About AlzBiomarker

Methods

This database contains summary-level data extracted from primary peer-reviewed publications. To identify eligible publications we systematically searched PubMed and the Web of Science database. Search results were evaluated according to predetermined inclusion criteria. Specialist readers extracted data from eligible articles and an independent reader verified the accuracy of the curated data. To facilitate meta-analysis, we attempted to standardize terms pertaining to biomarker names, biomarker quantification methods, and clinical conditions, see glossary.

Search Strategy


Version 1.0, December 2015

The following search terms were used to identify publications possibly containing eligible data:

("alzheimer disease"[MeSH Terms] OR ("alzheimer"[All Fields] AND "disease"[All Fields]) OR "alzheimer disease"[All Fields] OR "alzheimer"[All Fields]) OR ("alzheimer disease"[MeSH Terms] OR ("alzheimer"[All Fields] AND "disease"[All Fields]) OR "alzheimer disease"[All Fields] OR "alzheimer's"[All Fields])) AND (("biological markers"[MeSH Terms] OR ("biological"[All Fields] AND "markers"[All Fields]) OR "biological markers"[All Fields] OR "biomarker"[All Fields]) OR CSF[All Fields] OR ("plasma"[MeSH Terms] OR "plasma"[All Fields]) OR ("serum"[MeSH Terms] OR "serum"[All Fields]) OR cerebrospinal[All Fields]) NOT Review[ptyp] AND ("humans"[MeSH Terms] AND English[lang])

In addition, terms pertaining to a set of candidate biomarkers were included, including: Aβ42 (Aβ-42 OR Abeta42 OR “Abeta 42”), tau (T-tau OR TTau OR P-tau OR Ptau* OR P-tau*), NFL (NEFL OR NFL OR NF-L OR NF68 OR NFH OR NF-H OR NFM OR NEFM OR “NEUROFILAMENT PROTEIN LIGHT POLYPEPTIDE" OR “NEUROFILAMENT PROTEIN LIGHT CHAIN” OR “NEUROFILAMENT PROTEIN HEAVY POLYPEPTIDE” OR “heavy neurofilament subunit” OR “NEUROFILAMENT PROTEIN MEDIUM POLYPEPTIDE“ OR “neurofilament“), VLP-1 (VSNL1 OR VILIP OR VILIP1 OR VILIP-1 OR VLP-1 OR "VISININ-LIKE 1"), hFABP (HFABP OR FABP3 OR MDGI OR "FATTY ACID-BINDING PROTEIN 3" OR "FATTY ACID-BINDING PROTEIN MUSCLE TYPE" OR "MUSCLE TYPE FATTY ACID-BINDING PROTEIN" OR "MUSCLE TYPE FATTY ACID BINDING PROTEIN" OR " MAMMARY-DERIVED GROWTH INHIBITOR" OR "heart fatty acid binding protein"), NSE (ENO2 OR NSE OR “ENOLASE 2" OR “ENOLASE GAMMA” OR “NEURON-SPECIFIC ENOLASE”), GFAP (GFAP OR GFA OR "GLIAL FIBRILLARY ACIDIC PROTEIN" ), YKL-40 (CHI3L1 OR GP39 OR YKL40 OR YKL-40 OR "CHITINASE 3-LIKE 1" OR "CARTILAGE GLYCOPROTEIN 39" OR "CHONDROCYTE PROTEIN YKL40"), MCP-1 (CCL2 OR CCL-2 OR SCYA2 OR MCP1 OR MCP-1 OR MCAF OR "CHEMOKINE CC MOTIF LIGAND 2" OR “SMALL INDUCIBLE CYTOKINE A2” OR “MONOCYTE CHEMOTACTIC PROTEIN 1” OR “MONOCYTE CHEMOTACTIC AND ACTIVATING FACTOR”), albumin ratio (“albumin ratio”), Aβ38 (Aβ38 OR Aβ-38), Aβ40 (Aβ40 OR Aβ-40), and sAPPα and sAPPβ (APP OR APPα OR APPβ OR sAPPα OR sAPPβ OR AAA OR CVAP OR PN2 OR "AMYLOID BETA A4 PRECURSOR PROTEIN" OR "AMYLOID OF AGING AND ALZHEIMER DISEASE" OR "CEREBRAL VASCULAR AMYLOID PEPTIDE" OR "PROTEASE NEXIN II").

