Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disease that accounts for 60%–70% of all cases of dementia globally. As the number of people with AD is projected to reach 106 million by 2050, research has increasingly focused on moving beyond symptomatic treatment to target the underlying disease aetiology itself [1].
As we enter September, a month dedicated to raising awareness of AD, we are reminded of the importance of advancing our understanding of the complex biological processes that underpin this devastating disease. Research is moving beyond symptomatic management and towards disease modification. However, disease modification is complicated by the fact that AD is not characterised by a single pathology, but by an interconnected web of pathophysiological processes that feed into the progressive loss of functional brain matter [1,2].
In this article, we will break down the most prominently focussed disease hallmark: amyloid beta (Aβ) plaques. We will also explore emerging pathways that further complicate disease onset and progression, discussing how current research is creating a more holistic map of AD pathology to improve our understanding of this disease and how best to tackle it.
The ‘Amyloid Hypothesis’: A theory that dominates Alzheimer’s research
The amyloid cascade theory had been at the centre of Alzheimer’s aetiology for over three decades. This theory centres around oligomeric amyloid-β plaques (Aβ) [3].
Aβ is a normal product of cellular metabolism. Research has also shown that’s Aβ plays vital roles in [4]:
- Regulating synaptic function
- Antimicrobial function
- Neuroprotection
Aβ has the ability to assemble into a variety of forms: oligomers, protofibrils and amyloid fibrils. Importantly, amyloid fibrils are insoluble [4].
Aβ, through its continued accumulation can go onto exacerbate disease through effecting normal functions such as neuronal signalling and inflammatory activation, leading to the death of these neuronal cells [1,3].
The question is whether Aβ truly is the driver of this disease. Should we start to consider that Aβ is a piece of the puzzle and look at treatment options in a more holistic manner?
Neuroinflammation: How the brain’s defences turn against itself
Inflammation is the natural response by which the body’s immune system responds to any illness, infection or injury. Through this process, specialised cells help target, clear and repair any sustained damage.
Neuroinflammation is the brain and spinal cord’s reaction to illness, infection or injury. However, the brain is a unique and highly vulnerable structure, meaning that its delicate micro-environment is susceptible to subtle changes and can sustain damage if inflammation is not resolved swiftly [3].
Neuroinflammation is thought to be driven by two key cell types in the brain: microglia and astrocytes. These resident immune cells are activated by minute changes in the homeostasis of the brain microenvironment [5].
So how does neuroinflammation work and how does it become exacerbated in Alzheimer’s?
Research suggests that neuroinflammation precedes the clinical onset of neurodegenerative diseases, including Alzheimer’s, up to decades prior [6].
The immune response begins with microglia; activation of which leads to the release of pro-inflammatory messenger molecules known as cytokines and chemokines (Figure 1).
Figure 1: Impact of neuroinflammation induced through chronic Aβ plaque build-up on neuronal, astrocytic and microglial functions; Aβ accumulation promotes complement-mediated astrocyte–microglia crosstalk, pro-inflammatory cytokine release, blood–brain barrier dysfunction, and a reduction in neuronal survival and synaptic support mechanisms.
In Alzheimer’s, research has shown a significantly higher microglial activation, especially in regions that have higher Aβ plaques compared to plaque-free regions of the brain.
Breakdown of the blood-brain-barrier (BBB) in Alzheimer’s
The dysfunction of the BBB is a critical pathological hallmark of Alzheimer’s and other neurodegenerative diseases.
The human brain houses roughly 650km of capillaries. The BBB is a highly specialised brain endothelial cell membrane, surrounded by astrocytes and microglia, and held together via tight junction (TJ) proteins. Pericytes, a multifunctional and contractile cell type, share the basement membrane an regulate the permeability of the blood vessels. Together, the BBB ensures that neurons and glial cells can work at optimal conditions by stabilising the internal microenvironment of the brain [6,7].
This delicate barrier becomes dysfunctional in Alzheimer’s. Evidence from post-mortem brain tissue as well as neuroimaging data, show increasing infiltration of circulating cells, leakage of blood-derived proteins, and significant structural changes to the BBB in AD [6].
The breakdown of the BBB results in the build-up of proteins usually circulating in the blood:
- Albumin: the most common protein found in blood plasma and acts as a binding protein to a variety of molecules including vitamins, nutrients and drugs
- Thrombin: an enzyme found in the blood involved in blood clotting cascade
The presence of these (fairly large) proteins exacerbates the delicate balance of the brain microenvironment and show increased proliferation of peripheral macrophages leading to neuroinflammation [7].
What is oxidative stress and how does it contribute to Alzheimer’s?
Reactive oxygen species (ROS) and reactive nitrogen species (RNS), also referred to as ‘reactive species’, are by-products that are produced during normal metabolic processes. These highly reactive and unstable products are normally kept under control via the brain’s intrinsic antioxidant defence systems [8].
However, in the brains of people with AD, the accumulation of metals due to the BBB dysfunction, mitochondrial dysfunction and the overexpression of certain enzymes can lead to an oxidative imbalance.
This is further complicated in Alzheimer’s since oxidative stress drives further oligomerisation of Aβ further aiding the build of plaques that disrupt normal neuronal functioning.
What is the role of the gut-brain-axis in Alzheimer’s
There are growing research interests and data to show a significant correlation between a healthy and unhealthy gut microbiota and the development of certain diseases.
Our guts are colonised by a unique variety of microbes. The estimated number of these microorganisms is reported to outnumber human cells 10:1 [9]. Instead of causing disease, these ‘probiotic’ microorganisms are vital in health digestion, metabolism, mental health and immune function. These include bacteria, viruses, protozoa and yeast.
Interestingly, interactions with microglia and the gut-microbiome have been shown to be part of these cells maturation process; therefore, microbial imbalance (dysbiosis) can lead to significant impacts on the immune system.
Data from research in mouse disease models have shown that the gut microbiome influences the formation of Aβ plaques, synaptic dysfunction and the activation of microglia [10].
There are several key mechanisms by which dysbiosis can influence Alzhiemer’s:
- Compromisation of the intestinal walls: leading to ‘leaky gut’, which enables harmful pathogens and toxins to enter the bloodstream and results in chronic neuroinflammation
- Damage to the BBB: systemic inflammation caused by toxins in the blood steam leads to the breakdown of tight junctions in the BBB; further causing neuroinflammation and effecting blood supply to the brain
- Microbial amyloids: specific microbes in the gut can produce amyloid proteins that seed and further contribute to amyloid plaque formation
Connecting the pathways that shape Alzheimer’s disease progression
There is more to Alzheimer’s than just Aβ toxicity. Research continues to reveal compounding pathways that feed upon one another to drive the disease forward. However, by understanding the mechanisms of these pathways and developing a holistic, well -rounded understanding of the disease, we are becoming more aligned on how to overcome it. As we shall come to see, research is catching up and developing therapeutics to slow down progression and eventually prevent the onset of Alzheimer’s.
References:
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- Stefano, GB Front Biosci, 2026;31(6):53859.
- Chen, GF, et al. Acta Pharmacol Sin 2017;38(9):1205-1235
- Morley JE, et al. J Nutr Health Aging 2019;23(3):225-226.
- Heneka MT, et al. Nat Rev Immunol 2025;25(5):321-352.
- Chen Y, et al. Front Aging Neurosci 2023;15:1258640.
- Adamu A, et al. Front Aging Neurosci 2024;16:1347987.
- Houldsworth A. Brain Commun 2024;6(1):fcad356.
- Kumari S, et al. npj Dement 2025;1(1):41.
- Chen C, et al. Gut 2022;71(11):2233-2252.
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