26 Nov 2024

Alzheimer’s disease is a long, slow neurodegenerative calamity, and scientists are still hunting for blood biomarkers that reflect all its specific stages. At the Clinical Trials on Alzheimer’s Disease meeting, held last month in Madrid, β-synuclein emerged as a candidate indicator of early synaptic struggles.

Not to be confused with its infamous cousin α-synuclein, β-synuclein has no relationship to the Lewy bodies found in Parkinsonian disorders. However, it may have something to do with AD. Patrick Oeckl of the German Center for Neurodegenerative Diseases in Ulm reported that β-synuclein starts to rise in the blood more than a decade before the first flicker of cognitive symptoms arise in people who carry a dominantly inherited AD mutation. It changes after biomarkers of amyloidosis, but prior to indicators of axonal damage, suggesting it may help fill a current gap in staging AD.

β-synuclein is a presynaptic protein that is only expressed in the brain. Previously, Oeckl and colleagues had reported that its levels were down in brain homogenate from people who had died with sporadic AD (Halbgebauer et al., 2020). Later, the scientists found that β-synuclein started creeping upward in both plasma and CSF in the preclinical stages of LOAD (Barba et al., 2023; Oeckl et al., 2023). It continued to rise as AD progressed, and correlated with multiple AD biomarkers and cognitive decline.

To nail down when, and perhaps why, blood β-synuclein rises in presymptomatic AD, Oeckl and colleagues turned to the Dominantly Inherited Alzheimer’s Network. DIAN is a standing cohort that includes families with pathogenic APP and presenilin mutations from around the world, including Germany. The scientists used a validated mass-spectrometry-based technique to measure β-synuclein in blood samples from 69 noncarriers, 78 asymptomatic, and 31 symptomatic mutation carriers (Oeckl et al., 2020).

Why does Oeckl use serum? Simply put: Because he can. Some blood markers work only in plasma, creating much demand on increasingly scarce aliquots from unique longitudinal samples from cohorts such as DIAN. By contrast, serum is relatively plentiful and easier to obtain for research, Markus Otto of Martin Luther University Halle-Wittenberg told Alzforum, adding that the β-synuclein assay works in plasma, as well.

Serum β-synuclein concentrations, which tend to be in the low picogram/ml range in human blood, were higher among asymptomatic mutation carriers than noncarriers, and shot up several fold among carriers who already had memory loss. Using the average age at symptom onset unique to each participants’ mutation, the scientists charted serum β-synuclein levels with respect to expected years to onset (EYO). They found that serum β-synuclein started to rise around 11 years prior to a person’s expected onset, and continued to increase out to 15 years thereafter (image at right).

With respect to symptom onset, β-synuclein started to rise in blood around the same time as did p-tau205 and total tau in CSF. Its change came after biomarkers of amyloid accumulation, including CSF Aβ42/40, but before serum NfL (image below). Among the growing number of tau markers scientists are studying, β-synuclein’s fellow traveler, p-tau205, is considered an intermediate-stage one. It changes after p-tau217, p-tau181, and p-tau231, which indicate that brain amyloid is starting to affect tau processing, but before the later marker MTBR-243, which is a marker of aggregated filaments and tangles.

In keeping with this, Oeckl reported that serum β-synuclein started its ascent after cortical PiB-PET scans became positive, but before FDG-PET scans indicated flagging glucose metabolism and MRIs indicated brain atrophy.

Also fitting in, he reported that β-synuclein predicted amyloid-PET positivity with 75 percent accuracy—a far cry from the 99 and 95 percent predictive value of p-tau217 and p-tau181, respectively. “This means that β-synuclein is only an indirect marker of amyloid pathology,” Oeckl said.

β-synuclein was most strongly associated with markers of neurodegeneration, including waning glucose metabolism, hippocampal shrinkage and, most strongly, cognitive impairment. Its serum concentration rose sharply as scores worsened on the MMSE or the CDR-SB.

