Higher blood levels of Neurofilament Light Chain Linked to Cognitive Decline and Mortality in Centenarians: JAMA
Japan: A Japanese cohort study has found that higher blood levels of neurofilament light chain (NfL), a biomarker of neuronal injury, were associated with poorer cognitive performance and increased mortality among centenarians. Researchers suggested that elevated NfL may reflect broader systemic processes affecting both brain health and overall survival in extremely old adults.
The findings were published in JAMA Network Open by Ryo Shikimoto and colleagues from the Center for Supercentenarian Medical Research at Keio University School of Medicine.
Blood-based neural biomarkers are increasingly being investigated to better understand aging and neurodegeneration in adults aged 100 years and older. However, the biomarker most strongly linked to cognitive decline and survival in centenarians has remained unclear.
For this purpose, the researchers examined the associations of three plasma biomarkers—amyloid-β42/40 (Aβ42/40), phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL)—with cognitive function and all-cause mortality.
The population-based cohort study included Japanese centenarians enrolled between September 2000 and January 2021. Participants underwent baseline blood sampling and cognitive assessment using the Mini-Mental State Examination (MMSE), while mortality outcomes were followed for up to 17 years using ultrasensitive biomarker assays.
Overall, 495 centenarians were included, including 398 women, with a mean age of 104.1 years. Among them, 419 completed cognitive testing, with a mean MMSE score of 14.9. During follow-up, 466 participants died.
The study revealed the following findings:
- Lower amyloid-β42/40 (Aβ42/40) ratios were significantly associated with poorer cognitive performance after adjustment for confounding factors.
- Higher neurofilament light chain levels were significantly associated with lower cognitive function.
- Among the evaluated biomarkers, NfL showed the strongest and most consistent association with adverse outcomes.
- Elevated plasma NfL levels were associated with an increased risk of all-cause mortality in centenarians.
- NfL demonstrated the highest predictive value among the assessed biomarkers for both cognitive decline and mortality.
- Associations for Aβ42/40 and phosphorylated tau 181 (p-tau181) were no longer statistically significant after full adjustment.
The authors suggested that NfL may act as a broader marker of neurodegeneration and systemic aging rather than being limited to Alzheimer's disease–related pathology. Elevated NfL levels may reflect interactions between neurological, immune, and vascular systems that influence cognitive health and survival in extreme aging.
However, they acknowledged several limitations, including the absence of formal dementia diagnoses and the inability of blood-based biomarkers to fully capture brain-specific pathological changes. The study population was also limited to Japanese centenarians, which may affect the generalizability of the findings.
The investigators concluded that plasma NfL could serve as a promising biomarker for cognitive decline and mortality in extremely old adults and called for further longitudinal, neuroimaging, and autopsy-based studies to clarify its role in aging and healthy longevity.
Reference:
Shikimoto R, Sasaki T, Abe Y, et al. Biomarkers, Cognitive Function, and Mortality in Centenarians. JAMA Netw Open. 2026;9(5):e2611335. doi:10.1001/jamanetworkopen.2026.11335
Next Story