The University of California, Irvine (UCI) has announced findings from a new study suggesting that Alzheimer's disease can manifest with similar brain damage and memory loss even when driven by different biological mechanisms. Researchers at UCI identified two distinct inflammatory patterns in the brain, each linked to common indicators of the disease.
One pattern of inflammation was associated with damage to the brain’s small blood vessels, a marker known as white matter hyperintensities. The other pattern was linked to the buildup of amyloid beta, a protein widely considered a hallmark of Alzheimer’s disease. Despite these differences in their connection to inflammatory markers, both patterns were tied to higher levels of a blood marker associated with abnormal tau, another protein central to Alzheimer's disease. They were also connected to shrinkage in brain regions supporting memory and ultimately led to poorer memory performance.
The study's findings were published in *Alzheimer’s & Dementia: Diagnosis, Assessment and Disease Monitoring*. They support the idea that Alzheimer’s is not uniformly caused by the same process in every individual. Varying combinations of inflammation, blood vessel damage, amyloid buildup, and other biological issues may lead to similar outcomes in brain damage and memory loss.
These findings carry significant potential for clinical applications, potentially leading to the development of more targeted therapies. This approach could also provide an explanation for the limited success of some Alzheimer’s disease clinical trials to date. Michael A. Yassa, PhD, a professor at UCI’s Center for the Neurobiology of Learning & Memory and the study’s senior author, noted that the biology of Alzheimer's is complex. He suggested that different biological problems may lead the brain toward a similar damaged state. For treatment, the goal may be to identify which processes are most harmful in each person and how they interact.
The research involved 126 adults, aged 60 and older, none of whom had mild cognitive impairment or dementia. Participants were enrolled in Dr. Yassa’s NIH-funded Biomarker Exploration in Aging, Cognition, and Neurodegeneration (BEACoN) study. The research team utilized a combination of blood tests, magnetic resonance imaging (MRI), amyloid PET brain scans, and memory assessments. Scientists then used a statistical model to understand the pathways linking these markers to memory loss.
The study focused on two blood proteins, YKL-40 and glial fibrillary acidic protein (GFAP), both associated with brain support cell activity in response to injury or disease. Higher YKL-40 levels were connected to more white matter hyperintensities, visible as bright spots on MRI scans and often indicating small blood vessel damage. Conversely, higher GFAP levels were associated with greater amyloid buildup, measured with PET imaging.
Batool Rizvi, PhD, the first author of the study, explained that the two markers signaled different processes that ultimately connect to the visible signs of Alzheimer’s. Both small blood vessel damage and amyloid buildup were independently associated with higher levels of phosphorylated tau 217 (p-tau217), a blood marker used to detect abnormal tau changes. Higher p-tau217 levels were associated with thinning tissue in the medial temporal lobe and a smaller hippocampus, brain regions critical for learning and memory. Participants with smaller hippocampal volume also performed worse on memory tests.
Dr. Yassa suggested that understanding these distinct biological drivers is crucial, as a treatment targeting one mechanism might be effective for some individuals but not others. Future blood tests could combine several markers to offer a clearer picture of the processes affecting individual patients, helping to design better clinical trials and match patients with specific treatments. The researchers cautioned that the study offers a snapshot in time and involved a predominantly White sample, necessitating larger and more diverse studies over time.
