated with low plasma amyloid-beta peptide 42 (Abeta42) leading to a high ratio of Abeta40/Abeta42, a biomarker of Alzheimer disease (AD), may represent a unique depression subtype. The relationship between low plasma Abeta42 in depression and the major risk factor of AD, apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Abeta40 and Abeta42 were measured, and cognition were evaluated. In the absence of the ApoE4 allele, depressed subjects had lower plasma Abeta42 [median (Q1, Q3): 17.1 (11.6, 27.8) vs. 20.2 (12.9, 32.9) pg/mL, P=0.006], a higher Abeta40/Abeta42 ratio [median (Q1, Q3): 7.1 (4.6, 11.3) vs. 6.9 (3.4, 9.7), P=0.03], and lower cognitive function (mean+/-SD of Mini-Mental State Examination: 24.5+/-3.1 vs. 25.5+/-3.3, P<0.0001) than those without depression. In contrast, these relationships were not observed in the presence of ApoE4. Instead, regardless the depression status ApoE4 carriers had lower plasma Abeta42 and a higher Abeta40/Abeta42 ratio than non-ApoE4 carriers. Using multivariate logistic regression, it was found that depression was not associated with ApoE4 allele, but with the interaction between plasma Abeta42 and ApoE4 (odds ratio=3.94, 95% confidence interval=1.50, 10.33, P=0.005), denoting low plasma Abeta42 in the absence of ApoE4. Both ApoE4 carriers and non-ApoE4 carriers with depression had lower Abeta42 and a higher Abeta40/Abeta42 ratio in plasma compared with non-ApoE4 carriers without depression in the homebound elderly. As a combination of low plasma Abeta42 and high plasma Abeta40 has been shown to increase the risk of AD in 2 large cohort studies, amyloid-associated depression shown in this study may suggest a risk factor of AD in the absence of ApoE4.

Plasma Levels of Amyloid β1-42 Are Independent of Neuronal Function in Alzheimer's Disease

The aggregation of amyloid-beta42 (Abeta42) constitutes one of the major pathogenic events in Alzheimer's disease (AD), and the study of regional cerebral blood flow (rCBF), using single photon emission computed tomography (SPECT), aids the diagnosis of AD. In this study, we evaluated whether there was a correlation between rCBF in brain regions and plasma levels of Abeta1-42 in AD. 29 patients (mean age 71 +/- 9) with a diagnosis of AD who fulfilled NINCDS-ADRDA criteria with a mean Mini-Mental Status Examination score of 15 +/- 9 and 16 normal controls (mean age 64 +/- 8) underwent SPECT brain imaging with hexamethylpropylene amine oxime, and semiquantitative analysis of rCBF was performed. Plasma samples were collected the same day of the SPECT and plasma Abeta1-42 measured by ELISA. A significant reduction of rCBF was observed in most regions in AD compared to controls, whereas mean plasma Abeta42 did not differ between the two groups. There was no correlation between rCBF in any region and plasma Abeta42 nor any correlations between gender, age, and severity with plasma levels of Abeta42. Since rCBF is coupled to neuronal activity, we conclude that plasma Abeta1-42 concentration is independent of neuronal function in every single region of the brain.

Association of Cardiovascular Factors and Alzheimer's Disease Plasma Amyloid-β Protein in Subjective Memory Complainers

A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimer's disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Eepsilon4 (APOEepsilon4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-beta (Abeta) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Abeta levels. We explored this in 198 individuals with and without SMC (average age = 63 years). Correlations between Abeta40 and HDL were observed, which were stronger in non-APOEepsilon4 carriers (rho = -0.315, p < 0.001) and in SMC (rho = -0.322, p = 0.01). There was no relationship between percentage body fat and Abeta40 in this cohort. Age and HDL remained predictive for plasma Abeta40 using multivariate regression analysis. We report a novel negative association between HDL and Abeta, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Abeta and the potential significance of such an association needs to be validated in a larger longitudinal study.

Plasma Aβ, homocysteine, and cognition

Amyloid-beta protein (Abeta) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Abeta levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation-induced reduction of tHcy influences plasma Abeta levels in the Vitamin Intervention in Stroke Prevention (VISP) study. Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Abeta with 40 (Abeta40) and 42 (Abeta42) amino acids were measured at baseline and at the 2-year visit. tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Abeta40 but not Abeta42 concentrations. There was no difference in the change in Abeta40, Abeta42 (p = 0.40, p = 0.35), or the Abeta42/Abeta40 ratio over time (p = 0.86) between treatment groups. Abeta measures were not associated with cognitive change. This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Abeta40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Abeta, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Abeta40, they may be regulated by independent mechanisms.

Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

Plasma Abeta42 and Abeta40 levels are putative biomarkers for Alzheimer's disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Abeta42 and Abeta40 increase with age but subsequently decrease when Abeta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Abeta levels in elderly populations, we investigated how plasma Abeta42, Abeta40, and a protofibrillar subspecies of Abeta42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Abeta42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Abeta42, a decreased Abeta42/Abeta40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Abeta42 levels. Our results suggest individuals with elevated plasma Abeta42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Abeta may reflect compartmentalization of Abeta peptides in the brain.

P4-344: Oral curcumin for the treatment of mild-to-moderate Alzheimer's disease: Tolerability and clinical and biomarker efficacy results of a placebo-controlled 24-week study

Background: Curcumin is phenolic compound with anti-inflammatory and antioxidant properties that has been shown to have anti-amyloid activity in transgenic mice. The purpose of this study was to obtain tolerability and preliminary efficacy data of 2 gm/day and 4 gm/day of Curcumin C3 Complex in mild-to-moderate AD patients in a 24-week, randomized, double-blind study. Methods: Thirty-six patients were randomized to receive placebo, 2 gm, or 4 gm per day of curcumin in two divided doses. The MMSE, ADAS-Cog, NPI, and ADCS-ADL scales were performed at baseline and at 24 weeks’ time. Plasma and cerebrospinal fluid (CSF) samples were obtained at baseline and 24 weeks and Abeta40, Abeta42 measured in plasma and CSF and total tau and p-tau181 measured in CSF. Baseline and 24-week values were compared between groups using repeated measures ANOVA. Adverse events were recorded and the frequency of any adverse event at each visit compared between groups by chi-square. Results: Subjects’ age (mean 74 years), gender (62% female), baseline MMSE (mean 22.6), ADAS-Cog, NPI, and ADCS-ADL scores did not differ between treatment groups. 11 subjects on placebo, 9 on 2 grams and 10 on 4 grams of curcumin completed the study. In completer analyses, there were no differences or favorable trends between placebo and treatment groups on clinical measures. No difference in plasma or CSF biomarkers were found between groups except for a tendency (p 0.14) towards a lesser degree of increase in plasma Abeta42 in the combined group on 2 and 4 gm/day of curcumin. There were no differences between placebo and all treated patients’ change in laboratory values nor in the frequency of adverse events at any treatment visit. Conclusions: Orally administered Curcumin C3 Complex is safe in elderly persons treated for 24 weeks at doses up to 4 gm/day. Our data do not provide evidence for a large effect of curcumin on clinical and biochemical measures in mild-tomoderate AD patients at doses up to 4 gm/day. Limitations of this study include the small sample, short duration of treatment, and uncertain bioavailability of this curcumin formulation. Further analyses of clinical, pharmacokinetic, and biomarker data are pending.

P2-329: Lowering of brain and plasma Abeta42 in rats using gamma-secretase modulators

P2-329: Lowering of brain and plasma Abeta42 in rats using gamma-secretase modulators

Genetic association of CTNNA3 with late-onset Alzheimer's disease in females

Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal the ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60-107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Abeta42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-epsilon3*3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3 were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P-values(MH-F) = 0.000005945-0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-epsilon4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-epsilon4 allele.

Blood‐based neurochemical diagnosis of vascular dementia: a pilot study

Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.

Depression, Antidepressants, and Plasma Amyloid β (Beta) Peptides in Those Elderly Who Do Not Have Cardiovascular Disease

Low plasma amyloid-beta peptide 42 (Abeta42) is associated with depressive symptoms independently of cardiovascular disease (CVD) in the elderly. It is critical to investigate whether antidepressants modify this relationship. We evaluated 324 elders without CVD in a cross-sectional study. Depression was evaluated with the Center for Epidemiological Studies Depression (CES-D) scale. Antidepressants were documented. Plasma Abeta40 and Abeta42 were measured. In the absence of CVD, those with depression had lower plasma Abeta42 (median: 13.7 vs. 18.8 pg/mL, p = .003) than those without. Depressed subjects on antidepressant treatment had a lower concentration of plasma Abeta40 (median: 97.8 vs. 133.5 pg/mL, p = .008), but not Abeta42, than those without the treatment. Multivariate logistic regression showed that antidepressant use did not influence the relationship between depression and low plasma Abeta42 (odds ratio = .55; 95% CI = .33, .90; p = .02) after adjusting for confounders, but its use interacted with plasma Abeta40 in the model. Lower concentration of plasma Abeta42 is associated with depression in the absence of CVD that is not related to the antidepressant use by those subjects. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 predicts the onset of Alzheimer's disease.