Predict Alzheimer's Disease up to 10 years in advance from blood tests 

Clusterin, Adiponectin, β-amyloid(1-40) and Pancreatic Polypeptide assay kits now available for Alzheimer's Disease

(1) EK-054-02, FEK-054-02 and RK-054-02 for Pancreatic polypeptide (human) detection
(2) EK-018-01 β-amyloid(1-40) (human) ELISA kit
(3) EK-ADI-01 Adiponectin (human) ELISA kit
(4) EK-018-35 Clusterin (human) ELISA kit

A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI.

CONTEXT: There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level.
OBJECTIVE: To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma.
DESIGN, SETTING, PARTICIPANTS: Analysis of serum biomarker proteins were conducted on 197 Alzheimer's disease (AD) participants and 199 control participants from the Texas Alzheimer's Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The full algorithm was derived from a biomarker risk score, clinical lab (glucose, triglycerides, total cholesterol, homocysteine), and demographic (age, gender, education, APOE*E4 status) data.
MAJOR OUTCOME MEASURES: Alzheimer's disease.
RESULTS: 11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC?=?0.70, sensitivity (SN)?=?0.54 and specificity (SP)?=?0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/A?ratio AUC?=?0.92). However, the full algorithm yielded excellent accuracy (AUC?=?0.88, SN?=?0.75, and SP?=?0.91). The likelihood ratio of having AD based on a positive test finding (LR+)?=?7.03 (SE?=?1.17; 95% CI?=?4.49-14.47), the likelihood ratio of not having AD based on the algorithm (LR-)?=?3.55 (SE?=?1.15; 2.22-5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR)?=?28.70 (1.55; 95% CI?=?11.86-69.47).
CONCLUSIONS: It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses.

O'Bryant et al., PLoS One. 2011;6(12):e28092. Epub 2011 Dec 7.

Biomarkers and Clinical Labs Across Cohorts.

O'Bryant et al., PLoS One. 2011;6(12):e28092. Epub 2011 Dec 7.

Related article:

Amyloid Beta 40-S26C Monomer and Dimer
Pyroglutamate Amyloid-β Peptides

Alzheimer CSF biomarkers in routine clinical setting.

Objectives: Our work was aimed to evaluate Alzheimer's disease diagnosis improvement using cerebrospinal fluid biomarkers (CSF) in neurological daily practice.
Materials and Methods: For this purpose, 150 patients clinically and neurochemically classified as having AD or cognitive impairment with or without other dementia type were included in the study. The following CSF peptides were studied, blindly to the clinical diagnosis: beta-amyloid(1-42) peptide (A?1-42) ), Tau (T-tau), threonine-181 hyperphosphorylated tau protein (P-tau(181) ), and beta-amyloid(1-40) peptide (A?1-40) ). From these measurements, Innotest?Amyloid Tau Index (IATI) was calculated for each patient.
Results: This assessment allowed to separate 83 biochemical profiles of AD and 67 non-Alzheimer's disease (non-AD), both AD and non-AD categories match with clinical data amounting to 73% and 90%, respectively. Among mild cognitive impairment (MCI) patients, CSF biomarkers led to discriminate those who are likely to be AD. We devoted a special section to A?1-40) which is not a routine parameter but can help to confirm a pathological amyloid process as A?1-42) /A?1-40) ratio underlining the real decline of the A?1-42).
Conclusions: The interest of biomarkers and their ability to solve awkward cases were carefully noticed all the more when a discrepancy between clinical and CSF biological data was involved. The final proposed algorithm allowed to identify pathogenic forms of AD according to the prevailing role of hyperphosphorylated tau or amyloid beta peptide.

