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Elevated NfL levels tracked with poorer cognitive scores and higher death risk in centenarians
- Neurofilament light chain (NfL) is a measure of neuronal injury.
- Higher blood NfL levels in centenarians correlated with lower cognitive scores and increased mortality rates.
- NfL may reflect complex systemic interactions that influence mortality, researchers suggested.
Neurofilament light chain (NfL), a measure of neuronal injury, emerged as a key blood-based biomarker associated with both cognitive function and survival in centenarians, a Japanese cohort study showed.
Higher plasma NfL levels correlated with lower cognitive scores on the Mini-Mental Status Examination (MMSE) after adjusting for potential confounders (β = -0.92, 95% CI -1.62 to -0.23), reported Yasumichi Arai, MD, PhD, of Keio University School of Medicine in Tokyo, and co-authors.
Elevated NfL was also tied to increased mortality (HR 1.36, 95% CI 1.17-1.57), the researchers wrote in JAMA Network Open. Meanwhile, a lower level of plasma amyloid-beta 42/40, an Alzheimer's disease biomarker, was linked to worse cognitive scores (β = 0.99, 95% CI 0.46-1.52). However, neither that measure, nor plasma phosphorylated tau 181 (p-tau181), had a significant relationship with mortality after adjustment. Unlike amyloid and tau biomarkers, "NfL appeared to be a more generalizable marker of neurodegeneration that reflected the complex interactions between the nervous system and physiological systems such as immunity and vascular function," Arai and colleagues wrote. "These findings suggest that NfL could serve as a valuable biomarker for assessing the health trajectory of extremely old adults and provide critical insights into the mechanisms underlying cognitive aging at the limits of human life," they added. NfL is a structural component of nerve cells; when damaged, it is released in the blood and cerebrospinal fluid (CSF). The biomarker is assessed in a number of disorders, including
vascular brain injury,
multiple sclerosis, amyotrophic lateral sclerosis (
ALS),
traumatic brain injury, and
Huntington's disease. Higher blood or CSF levels of NfL are considered markers of neurodegeneration.
The Japanese study results mirror a key finding from earlier research that showed plasma NfL was associated with mortality in the oldest old.
"I'm delighted that our findings from the Danish nonagenarian and centenarian cohorts have now been replicated in a Japanese cohort," noted Mathias Jucker, PhD, of the German Center for Neurodegenerative Diseases in Tübingen. "This independent validation across distinct populations strongly supports the robustness of the findings," he told MedPage Today.
Other population-based studies have reported that NfL blood levels also may predict mortality in younger cohorts, Jucker added.
"In light of the growing interest in NfL as a biomarker for human neurological health and mortality, we have recently extended our analysis to include animals," he said. "Our findings suggest that NfL may serve as a cross-species blood biomarker for assessing aging interventions and predicting mortality."
Arai and colleagues studied a cohort of 495 Japanese centenarians recruited from 2000 to 2021 with a mean baseline age of 104.1 years; most (80.4%) were women. Participants had baseline cognitive tests and blood sampling, and were followed up to 17 years for mortality.
The MMSE evaluated cognitive function; scores can range from 30, indicating normal cognition, to 0, indicating severe impairment. The researchers assessed dementia severity with the Clinical Dementia Rating (CDR) scale, which ranges from 0 for no impairment to 3 for severe dementia.
Overall, 419 participants took the MMSE; the mean score was 13.7. Among 436 participants with a CDR assessment, 83 people had a score of 0; 59 people had a score of 0.5; and 129 people had a score of 1.
The mean NfL level was 114.6 pg/mL, but values ranged widely from 12.5 to 1,239.5 pg/mL. During the follow-up period, 466 participants (95.5%) died.
"While amyloid-beta deposition has long been considered a hallmark of Alzheimer's disease, and p-tau181 is a related protein to amyloid-beta, they appear to be less strongly associated with mortality in centenarians compared with neurodegeneration-associated biomarkers such as NfL," Arai and co-authors observed.
"This suggests that nonamyloid-beta pathology or systemic pathology affecting neurodegeneration rather than amyloid-beta pathology itself may play a more significant role in the morbidity and mortality of centenarians, which is compatible with recent findings showing a distinct pattern of cognitive decline in centenarians compared with patients with Alzheimer's disease," the researchers pointed out.
"The role of physical system decline in chronic inflammation, worsening nutritional status, and declining kidney function as reflected in NfL levels underscores the complex systemic interactions that likely influence mortality in this population," they added.
The study had several limitations, Arai and co-authors noted. It did not account for a formal diagnosis of dementia or incorporate imaging measures like cerebrovascular lesions. The cohort was also limited to a Japanese population.
"Replication in other ethnic groups and regions will be essential to evaluate the generalizability of these findings and to examine potential cultural or genetic influences on NfL as a biomarker of aging," the researchers wrote.
Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Connect: Disclosures
This study was supported by a grant from the Japan Agency for Medical Research and Development; the Ministry of Health, Welfare, and Labour for the Scientific Research Project for Longevity; a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; and the Program for Initiative Research Projects from Keio University and the Keio University Global Research Institute.
Arai reported receiving grants from Ezaki Glico, Johnson & Johnson, and Tuning Fork Bio. Co-authors reported relationships with Eisai, Otsuka, Kowa, K Pharma, and SanBio.
Jucker had no conflicts of interest.
Primary Source
JAMA Network Open
