In a recent study published in Nature Aging, researchers from China analyzed the proteomic data of adults without dementia. They found that GFAP (short for glial fibrillary acidic protein) is an optimal biomarker for predicting dementia, even greater than ten years before diagnosis, highlighting its potential role in screening high-risk individuals and enabling early intervention.

Study: Plasma proteomic profiles predict future dementia in healthy adults. Image Credit: mapush / Shutterstock

Background

Detecting the progression of dementia from asymptomatic stages to clinical manifestation is crucial, given the present lack of effective therapy. The emergence of blood-based biomarkers offers a possible breakthrough, presenting a promising tool for early risk screening and intervention within the preclinical phase of dementia. Previous efforts in biomarker discovery for dementia risk have focused on a limited variety of proteins attributable to technical constraints and a scarcity of systematic comparison. Prior investigations employing proteomics strategies revealed blood protein differences but were often cross-sectional and didn’t address temporal facets or specific dementia subtypes. Large-scale prospective studies with data on blood proteomics and various dementia types are essential for improving our understanding.

The predictive performance of proteins (individual or combined) in various incidence time groups (e.g., 10 years, >10 years) has been missed despite being an important aspect of ultra-early detection and prevention. Despite previous efforts, there stays a dearth of blood proteomic biomarkers with the needed sensitivity and specificity for predicting future dementia. Subsequently, researchers in the current study employed a large-scale proteomic approach to discover plasma biomarkers related to dementia, exploring their predictive performance and trajectories related to clinical progression.

Concerning the study

On this prospective cohort study, data from the UK Biobank (UKB) was used. The study included 52,645 dementia-free adults of median age 58 years; 93.7% were White and 53.9% were female. Although the blood samples were collected and preserved between 2007 and 2010, their proteomic profiling was conducted between 2021 and 2022. Normalized Protein eXpression (NPX) values were generated to account for variations.

The first outcomes were incident events related to AD, vascular dementia (VaD), and all-cause dementia (ACD). The outcomes were identified through comprehensive data sources, similar to reports from primary care records, hospital admissions, and death registry records. The earliest recorded date of diagnosis from these sources determined the dementia diagnosis date. Follow-up (median 14.1 years) for participants commenced from their attendance on the assessment center. It continued until the earliest of the recorded diagnosis date, mortality date, or the last available date provided by healthcare providers. The study ensured the reliability of dementia diagnoses by linking data to UK electronic health records, where skilled clinicians reported and classified cases based on the International Classification of Diseases (ICD)-9 and ICD-10 codes. Self-reported disease cases were excluded to boost diagnostic accuracy. Statistical evaluation involved using Cox proportional hazard models, chi-square tests, Student’s t-tests, enrichment evaluation, receiver operating characteristic (ROC) evaluation, Kaplan–Meier curves, and Mann-Kendall trend tests.

Results and discussion

Over the follow-up, the incidence of dementia was found to be 2.7%. The median age of incident AD participants was 66 years, with 48.5% females. The incidence rate of AD and other dementias increased with age, peaking at 6.26 per 1,000 person-years within the 65–69-year age group.

After adjusting for relevant aspects, GFAP and NEFL (short for neurofilament light) demonstrated essentially the most significant associations with incident all-cause dementia, AD, and VaD. Moreover, GDF15 (short for growth/differentiation factor 15) and LTBP2 (short for latent transforming growth factor beta binding protein 2) were implicated in increased dementia risk, with enrichments in pathways related to extracellular matrix organization, immune system, and infectious diseases. These proteins also ranked highest in predicting all-cause dementia and its subtypes.

NEFL, GFAP, and GDF15 exhibited modest individual predictive accuracy for all-cause dementia, with potential improvement when combined with demographic indicators and cognitive tests. Notably, combining NEFL or GFAP with demographic features and temporary cognitive tests showed significant enhancement in accuracy.

Further, individuals with higher baseline levels of GFAP had a 2.91 times greater likelihood of developing AD, while those with higher GDF15 levels had a 2.45 times greater likelihood of developing VaD. Interestingly, although GFAP levels were found to be related to an increased risk of other dementias, they didn’t look like related to other neurological ailments. The study is strengthened by an prolonged follow-up and the high-throughput proteomic evaluation of a giant community-based sample. Nevertheless, it is proscribed by potential biases, lower dementia incidence in participants, lack of external validation datasets, variability in detection techniques, and diagnostic uncertainty.

Conclusion

In conclusion, the study suggests that GFAP levels hold high predictive value in identifying the danger of dementia in the longer term, even ten years before onset. These findings could have significant implications for screening individuals at an increased risk of dementia and for implementing early intervention strategies for improved prognosis.