Biological sex influences how blood markers reflect Alzheimer’s severity

A new study suggests that a promising blood test for Alzheimer’s disease may need to be interpreted differently depending on whether the patient is male or female. The researchers found that for the same concentration of a specific protein in the blood, men exhibited more severe brain damage and cognitive decline than women. These findings were published in the journal Molecular Psychiatry.

Diagnosing Alzheimer’s disease has historically been a difficult and expensive process. Physicians currently rely on a combination of subjective memory tests and invasive or costly biological measures. The most accurate biological tools available today involve positron emission tomography, known as PET scans, or lumbar punctures to analyze cerebrospinal fluid.

PET scans use radioactive tracers to visualize plaques and tangles in the brain, while lumbar punctures require inserting a needle into the lower back to collect fluid for analysis. Because these methods are not easily scalable for routine screening, the medical community has sought a blood-based biomarker that could indicate the presence and severity of neurodegeneration without the need for specialized equipment or invasive procedures.

One of the most promising candidates for such a test is neurofilament light chain, often abbreviated as NfL. This protein acts as a structural component within the axons of neurons, functioning much like a skeleton to provide support and shape to the nerve cells. When neurons are damaged or die due to neurodegenerative diseases, this internal structure breaks down. The neurofilament light chain proteins are then released into the cerebrospinal fluid and eventually make their way into the bloodstream.

Elevated levels of NfL in the blood serve as a signal that injury to the brain’s cellular network is occurring. While the potential of NfL as a diagnostic tool is widely recognized, its clinical application is hindered by a lack of standardized reference ranges. Doctors do not yet have a universal set of numbers to define what constitutes a normal or abnormal level across different demographic groups.

Xiaoqin Cheng, alongside Fang Xie and Peng Yuan from Fudan University in Shanghai, sought to determine if biological sex influences how these protein levels correlate with the actual severity of the disease. Previous research regarding sex differences in NfL levels has produced inconsistent results. Some studies suggested no difference between men and women, while others indicated variations in specific genetic cases. Cheng and colleagues aimed to clarify this relationship by examining whether a specific amount of NfL in the blood reflects the same amount of brain damage in men as it does in women.

The research team began their investigation by analyzing data from the Alzheimer’s Disease Neuroimaging Initiative, a large, long-running study based in North America. They selected 860 participants who had available data on plasma NfL levels, brain imaging, and cognitive assessments.

This group included people with normal cognition, mild cognitive impairment, and diagnosed dementia. The researchers used statistical models to look for interactions between sex and NfL levels regarding their effect on clinical symptoms. They controlled for variables such as age, education, and genetic risk factors to isolate the effect of sex.

The analysis revealed a distinct divergence between men and women. The researchers observed that as NfL levels rose, men experienced a much steeper decline in cognitive function compared to women with similar protein increases.

When the researchers looked at specific cognitive tests, such as the Clinical Dementia Rating or the Mini-Mental State Examination, they found that a unit increase in NfL predicted a more significant drop in performance for male participants. This pattern suggested that the male brain might be more vulnerable to the neurodegenerative processes associated with these elevated protein markers.

To understand the physical changes driving these cognitive differences, the team examined brain scans of the participants. They looked at magnetic resonance imaging data to measure the volume of specific brain regions critical for memory and thinking. The results showed that for every unit increase in plasma NfL, men displayed a greater reduction in the volume of the hippocampus, a brain structure essential for forming new memories.

The team also analyzed metabolic activity in the brain using glucose PET scans. These scans measure how much energy brain cells are consuming, which is a proxy for how healthy and active they are. Men showed more severe hypometabolism, or reduced brain energy use, than women at comparable levels of plasma NfL.

To ensure these results were not specific to one demographic or geographic population, the authors attempted to replicate their findings in a completely different group of people. They utilized the Chinese Preclinical Alzheimer’s Disease Study, a cohort consisting of 619 individuals.

Despite differences in ethnicity and genetic background between the American and Chinese cohorts, the fundamental finding remained the same. In this second group, men again showed more prominent functional and structural deterioration associated with rising NfL levels compared to women. A third, smaller public dataset was also analyzed, which confirmed the pattern once more.

The study also investigated whether this sex difference was unique to neurofilament light chain or if it applied to other Alzheimer’s biomarkers. They repeated their analysis using two other blood markers: phosphorylated tau 181, which is linked to the tangles found in Alzheimer’s brains, and glial fibrillary acidic protein, a marker of brain inflammation. Neither of these markers showed the same sex-dependent effect. This specificity suggests there is a unique biological mechanism linking NfL levels to disease severity that differs between males and females.

The authors also explored the predictive power of the biomarker over time. Using longitudinal data, they tracked how quickly patients progressed from mild impairment to full dementia. The statistical models indicated that an increase in plasma NfL levels was predictive of a faster cognitive decline and a higher likelihood of disease progression in men compared to women. This implies that a high NfL test result in a male patient might warrant a more urgent prognosis than the same result in a female patient.

While the study establishes a correlation, the biological reasons behind this discrepancy remain a subject for future investigation. The researchers propose several hypotheses. One possibility involves the blood-brain barrier, the protective filter that separates the brain’s circulatory system from the rest of the body.

If the blood-brain barrier in men becomes more permeable or dysfunctional during Alzheimer’s disease than in women, it could alter how NfL is released into the blood. Another potential explanation involves microglia, the immune cells of the brain. Sex differences in how these cells react to injury and inflammation could influence the rate of neurodegeneration and the subsequent release of neurofilament proteins.

There are limitations to the study. The cognitive tests used to assess participants can have subjective elements, although the researchers attempted to mitigate this by using composite scores. Additionally, while the statistical methods used to predict disease progression were robust, the sample size for the survival analysis was relatively small, and validation in larger cohorts will be necessary. The authors also note that the mechanism remains theoretical and requires direct testing in laboratory settings to confirm exactly why male physiology reacts differently.

This research highlights a significant need for precision in how blood biomarkers are developed and used. If these findings are further validated, it suggests that using a single cutoff value for plasma NfL to screen for Alzheimer’s disease may be insufficient.

Instead, clinicians may need to use sex-specific reference ranges to accurately assess the level of neurodegeneration in a patient. As the medical field moves closer to routine blood tests for dementia, accounting for biological sex will be essential to ensure that both men and women receive accurate diagnoses and appropriate care.

The study, “Plasma neurofilament light reflects more severe manifestation of Alzheimer’s disease in men,” was authored by Xiaoqin Cheng, Zhenghong Wang, Kun He, Yingfeng Xia, Ying Wang, Qihao Guo, Fang Xie, and Peng Yuan.