Plasma Biomarkers Predict Cognitive Decline in Early-Onset Dementia
Key Clinical Summary
- In a South Korea–based multicenter cohort (n = 322), plasma phosphorylated tau217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were associated with cognitive decline in early-onset Alzheimer disease (EOAD).
- In frontotemporal dementia (FTD), only GFAP and NfL correlated with Mini-Mental State Examination (MMSE) decline; p-tau217 showed no association.
- Longitudinal biomarker increases predicted worsening outcomes in EOAD but not in FTD, supporting disease-specific prognostic utility.
According to a multicenter prospective cohort study published in JAMA Network Open, plasma phosphorylated tau217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) predicted clinical outcomes in early-onset Alzheimer disease (EOAD) and frontotemporal dementia (FTD), highlighting their potential utility in risk stratification.
Study Findings
The study analyzed 322 patients, including 245 with EOAD (mean age 61.8 years; 66.5% female) and 77 with FTD (mean age 65.1 years; 62.3% female), over approximately 2 years. Participants were recruited from 34 centers in South Korea (LEAF study, 2021–2023), and annual blood sampling and cognitive assessments were performed using Mini-Mental State Examination (MMSE) and Clinical Dementia Rating–Sum of Boxes (CDR-SB).
In EOAD, higher baseline levels of all 3 biomarkers—p-tau217, GFAP, and NfL—were significantly associated with faster cognitive and functional decline. MMSE decline estimates were –0.390 (p-tau217), –0.775 (GFAP), and –0.679 (NfL) (all P ≤ .002). Similarly, worsening CDR-SB scores were associated with each biomarker (estimates ranging 0.401–0.693; all P < .001).
However, in FTD, only GFAP and NfL were associated with MMSE decline (–2.118 and –2.360, respectively; P < .001), while p-tau217 showed no significant association (P =. 87). No biomarkers correlated with FTLD-modified CDR-SB changes.
Longitudinal analysis showed that all biomarkers increased significantly in EOAD (P ≤ .001), whereas only NfL increased in FTD (P = .05). Annualized increases in biomarkers also predicted worsening MMSE and CDR-SB scores in EOAD but showed no significant associations in FTD.
Clinical Implications
The study’s results highlight the differential prognostic value of plasma biomarkers in early-onset dementia subtypes. In EOAD, p-tau217, GFAP, and NfL consistently reflect disease progression, supporting their integration into risk stratification models and clinical monitoring.
For FTD, the lack of association between p-tau217 and clinical decline suggests limited utility of this biomarker in non-Alzheimer pathophysiology. GFAP and NfL may still serve as indicators of neurodegeneration, particularly for cognitive decline.
Clinicians should consider disease-specific biomarker profiles when interpreting plasma assays. The distinct longitudinal trajectories observed emphasize the need for tailored biomarker strategies in EOAD versus FTD, particularly for prognosis and potential therapeutic monitoring.
Expert Commentary
“These findings may inform future clinical practice and trial design regarding stratifying patient populations and monitoring clinical progression, particularly in EOAD,” concluded Hyemin Jang, MD, PhD, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, and study coauthors. “Further research is warranted to identify novel biomarkers and outcome measures for FTD.”
