The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context
Heli Soni1, Greg T Sutherland2, Markus J Hofer3
1School of Life and Environmental Sciences and Charles Perkins Centre, The University of Sydney, Camperdown, NSW, 2050, Australia.
Journal of Neuroinflammation
|June 24, 2026
Summary
Complement system markers show promise for Alzheimer's disease (AD) neuroinflammation insights but aren't standalone diagnostics. Their value lies within multimodal biomarker approaches, requiring standardization for clinical use.
Area of Science:
- Neuroimmunology
- Biomarker Discovery
- Alzheimer's Disease Pathophysiology
Background:
- Neuroinflammation significantly impacts Alzheimer's disease (AD) progression.
- The complement system, interacting with amyloid-β and tau, is a key focus for immune biomarkers in AD.
- Challenges exist in translating complement activation observations into reliable biomarker signals due to its complexity and influencing factors.
Purpose of the Study:
- To critically evaluate complement-derived measures as markers of neuroimmune activity in AD.
- To distinguish the biological plausibility from the analytical and clinical utility of these markers.
- To determine the current and future role of complement markers in AD research and diagnostics.
Main Methods:
- Systematic review and critical evaluation of existing literature on complement system markers in Alzheimer's disease.
- Analysis of factors influencing complement marker interpretation, including age, systemic inflammation, comorbidities, and blood-brain barrier integrity.
- Assessment of complement markers against established Alzheimer's disease biomarker frameworks (e.g., AT(N)).
Main Results:
- Complement-derived biomarkers currently lack the robustness for standalone diagnostic classification in AD.
- Factors like cohort heterogeneity, assay variability, and lack of longitudinal validation limit their current utility.
- Complement markers show potential for providing context-specific information on inflammatory states within multimodal frameworks.
Conclusions:
- The most defensible current role for complement markers is within multimodal biomarker frameworks for AD.
- They are unlikely to function as independent tools for diagnosis, staging, or treatment monitoring.
- Advancement requires rigorous standardization, mechanistic clarification, and validation in large, diverse, longitudinal cohorts.
Keywords:
Alzheimer’s diseaseBlood-Brain barrierBlood-based biomarkersCerebrospinal fluid biomarkersComplement biomarkersComplement systemInnate immunityLongitudinal validationMultimodal biomarkersNeuroinflammationMore Related Videos
07:08A High Throughput, Multiplexed and Targeted Proteomic CSF Assay to Quantify Neurodegenerative Biomarkers and Apolipoprotein E Isoforms Status
Published on: October 20, 2016
09:33Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Related Concept Videos
01:26Alzheimer's Disease: Overview
Alzheimer's Disease (AD) is a continually advancing neurodegenerative disorder, distinguished by escalating memory loss, cognitive dysfunction, and dementia. The disease unfolds in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Its onset is insidious, and the progression gradual, with the cause not well explained by other disorders.
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
01:27Complement System
The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a membrane...
01:23Alzheimer Disease ll: Pathophysiology
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
01:29Alzheimer Disease l: Introduction
Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...
01:22Alzheimer's Disease: Treatment
Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...