Neuroinflammation in Alzheimer’s Disease: Brain Impact

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory loss. While amyloid plaques and tau tangles are well-known hallmarks, growing evidence highlights neuroinflammation as a key driver of disease progression. Chronic brain inflammation exacerbates neuronal damage and disrupts function, contributing to cognitive impairment.

Understanding how neuroinflammation influences Alzheimer’s pathology may reveal therapeutic targets to slow disease progression.

Cellular Mediators of Inflammatory Processes

Neuroinflammation in Alzheimer’s arises from a complex interplay of cellular components responding to pathological changes. Microglia and astrocytes play pivotal roles in modulating inflammation, while cytokine signaling amplifies inflammatory cascades. Their activation and dysregulation contribute to neuronal dysfunction and disease progression.

Microglial Activation

Microglia, the brain’s resident immune cells, shift from a homeostatic to an activated state in response to pathological insults. In Alzheimer’s, amyloid-beta (Aβ) accumulation triggers their activation, leading to the release of pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and reactive oxygen species (ROS). Initially beneficial in clearing Aβ aggregates, prolonged activation results in chronic inflammation and neurotoxicity.

Positron emission tomography (PET) imaging with tracers like [11C]PK11195 has shown increased microglial activation in patients with mild cognitive impairment (MCI) and Alzheimer’s, correlating with disease severity (Hamelin et al., 2018, Brain). Genetic studies further support microglia’s role, linking TREM2 gene variants—essential for microglial phagocytosis—to increased disease risk. Targeting microglial activation through colony-stimulating factor 1 receptor (CSF1R) inhibitors is under investigation as a potential therapeutic approach.

Astrocytic Response

Astrocytes, crucial for neuronal homeostasis, undergo significant morphological and functional changes in response to Alzheimer’s pathology. Reactive astrocytes, marked by increased glial fibrillary acidic protein (GFAP) expression, cluster around amyloid plaques and release cytokines such as IL-6 and chemokines like C-C motif ligand 2 (CCL2), exacerbating neuronal dysfunction.

Reactive astrocytes also contribute to excitotoxicity by impairing glutamate uptake due to reduced excitatory amino acid transporter 2 (EAAT2) expression. Single-cell RNA sequencing has identified neurotoxic A1 astrocytes, induced by microglial cytokines, which contribute to synaptic loss (Liddelow et al., 2017, Nature). Efforts to modulate astrocytic reactivity, including targeting nuclear factor kappa B (NF-κB) signaling, are being explored to mitigate neuroinflammatory damage.

Cytokine Signaling

Cytokines regulate neuroinflammatory processes, with both pro- and anti-inflammatory signals influencing Alzheimer’s progression. Elevated IL-1β, TNF-α, and IL-6 levels have been detected in cerebrospinal fluid (CSF) and post-mortem brain tissue, correlating with disease severity. These cytokines activate Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK) pathways, promoting neuroinflammation and neuronal death.

Conversely, anti-inflammatory cytokines like IL-10 and transforming growth factor-beta (TGF-β) offer neuroprotection but are often insufficient to counteract chronic inflammation. Clinical trials have explored cytokine-targeting therapies, such as TNF-α inhibitors like etanercept, though their efficacy remains under investigation. Understanding the balance between inflammatory and anti-inflammatory signaling may provide new therapeutic avenues.

Effects on Synaptic Homeostasis

Synaptic integrity is essential for cognitive function, yet persistent neuroinflammation in Alzheimer’s disrupts the balance required for effective neurotransmission. Excess pro-inflammatory mediators interfere with synaptic plasticity, weakening long-term potentiation (LTP) while enhancing long-term depression (LTD). LTP, crucial for learning and memory, depends on regulated glutamatergic signaling through N-methyl-D-aspartate (NMDA) receptors. Elevated TNF-α and IL-1β levels alter receptor composition, reducing synaptic NMDA receptor density while increasing extrasynaptic NMDA receptor activity. This shift contributes to excitotoxicity, dendritic spine loss, and neuronal dysfunction.