What is going on? Oeckl thinks β-synuclein might spill out when synapses degenerate, casting it as an early marker of synaptic problems. Oskar Hansson of Lund University offered an alternative hypothesis. He suggested that β-synuclein could be released due to neuronal hyperactivity, which is known to occur in response to Aβ. Hansson, along with Oeckl, previously reported that β-synuclein rises modestly in sporadic AD. He said it was interesting that the marker appears to rise more steeply among those with autosomal-dominant forms of AD.

Other fluid biomarkers, such as neurogranin, SNAP-25, and neuronal pentraxin, have also been tied to synaptic woes. How does β-synuclein fit in, and what does it add? Oeckl told Alzforum that while he did not measure these other synaptic markers in samples from the DIAN cohort, his previous studies in people with sporadic AD suggest that β-synuclein rises in concert with these other synaptic markers, suggesting related mechanisms. That said, β-synuclein has one advantage, Oeckl told Alzforum: “It is so far the only synaptic marker that can be reliably measured in blood.” Not only is it detectable there, but its sole expression in the brain rules out interference from peripheral sources. He noted that neurogranin, for instance, is also expressed in peripheral tissues, while SNAP-25 is difficult to measure in blood.

How might this new blood marker be used? Oeckl said that in preclinical AD, it could signify the coming onset of cognitive impairment, and therefore suggest a possible time to start treatment. It might also come in handy for trial screening, or to monitor responses to treatment, he added. The scientists are characterizing β-synuclein in other neurological diseases, and evaluating its potential for clinical use. For now, they are optimizing their mass spec-based assay, which avoids the potential for cross-reactivity with α-synuclein that can happen with antibody-based tests.

On the Rise? Whether using an antibody specific for β-synuclein’s N- or C-terminus, an ELISA detected an uptick across clinical stages of AD, though with extensive overlap between groups. [Courtesy of Eugeen Vanmechelen, ADx Neurosciences.]

Speaking of immunoassays, Eugeen Vanmechelen of ADx Neurosciences in Gent, Belgium, at CTAD showed findings from one to detect β-synuclein. Using an ELISA with antibodies specific for the protein’s N- or C-terminus, they detected an uptick in CSF β-synuclein with worsening clinical stages of AD among 160 people from the Amsterdam Dementia Cohort (image below). To detect β-synuclein in serum or plasma, Vanmechelen and colleagues are validating their antibody-based assays on the Simoa platform.—Jessica Shugart

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References

Paper Citations

1. Halbgebauer S, Oeckl P, Steinacker P, Yilmazer-Hanke D, Anderl-Straub S, von Arnim C, Froelich L, Gomes LA, Hausner L, Huss A, Jahn H, Weishaupt J, Ludolph AC, Thal DR, Otto M. Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2020 Dec 30; PubMed.
2. Barba L, Abu Rumeileh S, Bellomo G, Paolini Paoletti F, Halbgebauer S, Oeckl P, Steinacker P, Massa F, Gaetani L, Parnetti L, Otto M. Cerebrospinal fluid β-synuclein as a synaptic biomarker for preclinical Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2023 Jan;94(1):83-86. Epub 2022 Aug 9 PubMed.
3. Oeckl P, Janelidze S, Halbgebauer S, Stomrud E, Palmqvist S, Otto M, Hansson O. Higher plasma β-synuclein indicates early synaptic degeneration in Alzheimer's disease. Alzheimers Dement. 2023 Apr 27; PubMed.
4. Oeckl P, Halbgebauer S, Anderl-Straub S, von Arnim CA, Diehl-Schmid J, Froelich L, Grimmer T, Hausner L, Denk J, Jahn H, Steinacker P, Weishaupt JH, Ludolph AC, Otto M. Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer's Disease. J Proteome Res. 2020 Mar 6;19(3):1310-1318. Epub 2020 Feb 26 PubMed.

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