April 18, 2024 | Researchers in Denmark have devised a blood-based diagnostic technique that can detect even trace amounts of an aggregated protein indicative of Alzheimer’s disease before any disease-related changes show up on a PET scan, one of the traditional testing methods. The same technology can be used for developing new therapies by revealing what part of the innate immune system is engaged in the fight, according to Thomas Vorup-Jensen, Ph.D., biomedicine professor at Aarhus University.
The single-particle reporter system is based on nanoparticle tracking analysis and quantum dots conjugated with detecting antibodies and has now been used in four published studies, most recently where large amyloid-β (Aβ) aggregates were being identified (Nature Communications, DOI: 10.1038/s41467-024-45627-y). Disease-relevant information on neuropathological processes were extracted by comparing size distributions of amyloid plaques in 38 patients with mild cognitive impairment (MCI) relative to 17 healthy controls.
Importantly, the Aβ aggregates were found to activate peripheral monocytes. This could help end uncertainty in the field about exactly which component of the innate immune system contributes to the disease process and whether any part of it plays a role, says Vorup-Jensen.
Existing literature supports the idea that the innate immune system is involved, he adds. Microglial cells residing in the brain seem to influence Alzheimer's disease progression, and in the blood low counts of monocytes are known to signal elevated risk for Alzheimer’s development. In the latter case, “our data shows there is actually a correlation [with] the absence or presence of amyloid in the brain.”
Monocytes could therefore serve as a functional biomarker of the microglial processes involved in AB aggregation that are predictive of disease as well as treatment response. The peripheral immune system can be more easily manipulated and activated compared to traversing the blood-brain barrier, which is already compromised in initial stages of Alzheimer’s disease, says Kristian Juul-Madsen, postdoc in the department of biomedicine at Aarhus University.
“The ability to detect at early stages... tells us something about how we can strengthen or even further activate the beneficial effects of the peripheral immune system,” he says. “It is an essential first step in developing new treatments to address what is causing the problem in the first place.”
In the latest study, researchers discovered that complement receptor 4 on immune cells recognized the formation of harmful amyloids and could effectively bind and neutralize them. By exchanging the antibody in the detection technology for the protein responsible for the amyloid motif seen in other diseases—i.e., neurodegenerative conditions such as Parkinson’s, Lewy body dementia, amyotrophic lateral sclerosis, and Huntington’s disease as well as diabetes where amyloid buildup occurs in the pancreas—the methodology could be broadly utilized, Juul-Madsen says.
The focus, for now, is primarily on Alzheimer’s disease where the researchers have experience, their clinical partners can provide access to specimens, and huge unmet clinical needs persist, he continues. He and his team are also creating a new biobank containing blood plasma samples collected from patients seen at a pair of hospitals in Denmark to expand the size of their study cohort.
The initial patient cohort was small, but the analyses done on individuals were extensive and time-consuming, notes Juul-Madsen. These included measures of nanoparticle concentration and blood flow velocity, tau and AB aggregation in the brain, neural inflammation, and cognitive scoring.
Early disease detection will require a testing modality that is less expensive and inconvenient than imaging scans and spinal taps and can also pick up even the slight initial stages of the protein aggregation process, says Juul-Madsen, speaking to advantages of the novel detection system. It also improves the odds of treatment success since cognitive damage, once it has occurred, may be impossible to reverse with any type of therapy.
In the future, he adds, the plan is to look at how this dynamic process evolves over time. The current study evaluates the link between AB plasma aggregates and brain pathology at only two time points—at baseline when plasma samples were drawn and at follow-up two years later.
A few years ago, Vorup-Jensen and Juul-Madsen were focused on protein-DNA complexes in the blood associated with lupus using their novel quantification technique, which they briefly considered commercializing as a diagnostic tool. While aggregated proteins were an unexpected finding in patients with lupus, Aβ aggregates have long been a recognized feature of Alzheimer’s.
In other previous work, investigators showed that complement receptor 4 is size-selective for aggregates of alpha-synuclein in Parkinson’s disease years prior to the appearance of classical motor symptoms in patients (The Journal of Immunology, DOI: 10.4049/jimmunol.1900494). The focus of the current study was to develop biomarkers for Alzheimer’s disease and use size distribution information of amyloid proteins within the blood as the motif of recognition of the receptor.
It is more an exercise in physics than chemistry, explains Vorup-Jensen, “where the distribution of this particular material is determined by physical forces in the blood flow.” An antibody, known commercially as Aduhelm (aducanumab), was used to shift attention from the aggregates in lupus to those in Alzheimer’s.
Biogen announced earlier this year that it is discontinuing sales of Aduhelm and an ongoing phase 4 post-marketing confirmatory clinical trial. Evidence of its efficacy was weak, says Vorup-Jensen, “but it really works in terms of binding specifically to Aβ aggregates.”
Moving forward, the research team will be expanding its diagnostic capability academically while exploring drug development opportunities with commercial partners. The focus will be on treatments that can halt progression of the disease at an earlier stage, since therapies approved to date have been able to clear some of the aggregates found in the brain but without restoring the loss of cognitive function, says Juul-Madsen.