Not All Amyloid Plaques Are the Same in Alzheimer’s Disease
Amyloid plaques in Alzheimer's disease vary in chemistry and structure, with implications for disease progression and therapy response.
Alzheimer’s disease—an age-related neurodegenerative disease—is the most common cause of dementia in older adults, with more than 49 million people worldwide affected by Alzheimer’s disease and related dementias.
Alzheimer’s disease is characterized by pathological changes to the brain, including the build-up of toxic protein aggregates, neuroinflammation, and the death of neurons.
The deposition of extracellular amyloid-β plaques is central to Alzheimer’s disease pathology. Amyloid-β monomers aggregate into different multimeric structures, creating amorphous and fibrillar deposits that are hallmarks of Alzheimer’s disease.
Amyloid-β biology is complex: while two main forms are found in the brain—amyloid-β42 and amyloid-β40—numerous truncations, modifications, and conformations also exist.
Studying the diversity of amyloid-β and the plaques it forms is key to understanding how plaques influence disease progression, which could inform drug discovery.
Alicja Szadziewska is a PhD student at the University of Gothenburg, whose research focuses on how amyloid-β plaques differ between patients and how these differences relate to the surrounding brain tissue environment.
Technology Networks spoke with Szadziewska ahead of her talk at the American Society of Mass Spectrometry (ASMS) Conference 2026 to learn more about the different types of amyloid plaques, how they are studied, and the interactions between plaques and their surrounding environment.
Understanding plaque diversity
Amyloid-β plaques are highly diverse. The two main morphologies are cored and diffuse; diffuse plaques are loosely organized, whereas cored plaques have a dense center, surrounded by activated microglia and reactive astrocytes. Cored plaques are related to synaptic loss.
“In human brain tissue, plaques differ both in morphology and molecular makeup,” explained Szadziewska. “Some are compact and cored, while others are diffuse, and they contain different amyloid-β peptide species, including full-length, truncated, and modified forms.”
The amount of amyloid in the brain does not correlate with the degree of clinical dementia, which puzzled researchers for decades. However, the composition and features of amyloid-β plaques may be more closely related to how the disease presents. The diversity in plaque morphology and biochemistry may therefore contribute to the clinical heterogeneity of Alzheimer’s disease.
“Diffuse plaques can also be found in individuals without cognitive impairment, suggesting that the presence of plaques is not sufficient to determine disease severity,” said Szadziewska. “Instead, the composition and maturation state of plaques, together with the surrounding tissue response, may help explain why Alzheimer’s disease progresses differently between patients.”
Previous work led by Szadziewska’s supervisor, Prof. Jörg Hanrieder, illustrated that cored plaques contain higher levels of amyloid-β40 compared to diffuse plaques.
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Another plaque type of interest is coarse-grained plaques, which are relatively large, with multiple cores and pores devoid of amyloid-β. These plaques are more abundant in early-onset Alzheimer’s disease, are only present in people with symptomatic disease, and are found in conjunction with aggregated tau and dystrophic neurites—abnormal neuronal projections that accumulate damage.
Studying amyloid plaques and species
By viewing amyloid plaques as more than just amyloid-β deposits, Szadziewska and her colleagues aim to understand the impact of the plaques on their local environments.
“A plaque is surrounded by many different cell types and pathological changes, so to understand it properly, we need to capture both its molecular composition and what is happening around it.”— Alicja Szadziewska
Using integrated spatial biology techniques, including MALDI mass spectrometry imaging, chemical imaging, and spatial transcriptomics, the team worked with sections of brain tissue that were cut consecutively. “This allowed us to study the same plaque across several molecular layers,” explained Szadziewska.
First, they used MALDI mass spectrometry imaging to map amyloid-β species in single plaques. “This approach detects different amyloid peptides in a label-free way, including full-length amyloid-β, N-terminally truncated species, and pyroglutamate-modified forms,” she noted.
Additional staining with fluorescent amyloid probes enabled the structural biology of the plaques to be interrogated.
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The team also employed immunostaining on adjacent tissue sections “to identify key pathological and cellular features, including plaques, tangles, neurites, and glial cells.”
Finally, spatial transcriptomics quantified gene expression in the regions surrounding the plaques.
“By integrating these datasets, we could ask whether specific amyloid-β peptide species are associated with specific local gene expression programs,” Szadziewska said. “This gave us a more complete view of plaque biology than either mass spectrometry imaging or spatial transcriptomics could provide on its own.”
Does amyloid plaque chemistry shape the local environment?
While it’s not yet clear whether amyloid plaque chemistry influences responses in local tissues or whether the microenvironment shapes plaque composition, understanding the links between the two may shed light on the processes that contribute to Alzheimer’s disease.
“The chemical composition of a plaque is linked to the molecular state of the tissue around it.” — Alicja Szadziewska.
Szadziewska and colleagues’ work in mice showed that plaque maturation—the structural changes towards a more compact morphology that occur as the plaque ages—is associated with decreased synaptic gene expression and is linked to greater synaptic loss and toxicity.
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“In human data, we saw an association of amyloid-β42 levels with axonal neurofilament genes, which may indicate local axonal stress or degeneration near these plaques,” noted Szadziewska. “In coarse-grained plaques, higher levels of amyloid-β40 were associated with changes in astrocytic genes, including AQP4 and S100B.”
“These findings support the idea that plaques with different amyloid peptide compositions are not biologically equivalent,” she continued. “They may be associated with different local pathways, which could be relevant for understanding why Alzheimer’s disease looks so different across patients.”
What this means for amyloid-β therapies
Two anti-amyloid therapies, lecanemab and donanemab, have already received FDA approval for Alzheimer’s disease. These therapies target different forms of amyloid-β. Lecanemab binds to soluble amyloid-β protofibrils, whereas donanemab targets a pyroglutamate-modified form of amyloid-β.
As more anti-amyloid therapies are developed, understanding how different plaque types respond will be critical.
“Amyloid pathology should not be viewed as one uniform target,” said Szadziewska. “If plaques differ in their peptide composition and in the tissue responses around them, then different plaque types may also interact differently with therapeutic approaches.”
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“The molecular composition of plaques may influence which amyloid species are most effectively engaged by a given therapy,” she continued. “More broadly, understanding plaque diversity in human brain tissue could provide important biological context for studying how amyloid pathology is affected by different therapeutic strategies.”
The importance of a combined approach
Szadziewska highlighted that combining mass spectrometry imaging with spatial transcriptomics was particularly important for connecting the molecular composition of a plaque with the biological state of its microenvironment.
“MALDI mass spectrometry imaging allows us to directly map the chemistry of amyloid plaques, including specific amyloid-β peptide species and modifications. Spatial transcriptomics, on the other hand, tells us how nearby cells are behaving at the gene-expression level,” she explained. “The two technologies provide complementary, omics-scale information, while maintaining the spatial context.”
Spatial context is essential for understanding how plaques contribute to Alzheimer’s disease. Analysis of bulk tissues may miss differences in the plaque-specific microenvironments, which are highly spatial.
“A plaque does not exist in isolation. It is surrounded by neurons, astrocytes, microglia, oligodendrocytes, blood vessels, and degenerating neuronal processes,” said Szadziewska.
At her talk at ASMS, Szadziewska will focus on how MALDI mass spectrometry imaging and spatial biology were integrated for this research.
“I will discuss what each technology contributes, the challenges of combining them, and how this approach can help us better understand plaque-specific molecular microenvironments,” she said. “I am looking forward to sharing these results with the community and discussing how spatially resolved approaches can be used more broadly in neurodegeneration research.”
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