Blood Biomarkers Reveal Early Signs of Neurodegeneration in REM Sleep Disorder

Neurodegenerative diseases rarely begin with obvious symptoms.Early signs are often invisible, missed by patients, overlooked in exams, and absent on scans. Yet recent research suggests we may detect these changes earlier than ever. Not through imaging, but through blood.

Table of Contents:

1. The Bigger Picture

2. What We’re Learning From Blood

3. Case Study

4. A New Way to Stratify Risk

5. What About Brain Imaging

6. Preclinical Alzheimer’s Risk

7. The Future of Early Detection

The Bigger Picture

In my clinic, I’ve long been searching for a way to detect the earliest signs of neurodegeneration before a patient’s symptoms disrupt their life, before changes appear on scans, before we lose valuable intervention time. In the past, REM sleep behavior disorder (RBD) was treated as a curious sleep condition. But now we know better.

Isolated REM Sleep Behavior Disorder (iRBD) isn’t just about sleep; it’s a clinical window into the future of neurodegeneration. What seems like simple dream enactment or restlessness during sleep may, in fact, be the earliest clinical sign of a brain already under stress. Studies show that around 80% of patients with iRBD go on to develop neurodegenerative conditions like Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy (Liguori C. et al., 2025).

This strong association has shifted the way we think about iRBD. It’s no longer viewed as a benign sleep disturbance, but as a prodromal phase, a preclinical signal of something deeper and more insidious. It gives us a rare opportunity to intervene, to monitor, and to study the progression of neurodegeneration from its earliest moments.

So the question became: can we see that neurodegeneration, before it starts changing the brain structure, before symptoms manifest, in the blood?

What We’re Learning From Blood

Recent studies suggest that yes, we can. In patients with iRBD, certain proteins in the blood are showing measurable shifts long before a clinical diagnosis of Parkinson’s or dementia is made.

The first major shift: Neurofilament light chain (NfL), a marker of axonal damage. In iRBD patients, NfL levels are already significantly elevated compared to healthy controls (Liguori C. et al., 2025).

The second shift: Glial fibrillary acidic protein (GFAP), a marker of astrocyte activation and inflammation, often rises well before a clinical diagnosis is made. In practice, I see this as a red flag, especially since research shows these elevations are more pronounced in patients who later develop Parkinsonism or dementia (Liguori C. et al., 2025). This means we can’t dismiss inflammation markers as incidental; they may be the earliest biochemical whisper of disease.

The third: Phosphorylated tau at threonine 181 (pTau181). While often discussed in the context of Alzheimer’s, elevated pTau181 in iRBD patients was linked to a higher risk of progression to cognitive impairment (Liguori C. et al., 2025).

Case Study: The Patient Who Came Just in Time

A 56-year-old man came to my clinic after his wife noticed he was “fighting in his sleep” and shouting during dreams. His daytime function was intact, and his MRI scan was normal.

However, blood testing revealed elevated NfL and GFAP, along with subtle changes in pTau181. These findings suggested early neurodegenerative stress, even before any structural changes could be seen. By combining biomarker tracking with gut microbiome analysis, circadian rhythm evaluation, and anti-inflammatory nutritional strategies, we created a personalised monitoring plan.

Three years later, while his biomarkers have shifted slightly, his cognitive and motor function remain stable, a window of stability we might have missed without early testing.

A New Way to Stratify Risk

These three biomarkers, NfL, GFAP, and pTau181, aren’t just warning signs; they’re powerful tools for identifying which iRBD patients are most likely to progress to a neurodegenerative disease.

Research shows that higher baseline plasma pTau181, when combined with amyloid-beta ratios, is strongly associated with conversion to dementia (Delva A. et al., 2025). Lower Aβ42/40 ratios and changes in pTau181 point towards Alzheimer’s-type risk, while NfL and GFAP patterns are more closely tied to Parkinsonian outcomes (Liguori C. et al., 2025). Tracking these biomarkers over time can reveal progression long before symptoms are clinically apparent (Ingannato A. et al., 2024). This reinforces an important truth: iRBD is not a one-size-fits-all condition. Some patients show a more Alzheimer’s-like blood profile, others present with Parkinson’s-type patterns.

In my own practice, I’ve seen parallels in patients with vague neurological complaints, disrupted sleep, subtle memory changes, unexplained fatigue, yet entirely “normal” MRI scan. By integrating plasma biomarkers with gut microbiome, circadian, and metabolic assessments, patterns emerge that would otherwise go unnoticed.

What About Brain Imaging?

