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Novel Plasma Biomarkers May Improve Prediction of Alzheimer Disease

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The incorporation of plasma cell-free (cf)-mRNA levels may be a possible contributor to the improved predictive value of Alzheimer disease (AD) biomarker panels, according to study findings published in the journal eBioMedicine.

Recognizing that African Americans are underrepresented in AD research, despite the fact that the prevalence of AD in this population is twice that of non-Hispanic Whites, the researchers established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS). The purpose of FCA3DS was to focus on the identification of genetic risk factors and novel plasma biomarkers for AD.

The study conducted included African American patients with AD (recruited from the Mayo Clinic in Jacksonville, Florida, or the Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai, in Miami, Florida) and cognitively unimpaired (CU) control individuals.

Whole exome sequence (WES) and plasma RNA samples from 151 patients with AD and 269 CU older control individuals were used to perform differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts that were measured with a custom nanoString® panel. The researchers designed this panel in an effort to calculate, in plasma, cf-mRNA levels of AD-related genes. 

Following Bonferroni correction, the association with higher plasma CLU in CU control individuals vs patients with AD remained significant. Studywide significant eQTL associations were reported with 105 WES variants in cis with 22 genes, which included variants in genes that were previously linked to risk for AD in African American individuals, such as ABCA7 and AKAP9. This plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that have been shown to be significantly associated with lower and higher plasma mRNA levels of these genes, respectively.

Receiver operating characteristic (ROC) analysis of age, sex, apolipoprotein E ε4 allele (APOE-ε4) dosage, CLUAPPCD14ABCA7AKAP9, and APOE mRNA levels, as well as ABCA7 and AKAP9 eQTLs, attained 77% area under the curve (AUC) for distinguishing AD from CU—representing an 8% improvement over a model that included only age, sex, and APOE-ε4 dosage.

The current study is the first of its kind to focus on the African American population and possible biomarkers of AD in these patients. A set of 6 plasma cf-mRNAs were identified, which, along with sex, age, and APOE-ε4 allelic dosage, yielded an ROC AUC of 0.77 for differentiating between patients with AD and CU control individuals. The value of this study rests in the novelty of the targeted approach of testing specific plasma cf-mRNA levels as possible biomarkers of AD, its emphasis on an underserved and understudied population, and the identification of a predictive set of plasma cf-mRNAs that may pave the way toward improved accuracy in AD diagnosis.

There are several limitations to the present study, including its relatively small sample size, the fact that AD was clinically diagnosed without validation on autopsy, and the lack of a replication cohort.

The researchers concluded that the results of the current analysis “…provides an estimate of the AD predictive value for a plasma cf-mRNA panel in African Americans that will guide future studies of these novel biomarkers in this underrepresented and other populations.”

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Schedule8 Jun 2023