Neuroinflammation also affects synaptic structure by disrupting cytoskeletal dynamics. Hyperphosphorylated tau destabilizes microtubules, leading to synaptic disconnection. Proteins like postsynaptic density-95 (PSD-95) and synaptophysin, critical for synaptic function, are downregulated in Alzheimer’s-affected brains, correlating with cognitive decline severity (DeKosky & Scheff, 1990, Annals of Neurology).

Additionally, GABAergic interneurons, essential for modulating excitatory activity, are vulnerable to inflammatory insult. Reductions in parvalbumin-positive interneurons disturb excitatory-inhibitory balance, contributing to aberrant network activity. Electroencephalographic (EEG) recordings from Alzheimer’s patients have detected epileptiform discharges, which further accelerate synaptic degradation (Lam et al., 2017, Brain).

Interplay With Amyloid and Tau Pathologies

Amyloid-beta (Aβ) and hyperphosphorylated tau proteins drive Alzheimer’s pathology, with each exacerbating the toxicity of the other. Aβ aggregation initiates molecular disruptions, particularly through soluble oligomers that impair neuronal signaling before plaque deposition. Studies using human induced pluripotent stem cell (iPSC)-derived neurons suggest that Aβ oligomers promote early tau misfolding, acting as a catalyst for tau pathology (Shi et al., 2017, Neuron).

Hyperphosphorylated tau destabilizes microtubules, impairing axonal transport and synaptic function. Tau pathology spreads between neurons via synaptic connections, exhibiting prion-like properties. In vivo PET imaging with tracers such as [18F]AV-1451 indicates that tau deposition correlates more closely with cognitive decline than Aβ burden (Jack et al., 2018, Brain).

Regions with high Aβ deposition, such as the default mode network (DMN), exhibit early tau accumulation in the entorhinal cortex, essential for memory consolidation. Longitudinal imaging studies show that individuals with high Aβ but minimal tau pathology remain cognitively intact for years, whereas those with both experience rapid decline (Hanseeuw et al., 2019, JAMA Neurology). This suggests Aβ primes neural circuits for tau-mediated degeneration, accelerating synaptic collapse and cognitive impairment.

Biomarkers Indicative of Inflammation

Identifying neuroinflammatory biomarkers is crucial for tracking Alzheimer’s progression and therapeutic response. Cerebrospinal fluid (CSF) and blood-based markers provide insights into brain inflammation. Elevated glial fibrillary acidic protein (GFAP) levels in CSF and plasma reflect astrocytic reactivity, with studies linking GFAP to early pathological changes. Similarly, YKL-40, a glycoprotein associated with neuroinflammation, correlates with disease severity and brain atrophy patterns in neuroimaging studies.

Advances in ultrasensitive immunoassays enable the detection of low-abundance cytokines in peripheral blood, reducing reliance on invasive lumbar punctures. Increased IL-6 and TNF-α levels have been identified in Alzheimer’s patients, though their specificity requires further validation. Plasma phosphorylated tau (p-tau) has emerged as a complementary biomarker, improving diagnostic accuracy, particularly when combined with inflammatory markers.

Blood-Brain Barrier Disruption

The blood-brain barrier (BBB) regulates molecular passage to maintain neural homeostasis, but in Alzheimer’s, it becomes compromised, allowing neurotoxic substances, immune cells, and inflammatory mediators to infiltrate brain tissue. This exacerbates neuroinflammation and accelerates neuronal injury. Magnetic resonance imaging (MRI) with contrast agents like gadolinium has revealed increased BBB permeability in Alzheimer’s patients, particularly in the hippocampus, a key memory region.

At the molecular level, BBB disruption stems from altered endothelial tight junction proteins, including occludin and claudin-5. Reduced expression weakens barrier integrity, facilitating the entry of circulating cytokines and immune cells. Additionally, pericytes, essential for BBB stability, degenerate in Alzheimer’s, further compromising vascular function. Post-mortem analyses of Alzheimer’s brains show reduced pericyte coverage, correlating with capillary leakage and fibrinogen accumulation, a marker of vascular damage.

Therapeutic strategies aimed at preserving BBB integrity, such as targeting the Wnt/β-catenin signaling pathway, are being explored to mitigate neurovascular dysfunction and slow cognitive decline.