Can biomarkers and genetic analysis help predict Alzheimer’s disease?

A study published in Brain identified novel plausible and significant genome-wide genes associated with biomarkers of Alzheimer’s disease (AD).

Alzheimer’s disease affects tens of millions of people worldwide, however, at autopsy approximately 25% of patients with Alzheimer’s disease have no underlying pathology, indicating a diagnosis potentially inaccurate. Despite the difficulties of diagnosis, early detection is essential to combat the effects of the disease.

To assess the accuracy of the biomarkers and identify new related genes, researchers at Cardiff University in the UK obtained data from the Alzheimer’s Disease Cardiff Cohort (ADCC). Plasma samples were collected between 2004 and 2020 from 1439 patients with sporadic early- and late-onset AD and 508 control individuals. Single nucleotide polymorphism (SNP)-based association analysis was performed for plasma biomarkers.

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Plasma concentrations of 42 amino acid amyloid b fragments (Ab42) and 40 amino acid amyloid b fragments (Ab40) were correlated between cases (r, 0.8) and controls (r, 0.7; P16).

Among cases, age of onset was strongly correlated with circulating levels of Ab40, Ab42, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL; all P £4.2´1023), moderately correlated with phosphorylated tau at amino acid 181 (P-tau181; P =.0023), and negatively associated with the Ab42/Ab40 ratio (P £4.8´104).

These biomarkers could predict disease state with an area under the curve (AUC) of 0.74. On their own, the AUC prediction accuracies for Ab42 and P-tau181 were 0.66 and 0.65, respectively.

The prediction model using the biomarkers combined with previously associated genes had an AUC of 0.81.

In the genetic analysis, relating genes with Ab40, Ab42, NfL, P-tau181, GFAP and the Ab42/Ab40 ratio, the top 5 SNPs had a significance level of P £1´105 and 2 regions achieved genome-wide significance.

The first significant genome-wide locus was on chromosome 7 and included the COPI genes coat complex subunit gamma 2 (COPG2) and specific to the testicles 13 (TSGA13). This region exhibits high linkage disequilibrium. The 2 main SNPs in the region had high combined annotation-dependent deletion (CADD) scores (more than 12.37), indicating that they were deleterious and one intergenic variant had a RegulomeDB (RDB) score ( 3a) indicating a functional impact on gene regulation.

The second genome-wide significant region was on chromosome 16 and contained the WW domain-containing oxidoreductase (WWOX) gene that has previously been linked to Alzheimer’s disease in a genome-wide association study.

These results need to be confirmed by an independent data set.

“The idea that biomarkers alone might provide a more accurate prediction of Alzheimer’s disease remains to be fully validated,” the researchers concluded. Further longitudinal study is needed to assess whether biomarkers alone can provide an accurate prediction of AD.

Disclosure: Several authors have declared industry affiliations. Please refer to the original article for a full list of disclosures.


Stevenson-Hoare J, Heslegrave A, Leonenko G, et al. Plasma and genetic biomarkers in the diagnosis and 1 prediction of Alzheimer’s disease. Brain. April 6, 2022 doi:10.1093/brain/awac128

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