Alzheimer’s biomarkers may improve ALS diagnosis, predict outcomes
Study finds potential impacts on physical function, survival
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- Combining Alzheimer’s biomarkers and neurofilament light chain levels may improve ALS diagnosis and prognosis, a study reports.
- Amyloid-beta positivity combined with elevated neurofilament light chain (NfL) predicts faster physical decline and earlier death in ALS.
- The same NfL level may be associated with different disease trajectories depending on whether Alzheimer’s-related changes are also present.
Combining spinal fluid biomarkers associated with Alzheimer’s disease with levels of neurofilament light chain (NfL), a biomarker of nerve damage, may improve the diagnosis of people with amyotrophic lateral sclerosis (ALS) and predict their long-term outcomes, a study suggests.
For example, people with ALS who test positive for the Alzheimer’s biomarker amyloid-beta and have elevated NfL levels may face a faster decline in physical function and a greater risk of earlier death than people with elevated NfL levels only.
“The findings suggest that the same NfL level may have different prognostic significance depending on what other changes are present in the brain. One possible explanation is that several disease processes together make the nervous system more vulnerable, but the underlying mechanisms have not yet been established,” Niklas Mattsson-Carlgren, MD, PhD, a researcher at Lund University in Sweden and a study author, said in a university news story.
The study, “Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study,” was published in eBioMedicine.
Reliable biomarkers could aid in clinical trial design
ALS is characterized by progressive degeneration of motor neurons, the nerve cells that control muscle movement. Current diagnostic criteria rely on clinical observations, which can be unclear and often require prolonged follow-up, contributing to delays in diagnosis.
Reliable biomarkers to help diagnose ALS and predict outcomes are urgently needed. Not only could they support earlier diagnosis and guide treatment, but biomarkers could also help researchers design clinical trials that account for differences in how the disease progresses.
“A more detailed prognosis may also be valuable in clinical trials,” said Mattsson-Carlgren. “If participants with very different expected disease courses are included in the same study, it becomes more difficult to determine whether a treatment has an effect. Biomarkers may therefore contribute to better patient stratification and more efficient studies of new treatments.”
NfL, a protein released when nerve fibers are damaged, is an established biomarker for ALS. Changes in protein biomarkers related to Alzheimer’s have also been reported in ALS patients, including versions of phosphorylated tau, amyloid-beta, and GFAP.
But it remains unclear whether these biomarkers can complement NfL. Moreover, it’s unknown whether Alzheimer’s-related changes that occur alongside ALS can affect disease progression.
ALS patients had higher cerebrospinal fluid levels of several biomarkers
To find out, researchers in Sweden, Japan, and Italy measured Alzheimer’s-related biomarker levels in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord, and investigated whether these biomarkers could improve the diagnosis and prognosis of ALS, either alone or in combination with NfL.
The study included 264 adults with ALS and 164 sex-matched adults with other neurological diseases, who served as controls.
Overall, results showed that ALS patients had higher CSF levels of several biomarkers than controls, including amyloid-beta-38, amyloid-beta-40, amyloid-beta-42, the amyloid-beta-38/amyloid-beta-40 ratio, phosphorylated tau 181, phosphorylated tau 217, and NfL.
These results indicate that while NfL remains the dominant diagnostic marker, additional biomarkers may provide complementary information that cannot be captured by simple additive models.
But among individual biomarkers, NfL was the best at distinguishing people living with ALS from controls, with an area under the curve (AUC) of 0.84. An AUC of 1 indicates perfect discrimination between patients and controls, while 0.5 indicates performance equivalent to random chance.
Other individual biomarkers performed less well, and adding any single biomarker to NfL did not improve its ability to distinguish ALS from other neurological diseases.
However, machine-learning models combining the CSF biomarkers with blood levels of creatine kinase (CK), a marker of muscle damage, and creatinine, a marker used to assess kidney function, achieved an AUC of 0.90, compared with 0.85 for NfL alone.
“These results indicate that while NfL remains the dominant diagnostic marker, additional biomarkers may provide complementary information that cannot be captured by simple additive models,” the researchers wrote.
Alzheimer’s-related changes may influence survival
The researchers next examined whether the biomarkers were associated with changes in physical function over time, measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), which tracks how well people perform everyday activities.
NfL remained a significant predictor of faster functional decline after the researchers accounted for age, the rate of disease progression at the initial assessment, and lung function. No other individual biomarker independently improved predictions beyond age and NfL.
Yet, the relationship between NfL and disease progression differed according to amyloid-beta status. Among people who tested positive for amyloid-beta-related changes, higher NfL levels were more strongly associated with faster functional decline than among those who tested negative.
A similar pattern emerged for survival. In the ALS group, median survival from the initial assessment was 33.9 months. Higher NfL levels were associated with shorter survival, with the association being stronger among amyloid-beta-positive patients (4.38 times higher risk of death versus low NfL levels) than in amyloid-beta-negative patients (1.72 times higher risk of death).
An independent group of 152 ALS patients from Italy, with a median survival of 25.6 months (about two years), showed similar results (4.02 times higher risk of death vs. 1.62 times).
These results suggest that amyloid-beta status may help clarify the prognostic significance of NfL levels. In other words, the same NfL level may be associated with different disease trajectories depending on whether Alzheimer’s-related changes are also present.
“Multiple biomarker assessments can reduce misclassification of individuals with intermediate NfL values,” the researchers concluded.
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