Diagnosing dementia is rarely straightforward, particularly early in the disease course. Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia can overlap clinically, while mixed pathology is common in older patients. This creates a major barrier for precision medicine: treatment selection, trial enrolment, prognosis, and patient counselling increasingly require a more biologically grounded diagnosis.
Blood biomarkers have already begun to change Alzheimer’s disease diagnostics, especially for detecting amyloid and tau pathology. But the field still lacks robust plasma tools for distinguishing Alzheimer’s disease from dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD).
Proteomics across dementia cohorts
A new study, published in Nature Aging, used proximity extension assay proteomics to profile plasma proteins across international dementia cohorts. In the discovery phase, researchers analyzed more than 1,300 plasma samples, including controls and individuals across preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia.
The analysis identified more than 200 dysregulated proteins across disease groups. For Alzheimer’s disease, glial fibrillary acidic protein, or GFAP, showed the strongest increase across the disease continuum. Neurofilament light chain also rose with clinical stage, while several other proteins declined as Alzheimer’s disease progressed. However, the authors emphasize that these proteomic markers did not outperform established plasma markers of amyloid and tau pathology for detecting Alzheimer’s disease.
The more clinically novel findings came from the non-Alzheimer’s dementias. In dementia with Lewy bodies, integrin alpha-V and integrin alpha-M were consistently reduced, including in analyses stratified by amyloid status and in autopsy-confirmed Lewy body disease. The same integrin-related signal was also seen in Parkinson’s disease data from the PPMI cohort, supporting a broader link to Lewy body pathology.
For frontotemporal dementia, neurofilament light chain remained one of the strongest markers, consistent with its role as a general marker of neuroaxonal injury. Lower GFAP helped distinguish frontotemporal dementia from Alzheimer’s disease, while proteins such as OSM appeared more relevant in earlier frontotemporal degeneration.
A 21-protein dementia panel
The researchers then refined these signals into a custom 21-protein plasma panel and tested it in an independent multicenter cohort. The panel showed its strongest value in differential diagnosis, helping separate dementia with Lewy bodies and frontotemporal dementia from both controls and Alzheimer’s disease dementia. Its performance was moderate to good across these comparisons, suggesting that plasma proteomics may be most useful as an added layer of biological stratification when clinical symptoms overlap.
These values are not sufficient to replace specialist clinical assessment, CSF testing, imaging, or established Alzheimer’s blood biomarkers. But they suggest that plasma proteomics could provide clinically useful support where diagnostic uncertainty remains high.
Toward biomarker-based dementia stratification
The immediate relevance is not simply another biomarker list. The study addresses a practical gap in dementia medicine: identifying scalable blood-based tools that help separate biologically different diseases with overlapping symptoms. That could improve referral pathways, enrich clinical trials with the right patient populations, and support future disease-modifying therapies beyond Alzheimer’s disease.
Important limitations remain. Many DLB and FTD diagnoses were clinical rather than autopsy-confirmed, prodromal groups were relatively small, and biomarker performance may depend on assay platform and cohort calibration. Mixed pathology, especially coexisting Alzheimer’s and Lewy body disease, remains a major challenge.
Even so, the study provides a strong proof of concept. Plasma proteomics may help move dementia diagnostics from broad syndromic categories toward molecular stratification, an essential step if precision neurology is to match the progress already seen in Alzheimer’s biomarker development.
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