Neuroinflammation in Dementia: Mechanisms and Implications

Globally, over 55 million people live with dementia, and this number is projected to increase in coming years. Considering the substantial burden imposed by this disease, there have been considerable research efforts aimed at effective prevention and treatment. Unfortunately, the molecular mechanisms underlying dementia are complex and multifactorial. As such, the condition remains somewhat of a scientific mystery. Today, we will delve into how the recently discovered link of neuroinflammation to dementia could contribute to new advances in the treatment of this debilitating disorder.
Faith Wershba

Faith Wershba

Postgraduate researcher at the University of Cambridge.

An image of a brain on fire.

Dementia and Neurodegenerative Disease

Dementia is a neurological syndrome caused by a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and Lewy body dementia (LBD) [1]. Dementias share a set of symptoms, such as impairments in memory, language, attention, spatial awareness, executive function, and mood regulation [2, 3]. These symptoms can vary in severity and tend to worsen over time as the disease progresses.

Symptoms can pose challenges to activities of daily life, and patients often experience frustration as their independence and autonomy declines. Patients’ families may also suffer emotional and financial hardship, as they watch their loved one struggle with the disease and must face complex decisions about end-of-life care.

Various biological models have been proposed to explain dementia’s contributing causes; for example, AD development has been linked to the accumulation of amyloid-beta (αβ) plaques and neurofibrillary tangles in the brain [4, 5], while PD pathogenesis has been explained by the aggregation of α-synuclein-containing Lewy bodies (LBs) in dopaminergic neurons [6].

These models have been highly influential in shaping understandings of dementias and suggesting avenues for treatment. However, they have come under scrutiny in recent years, in light of conflicting clinical findings. In the case of AD, researchers have shown that the number of αβ-plaques does not correlate well with neuronal loss or degree of memory impairment, which undermines their putative causal role in AD pathogenesis [4].

In a similar vein, the density of Lewy bodies—long-considered to be the ‘neuropathological hallmark’ of PD—does not reliably correlate with symptom severity or degree of cognitive decline in patients with PD [7]. These findings suggest that there may be other biological culprits contributing to the development of dementias and that existing accounts represent only one piece of the puzzle. To reconcile these findings and explain dementias’ underlying causes, we need alternative models of relevant cellular and molecular processes that better explain current evidence.

What is Neuroinflammation?

Most of us are familiar with the concept of inflammation. When the body is exposed to an immune-activating stimulus—for example, an allergen, a pathogen, or physical injury—our immune cells produce inflammatory molecules and initiate processes to eliminate the threat and repair the damage.

Neuroinflammation refers to inflammatory processes that occur in the brain and spinal cord. Unlike most tissues, the central nervous system (CNS) is largely shielded from infiltrating immune cells and pathogens by the blood-brain-barrier (BBB); such immune privilege [8] prevents damage to sensitive brain tissue. However, immune processes are not completely absent within the CNS. Populations of sentinel cells—which patrol the brain for damage or toxic cell products—reside within nervous tissues and perform immune-like functions in cases of damage or infection.

A crucial cell type involved in neuroimmunity is microglia. Microglial cells display key immune functions: they engulf and digest pathogens and cellular waste; secrete cytokines, immunomodulatory molecules that shape the inflammatory and repair responses; and present protein antigens, which serve as identificatory ‘fingerprints’ that alert other cells to the nature of the threat [1]. These processes are essential to protect the brain from infection and clear away toxic wastes, such as misfolded proteins or cellular metabolites.

Despite these essential functions, there can be ‘too much of a good thing.’ If neuroinflammation is not appropriately balanced by anti-inflammatory and repair processes, it can lead to neurodegeneration and irreversible tissue damage. This process, whereby the immune response causes damage to the body rather than protecting it, is called immunopathology.

The Role of Neuroinflammation in Dementia

Neuroinflammation is consistently observed among patients with dementia [1]. Studies have shown that microglial activation, inflammatory cytokine levels, and oxidative stress correlate with neuronal cell death, loss of synaptic connections, and overall neurodegeneration [1].

