POORER cognition linked to altered blood-based inflammatory signatures and neurodegeneration in Alzheimer’s disease (AD) according to new research investigating immune profiles across a diverse patient cohort. The findings suggest that plasma cytokine patterns could help identify biological subgroups of patients and support more targeted approaches to immunomodulatory therapies.
Study Identifies Distinct Inflammatory Signatures in AD
Chronic neuroinflammation is increasingly recognised as a contributor to AD progression, but the variability of immune responses between patients remains poorly understood. Researchers analysed plasma cytokine profiles, including participants with amyloid-positive mild cognitive impairment (MCI) or AD and age-matched cognitively unimpaired controls.
The study used principal component analysis to identify patterns of cytokine co-expression rather than assessing individual inflammatory markers in isolation. Two distinct inflammatory profiles were identified, reflecting different relationships between immune activation, neurodegeneration, and cognitive outcomes.
Pro-inflammatory Cytokine Profile Associated with Worse Cognition
One inflammatory signature was elevated in participants with AD/MCI and associated with poorer cognition. The profile was driven by pro-inflammatory cytokines including TNF-α, IL-7, IL-17A, and CXCL5, suggesting broader immune activation.
The association remained independent of key AD biomarkers including p-tau217, NfL, and GFAP. Higher levels were also observed in Black/African American participants, highlighting the need for diverse cohorts when developing inflammatory biomarkers.
Neurodegeneration May Mediate Effects of Broader Inflammatory Changes
A second inflammatory profile was linked to neuroaxonal injury rather than directly to cognition. Markers including TNF receptor II, MIF, IL-16, and CXCL10 suggested a broader inflammatory-remodelling response.
Further analysis showed that this profile was linked to increased plasma NfL levels, indicating a relationship between immune activation and neuronal damage. NfL subsequently showed an association with poorer cognitive performance, suggesting inflammation may contribute to cognitive decline through neurodegeneration-related pathways.
Findings Support Biomarker-Guided Immunotherapy Development
The researchers conclude that inflammatory signatures in AD are heterogeneous, with different immune profiles appearing to influence cognition through distinct mechanisms. Rather than a single inflammatory pathway driving disease, the findings suggest that coordinated immune patterns may help explain differences in disease progression.
Blood-based inflammatory panels, particularly when combined with established biomarkers such as NfL, could support patient stratification in future clinical trials evaluating immune-targeting treatments. However, the authors note that longitudinal studies incorporating imaging and additional biomarker approaches are needed to determine whether these inflammatory profiles predict disease progression or treatment response.
Reference
Birditt KR et al. Inflammation profiles in Alzheimer’s disease relate to cognition and neurodegeneration. Alzheimers Dement. 2026;DOI:10.1002/alz.71642.
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