Chapter 1: Understanding Alzheimer's Disease

What triggers Alzheimer’s disease (AD)? Unfortunately, there isn't a straightforward answer. The complexity lies in the term ‘cause.’ While we have identified numerous risk factors that elevate the likelihood of developing this condition, including well-documented genetic predispositions—most notably variations of the APOE gene—there are also lifestyle influences to consider. Factors like diet, physical activity, and sleep patterns all contribute to the risk of AD.

In addition to these risk factors, we have substantial knowledge regarding the symptoms and progression of the disease. The characteristic plaques and tangles in the brain are often highlighted, but AD encompasses a broader array of issues: the malfunctioning of the blood-brain barrier, mitochondrial dysfunction, altered glucose metabolism, impaired microglia, and irregular serotonin signaling, to name a few.

Moreover, the immune system plays a crucial role in this equation. Some researchers propose that AD could be partially classified as an autoimmune disorder, driven by an exaggerated response of amyloid-beta to infections. This notion has prompted investigations into immune therapies and antibody treatments for AD, although promising results are still awaited.

Intriguingly, viral infections may serve as potential precursors to Alzheimer’s disease, with COVID-19 being a notable contender. Supporting this idea, studies indicate that flu vaccinations may offer some protective benefits against the onset of AD. Over evolutionary time, the burden of viral infections might have heightened human vulnerability to this condition.

The Role of Fungal Infections

However, infections are not limited to viruses and bacteria. Fungi, as illustrated by popular media like The Last of Us, are also adept at causing infections. A particularly concerning fungus is Candida albicans, which is gaining notoriety in healthcare settings due to its potential to cause bloodstream infections, or candidemia—a severe condition sometimes resulting in fatal outcomes.

When Candida reaches the brain, research involving mice indicates that the brain's immune cells, microglia and astrocytes, spring into action to combat the infection. This immune response leads to the formation of granulomas—aggregates of white blood cells encased in amyloid beta, the protein that misfolds and accumulates into the plaques characteristic of AD.

A recent study further investigates how this fungus penetrates the brain, and the findings are concerning.

To invade the brain, the fungus must breach the blood-brain barrier—a challenging feat. However, Candida has developed a strategy. It secretes aspartic proteases, enzymes that dismantle the barrier. Alarmingly, these enzymes also degrade amyloid precursor proteins into harmful amyloid beta-like peptides, setting the stage for plaque formation.

Fortunately, the brain is not defenseless. Upon encountering the fungus, its immune system activates. Toxic amyloid-beta attaches to Toll-like receptor 4, prompting microglia to initiate a cleanup process. While this response can mitigate the fungal threat, it doesn't eliminate it entirely. For complete eradication, another receptor on the microglia must be engaged—akin to unlocking a door with two locks. The second receptor, CD11b, is triggered by a fungal protein named candidalysin.

Unless both receptors are activated, the fungus remains entrenched in the brain, continuously producing toxic amyloid beta.

Insights from Research

To delve deeper into this topic, consider watching the following videos:

The first video, Fungi In The Blood, Fungi In The Brain: Rapamycin To The Rescue?, discusses the implications of fungal infections on brain health and potential therapeutic avenues.

The second video, Are Infections Causing Alzheimer's Disease? | Robert Moir | TEDxCambridgeSalon, explores the relationship between infections and the development of Alzheimer’s, shedding light on current research findings.