One Blood Test, Two Different Diagnoses? Scientists Uncover Unexpected Sex Differences in Alzheimer's Biomarker

The same blood test result may indicate different levels of brain damage in men and women, according to a review of scientific evidence published by Chinese researchers in the journal Brain Medicine. The authors argue that one of the most promising biomarkers for Alzheimer's disease should be interpreted differently depending on a patient's sex.

The biomarker in question is neurofilament light chain (NfL), a structural protein found within nerve cells. When the long projections of neurons, known as axons, are damaged, NfL is released into the bloodstream. Although the protein is not specific to Alzheimer's disease, it is considered a reliable indicator of ongoing neurodegeneration and is increasingly used to monitor the progression of Alzheimer's and other neurodegenerative disorders.

The review was conducted by researchers from Fudan University and Wuhan University, who analyzed studies published over the past decade. They found that blood NfL levels increase not only in patients with dementia but also during the earliest stages of Alzheimer's disease, before symptoms appear. In people with inherited forms of Alzheimer's, elevated NfL levels may be detectable up to 15 years before the expected onset of memory impairment.

Previous studies have also shown that higher NfL concentrations are associated with poorer cognitive test performance, reduced hippocampal volume on magnetic resonance imaging (MRI), and decreased brain activity detected by positron emission tomography (PET).

A key focus of the review was the difference between men and women. According to data from three independent studies, men with the same increase in NfL levels experienced more pronounced declines in memory, brain function, and brain structure than women with comparable biomarker levels. This suggests that an identical blood test result may reflect different stages or severity of disease depending on the patient's sex.

"A one-size-fits-all approach to interpreting this biomarker is no longer justified. A moderate NfL level in a man may indicate more advanced neurodegeneration than the same value in a woman," said the review's lead author, Yinfeng Xia.

The researchers do not yet know why these differences occur. Possible explanations include sex-related differences in the brain's immune response, the influence of sex hormones, and variations in brain size between men and women. However, all of these hypotheses require further investigation.

The authors emphasize that the current evidence is not yet sufficient to change clinical guidelines.

They conclude that the next step should be large international studies to establish sex- and age-specific reference ranges for NfL, potentially improving the accuracy of Alzheimer's disease diagnosis and monitoring in the future.

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