Version 1.1, April 2016

Search performed February 7, 2016 using the keywords neurogranin AND Alzheimer*. Search results were evaluated based on the same inclusion criteria as version 1.0 (described below), with the exception that articles were not restricted by publication date.

Version 1.2, June 2016

Search performed April 30, 2016 using the keywords TREM2 AND Alzheimer*. Search results were evaluated based on the same inclusion criteria as version 1.1.

Inclusion Criteria


  Included Excluded

Study Design

Biomolecule assessed as a potential biomarker

Biomolecule assessed during routine clinical testing

Language of Publication

English

Language other than English

Year of Publication

1984 -June 2014

Pre-1984

Number of Conditions

≥ 2 eligible conditions

< 2 eligible conditions

Conditions

Study includes AD or MCI-AD

Study lacks AD or MCI-AD

Study Subjects

Human

Non-human

Age of Subjects

Mean age of onset ≥ 18 years

Mean age of onset < 18 years

Number of Subjects

≥ 10

< 10

Diagnostic Criteria

Conditions defined by published criteria. Exceptions are controls and certain conditions (e.g., Parkinson's disease and Normal Pressure Hhydrocephalus)

Conditions not defined by published criteria. Exceptions are controls and certain conditions (e.g., PD and NPH). Heterogeneous groups (e.g., "other dementias") and those lacking published diagnostic criteria

Source of Biomarker

CSF, serum, and plasma

Other body fluid samples (e.g., saliva, urine). Biomolecules measured within blood cells (e.g., lymphocytes)

Measurement Methods

Methods that provide quantitative data (e.g., ELISA, xMAP). Selected reaction monitoring (SRM) with an internal standard

Methods that do not provide quantitative data (e.g., Western blot and exploratory proteomics). Selected Reaction Monitoring (SRM) without an internal standard

Format of Biomarker Measurement

Quantitative data reported as mean ± SD or mean ± SEM

Data reported in formats other than mean ± SD or mean ± SEM (e.g., graphical, ROC). Authors are invited to provide data in eligible formats

Mild Cognitive Impairment (MCI) Groups

Groups are considered MCI-Stable if subjects maintained MCI status ≥ 2 years after baseline. MCI groups with subjects converting to AD (i.e., MCI-AD) are included regardless of follow-up time

MCI without cognitive follow-up. MCI-Stable with mean follow-up of <2 years. Heterogeneous groups at cognitive follow-up (e.g., MCI-other dementias)

Previously Reported Data

Original data are only included once to the best of our ability. Only the first cross-sectional study of each biomarker for large studies such as ADNI will be included. Studies with the longest follow-up time in follow-up studies will be included. If the same baseline data of one cohort are re-analyzed in relation to diagnoses at later follow-up time points, the first study is deleted and replaced by a new study. If a later paper reports a new biomarker in the same cohort, only the new biomarker data are added

 


When a study met all required eligibility criteria with the exception of reporting measurement data in a format other than mean ± SD or mean ± SEM (e.g., median and range) we attempted to obtain data in the format required for meta-analysis. In general, the first and last authors of the report were contacted and asked to provide the data as mean ± SD. When possible, the converted data were included in the database and indicated as such.

Meta-Analysis

Meta-analyses were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Liberati et al., 2009). Biomarkers with two or more data points were eligible for meta-analysis. For the purposes of meta-analysis, plasma and serum results were meta-analyzed together.

Meta-analyses were perfomed using ratios of mean biomarker levels (e.g. the AD/control ratio and the MCI-AD/stable MCI ratio). In studies with more than one control cohort, only the most cognitively normal and age-appropriate cohort was used. In studies with more than one AD cohort, all AD cohorts were included and divided by the control group to generate multiple ratios per study. In studies which analyzed eligible biomarkers using more than one assay, only the most common commercial assay was included in the meta-analysis.

The variance of the natural log-transformed ratio of the mean values was estimated using the delta method according to Friedrich et al., 2008.  Random effects meta-analysis using the method of DerSimonian and Laird with the estimate of heterogeneity taken from the inverse-variance fixed-effect model was applied in Stata 13.1 (metan command sbe24_3)(DerSimonian and Laird, 1986). The overall effect size is a weighted average of all individual effect sizes where the inverse of the variances is used as weights.