Interestingly, plasma levels of NfL and GFAP also correlate with changes in cerebral glucose metabolism, especially in regions typically affected by Parkinson’s disease (Li S. et al., 2025). This strengthens the argument that what we see in the blood reflects real, measurable changes in the brain.

These imaging correlations provide biological validation that blood biomarkers are not abstract indicators, they mirror functional disruptions detectable on PET scans. In particular, individuals with higher plasma NfL and GFAP levels show reduced glucose metabolism in the nigrostriatal and cortical areas, consistent with neurodegenerative trajectories. This is especially relevant for identifying differences between brain-first and body-first Parkinson’s subtypes, where biomarker levels and metabolic patterns may diverge (Li S. et al., 2025). Such integration of fluid biomarkers and imaging could enhance both diagnostic precision and personalized monitoring in prodromal states.

From a functional medicine perspective, this is where circadian biology and gut health testing become indispensable. For patients with iRBD or early neurodegenerative patterns, I typically run a comprehensive stool analysis, inflammatory mediator panels, and nutrigenomic profiling to pinpoint accelerators of neural stress. Based on results, my protocols often include polyphenol-rich anti-inflammatory nutrition, melatonin rhythm support, targeted probiotics to reduce gut-derived inflammation, and magnesium threonate for neuronal protection. Every intervention is personalised to the patient’s biomarker profile and their circadian type.

Preclinical Alzheimer’s Risk

Another large study extended these findings beyond iRBD, looking at people with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). It showed that plasma levels of GFAP, NfL and pTau181 rise progressively from SCD to MCI to Alzheimer’s dementia (Ingannato A. et al., 2024).

Even more compelling: plasma NfL and pTau181 were significantly higher in carriers of the APOE ε4 gene, a known genetic risk factor for Alzheimer’s (Ingannato A. et al., 2024).

The Future of Early Detection

Plasma biomarkers are cheap, fast, and non-invasive. They could soon become a frontline tool for risk assessment and early diagnosis, not just for Alzheimer’s disease, but for patients with iRBD who are silently progressing toward Parkinsonism or dementia.

While no single biomarker can provide certainty, the combination of NfL, GFAP, and pTau181, especially when tracked over time, offers a new way to watch neurodegeneration unfold in real time (Liguori C. et al., 2025).

And in conditions like iRBD, where the clock starts ticking years before clinical diagnosis, that window of foresight could be everything.

Access and Availability

At this stage, blood biomarkers such as NfL and GFAP are mostly measured in research contexts or specialist European labs. Some automated platforms (e.g., Siemens Healthineers, Fujirebio) and central research labs like Eurofins or Cerba are beginning to make them more accessible. Still, more validation is needed before these assays become routine in hospitals.

Conclusion

Plasma biomarkers are reshaping how we understand the earliest stages of neurodegeneration. In conditions like iRBD, they offer a non-invasive window into brain changes long before symptoms arise, opening the door for earlier, more personalized interventions

If this article resonated with your clinical perspective or scientific curiosity, consider sharing it with colleagues. And if you’d like more insights like this, subscribe to my monthly newsletter for clinical commentary, protocol strategies, and curated research on neurobiology, gut health, and circadian science.

References:

1. Liguori C., Fernandes M., Zatti C., Carpi M., Tolassi C., Testone G., Cirillo F., Antonucci M., Bergamo G., Risino I., Benedetti R., Caon D., Quaresima V., Galli A., Rizzardi A., Girotto I., Trasciatti C., Lupini A., Eshja K., Giliani S., Padovani A., Biagio Mercuri N., Pilotto A. (2025). Plasma NfL, GFAP and pTau181 in patients with Isolated REM Sleep Behaviour Disorder. Oxford Academic. https://doi.org/10.1093/sleep/zsaf163

2. Delva A., Pelletier A., Somerville E., Montplaisir J., Gagnon J-F., Kollmorgen G., Kam-Thong T., Kustermann T., Machado V., Gan-Or Z., Postuma R. (2025). Plasma pTau181 and amyloid markers predict conversion to dementia in idiopathic REM sleep behaviour disorder. Brain. doi: 10.1093/brain/awaf003

3. Li S., Jiao F., Li X., Xu Z., Hu T., Liang X., Wu J., Wang J., Zuo C., Tang Y. (2025). Plasma GFAP and NfL associate with cerebral glucose metabolism in putative brain-first and body-first Parkinson’s disease subtypes. Nature. https://doi.org/10.1038/s41531-025-00898-0

4. Ingannato A., Bagnoli S., Mazzeo S., Giacomucci G., Bessi V., Ferrari C., Sorbi S., Nacmias B. (2024). Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia. Frontiers in Endocrinology. https://doi.org/10.3389/fendo.2024.1375302