- Two blood markers of inflammation were associated with different forms of disease markers in the brain.
- YKL-40 was linked to damage in the brain’s small blood vessels, while GFAP was linked to amyloid buildup.
- The two routes were associated with a shared pattern involving greater abnormal tau, shrinkage in memory-related brain regions and poorer memory.
- Findings may lead to the design of more targeted therapies and help explain the failure of clinical trials in Alzheimer’s disease so far.
Irvine, Calif., Aug. 7, 2026 — Alzheimer’s disease may look similar from one person to another even when different biological processes are driving the damage, according to a new study led by researchers at the University of California, Irvine
The researchers identified two distinct patterns involving inflammation in the brain. One was associated with damage to the brain’s small blood vessels, a marker known as white matter hyperintensities. The other was associated with the buildup of amyloid beta, considered a hallmark protein of Alzheimer’s disease
Although the two patterns differed by their connection to inflammatory markers, both were connected to higher levels of a blood marker associated with abnormal tau. They were also connected to shrinkage in brain regions that support memory and, ultimately, to poorer memory performance
The findings were published in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. They support the idea that Alzheimer’s is not driven by exactly the same process in every person. Different combinations of inflammation, blood vessel damage, amyloid buildup and other biological problems may produce similar patterns of brain damage and memory loss
The findings have potentially profound clinical impacts. They may lead to the design of more targeted therapies and provide one explanation for the failure of clinical trials in Alzheimer’s disease thus far.
“We keep talking about Alzheimer’s as though it is one disease with one cause, but the biology is much messier than that,” said senior author Michael A. Yassa, PhD, professor and James L. McGaugh Endowed Chair in Neurobiology and Behavior and director of UC Irvine’s Center for the Neurobiology of Learning & Memory. “Different biological problems may push the brain toward the same damaged state. For treatment, the key may be figuring out which processes are doing the most harm in each person and how they interact.”
Different markers point to different kinds of damage
The researchers studied 126 adults aged 60 and older who did not have mild cognitive impairment or dementia. The participants were enrolled in Yassa’s NIH-funded Biomarker Exploration in Aging, Cognition, and Neurodegeneration, or BEACoN, study
The research team combined blood tests, magnetic resonance imaging, amyloid PET brain scans and memory assessments. The scientists then used a statistical model to understand the pathways that connected these markers to downstream memory loss
They focused on two proteins found in blood, YKL-40 and glial fibrillary acidic protein, or GFAP. Both are associated with the activity of support cells in the brain that respond to injury and disease, but the study found that the two markers were linked to different biological patterns. Higher YKL-40 levels were associated with more white matter hyperintensities. These appear as bright spots on MRI scans and often reflect damage caused by disease in the brain’s small blood vessels. Higher GFAP levels, by contrast, were associated with greater amyloid buildup measured with PET imaging.
“The two markers were signaling different processes or pathways that ultimately connect to the visible signs of Alzheimer’s,” said first author Batool Rizvi, PhD, who conducted the work while a graduate student with Yassa and is now a postdoctoral fellow at UC Davis. “Our results suggest that inflammation in Alzheimer’s is not one single process and that different inflammation mechanisms may act in parallel and converge on the same downstream outcome of cell loss.”
Different routes, similar outcomes
Both the small blood vessel damage and amyloid buildup were independently associated with higher levels of phosphorylated tau 217, or p-tau217. This blood marker is commonly used to detect abnormal changes involving tau, another protein central to Alzheimer’s disease
Higher p-tau217 levels were associated with thinning of tissue in the medial temporal lobe and with a smaller hippocampus. These brain regions play major roles in learning and memory. Participants with smaller hippocampal volume also performed worse on a memory test that measured how well they retained previously learned information after being presented with new material
The results suggest that inflammation connected to blood vessel damage and inflammation connected to amyloid may represent separate biological routes that become associated with a common pattern of tau-related changes and damage in memory systems
“This may help explain why a treatment aimed at one target works for some people but has little effect on others,” Yassa said. “A person whose disease is driven largely by vascular injury may need a different treatment from someone whose dominant problem is amyloid-related inflammation. Many people will probably have a mixture of both, along with other processes that we did not measure here.”
The researchers said that future blood tests could combine several markers to provide a clearer picture of the processes affecting an individual patient. That information could help researchers design better clinical trials and eventually match patients with treatments aimed at the biological drivers most important in their disease
“Amyloid and vascular injury should not necessarily be treated as competing explanations,” Rizvi said. “They may be different parts of the disease in different people, or they may occur together. Following these markers over time could help us understand which process becomes active first and which one is most closely tied to cognitive decline.”
Alzheimer’s may be many biological problems with a common endpoint
The study reflects a broader view of Alzheimer’s that Yassa described in a 2025 essay in The Transmitter, titled “Everything, everywhere, all at once: Inside the chaos of Alzheimer’s disease.”
In the essay, Yassa argued that Alzheimer’s may appear to be one disease because several biological problems can eventually produce similar symptoms. Amyloid may be an important driver in some people, while inflammation, blood vessel injury, problems with glucose use or excessive brain activity may play larger roles in others. These processes can also interact with one another. Over time, they may push the brain into a damaged and unstable condition that persists even after the original trigger is reduced.
The current study provides evidence for one part of that framework by showing that two distinguishable patterns involving inflammation were associated with a common set of downstream brain changes
“Alzheimer’s may be less like a single chain of events and more like several roads leading to the same place,” Yassa said. “That makes the disease harder to understand, but it also opens more opportunities for treatment. We need to identify the main biological drivers in each person instead of assuming that everyone should receive the same therapy.”
Study limitations and next steps
The researchers cautioned that the study provides a snapshot in time. It cannot determine which changes occurred first or prove that one biological factor caused another. The participants were cognitively unimpaired, and some blood measurements were available in only a subset of the study group. The sample was also predominantly White, which limits how broadly the results can be applied. Larger studies will need to follow more diverse groups of people over time. Future research should examine whether these patterns predict memory decline, whether they change as Alzheimer’s progresses and whether they can be used to select and inform treatments.
The study was supported by the National Institute on Aging grant R01AG053555
About the Center for the Neurobiology of Learning & Memory
Established in 1983 by the UC Regents, with James L. McGaugh as its Founding Director, the CNLM is the first research institute in the world dedicated to the interdisciplinary study of the fundamental brain mechanisms of learning and memory. It is credited with numerous seminal discoveries about how memory works and is recognized as a global leader in the area. Led by Director Michael Yassa, the CNLM is home to more than 120 faculty scientists at UC Irvine and beyond. For more information, visit cnlm.uci.edu.
About the University of California, Irvine: Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UC Irvine, visit www.uci.edu.
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