Given the close link between neuroinflammation and neurodegeneration, there has been a proliferation of research on the molecular mechanisms connecting neuroinflammation with the development and progression of dementia.

Identifying Neuroinflammation

Neuroinflammation can be detected clinically in several ways:

Microglial activation

Inflammatory stimuli trigger distinct cellular changes in microglia. For example, activated microglia significantly increase their expression of the TSPO receptor. As such, the TSPO receptor serves as a useful marker for neuroinflammation. Positron emission tomography (PET) scanning can be employed to detect this change. Using the radiolabeled drug PK-11195, which preferentially binds to TSPO, allows for the detection of TSPO expression levels in patients.

As the radiolabeled drug decays, it emits positrons, detectable by the PET scan. This provides information on the spatial and temporal distribution of radioactivity and enables clinicians to estimate the degree of microglial activation. While this method is relatively non-invasive and valuable for assessing neuroinflammation in human patients, it is an indirect measure of neuroinflammation and may be confounded by factors like drug metabolism and nonspecific binding to other receptors [1,9].

Cytokine detection

Cytokines are soluble molecules produced by activated immune cells and can influence various cellular behaviors. Proinflammatory cytokines play an activating role in immune responses, and their levels in cerebrospinal fluid (CSF) can serve as an indirect marker of neuroinflammation.

Analyzing CSF components, including cytokines, provides insight into the brain's physiological state. To measure proinflammatory cytokines, lumbar puncture extracts CSF, which is then analyzed through a multiplex cytokine assay using antibody probes. This method can identify neuroinflammation that is not detectable by microglial activation imaging and avoids complications associated with drug administration.

However, the procedure is invasive and painful. Moreover, itrequires careful handling of CSF and quick assays to obtain accurate results [10,11,12]

Targeting Neuroinflammation: A New Frontier in Dementia Research

Scientific knowledge surrounding neuroinflammation in neurodegenerative diseases has burgeoned in recent years. How might this information be put to clinical use?


Considering the role that neuroinflammation plays in dementia progression, identifying markers of neuroinflammation could aid the diagnosis of pre-symptomatic or early-stage disease. Using PET scanning to detect microglial activation or performing cytokine assays of CSF, clinicians may be able to assess levels of neuroinflammation in
patients and thereby assess their risk for neurodegenerative disease.


Interventions that inhibit the effects of proinflammatory cytokines or modulate the functions of microglia could be promising strategies for treating dementia [13].


Limiting neuroinflammation could be a protective strategy towards preventing neurodegeneration and dementia. Neuroinflammation has been linked with myriad factors, ranging from environmental pollutants, sleep deprivation, emotional stress, microbiome imbalance, heavy metal exposure, and obesity [14], though the strength of such associations can vary between studies.

Further research into specific causes of neuroinflammation should be prioritized in order to develop effective prevention strategies for at-risk individuals. But one thing is clear - prioritizing general health through nutritious eating, physical activity, and sleep regulation certainly can’t hurt, and may help prevent neuroinflammation.

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The importance of neuroinflammation in dementia has become increasingly recognized in recent years, and collaborations between neuroscientists and immunologists have shed some light on etiological mechanisms involved in dementia. With the increasing evidence suggesting the contribution of neuroinflammation on dementia progression, further research into specific causes of neuroinflammation should be prioritized. While a cure for dementia still remains out of reach, understanding the role of neuroinflammation is a promising step forward in improving diagnosis, treatment, and prevention of the disorder.


This article does not offer health advice. Always consult a medical professional regarding your condition.

Faith Wershba

Faith Wershba

Faith obtained her Honour’s Bachelor Degree in Human Biology, Immunology and History & Philosophy of Science at the University of Toronto. Currently, she is a postgraduate researcher at the University of Cambridge, focusing on the philosophy of medicine, science, biomedical research methods, and bioethics.