Tabaraud, et al., Acta Neurol Scand. 2011 Sep 28. doi: 10.1111/j.1600-0404.2011.01592.x. [Epub ahead of print]

 

Synergistic combination of Aβ40 oligomer signal with monomeric Aβ42 concentration

A. The concentration of monomeric Aβ42 was measured in normal (open circles) and AD (closed circles) CSF (***p<0.001). B. The ratio of Aβ40 oligomers (RLU) and Aβ42 concentration (pg/mL) was calculated and plotted for both normal (open circles) and AD (closed circles) populations (***p<0.001). Three AD samples were not included in this analysis because of insufficient sample to measure Aβ42 concentrations. The mean and SEM are shown for all groups.

From: Gao CM et al., PLoS One. 2010 Dec 30;5(12):e15725.

Standard curve of Amyloid β(1-40) (Human) ELISA assay

%18-01%

Related article:

Adiponectin, Adiponectin Receptors & Adiponectin EIA Kits

Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease: Results From the Framingham Heart Study.

OBJECTIVE: To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2) levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.
DESIGN: Prospective cohort study.
SETTING: Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia.
PARTICIPANTS: Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.
MAIN OUTCOME MEASURES: We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE e4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.
RESULTS: Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P= 0.054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P= 0.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P= 0.04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P= 0.01) as compared with those with values less than the median.
CONCLUSION: In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

van Himbergen et al., Arch Neurol. 2012 Jan 2. [Epub ahead of print]

%Adiponectin%

Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.

CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD).
OBJECTIVE: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model.
SETTING: A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging.
PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging.
MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid.
RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques.
CONCLUSIONS: These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.

Thambisetty et al., Arch Gen Psychiatry. 2010 Jul;67(7):739-48.

The subtle difference in the Aβ peptide composition of the soluble pool of brain Aβ is revealed by acid-urea polyacrylamide gels.

The Aβ peptide composition of the carbonate-soluble hippocampal extracts from 12-month-old PDAPP+/+, clusterin+/+ and PDAPP+/+, clusterin-/- mice was determined by acid-urea gel analysis (n = 4 per group). Human Aβ 40 and Aβ 42 synthetic peptides are used for mass and migration comparisons. Soluble extracts analyzed under the completely denaturing conditions demonstrate that human Aβ 2 is the predominant Aβ peptide present. Human Aβ 40 was readily detectable in extracts from all PDAPP+/+, clusterin+/+ mice examined, whereas human Aβ 40 could not be detected in PDAPP+/+, clusterin-/- extracts.

From: DeMattos R B et al. PNAS 2002;99:10843-10848

Dissociation between amyloid plaques and neurite toxicity in PDAPP+/+, clusterin-/- mice.

(A) Brain sections from 12-month-old PDAPP+/+, clusterin+/+ and PDAPP+/+, clusterin-/- mice were labeled with the de Olmos silver stain with or without thioflavine-S (Thio-S) to identify the neuritic dystrophy associated with the fibrillar amyloid. Vast numbers of dystrophic neurites (DN) were observed in the locale of thioflavine-S-positive deposits in PDAPP+/+, clusterin+/+ mice (Upper) at low and high power. Little neuritic dystrophy surrounded thioflavine-S-positive deposits in the PDAPP+/+, clusterin-/- mice (Lower). (B) PDAPP+/+, clusterin-/- mice had significantly fewer dystrophic neurites (mean ± SEM: 42.9 ± 13.8, n = 15) in three equally spaced sections than PDAPP+/+, clusterin+/+ mice (456.6 ± 155.2, n = 13). *, P = 0.0083. (C) The number of dystrophic neurites normalized to the percent area of the hippocampus covered by thioflavine-S was significantly decreased (5-fold) in PDAPP+/+, clusterin-/- mice (mean ± SEM: 40.0 ± 10.1, n = 15) compared with the PDAPP+/+, clusterin+/+ mice (197.3 ?45.8, n = 13). **, P = 0.0014.

From: DeMattos R B et al. PNAS 2002;99:10843-10848

Standard Curve of EIA Kit for Plasma Clusterin Level Detection (EK-018-35)

%clusterin%