Chapter 1: Understanding Alzheimer’s Disease

Alzheimer's disease remains a complex and persistent condition that warrants a broader perspective.

(Pixabay, GDJ) Alzheimer’s disease overview

In 1901, Alois Alzheimer, a German psychiatrist, encountered a 51-year-old woman suffering from gradual memory loss, confusion, and paranoid thoughts. His 1907 case report became the first formal account of what we now know as Alzheimer’s disease (AD).

Currently, around fifty million individuals worldwide are afflicted by dementia, with Alzheimer's accounting for approximately 60-70% of these cases. With life expectancy rising globally, this figure could potentially triple by 2050.

The likelihood of developing Alzheimer's is influenced by a multitude of factors. While age remains the most significant risk, various genetic and lifestyle components—such as diet, exercise, and sleep—can either elevate or reduce one’s risk. This underscores the potential for individuals to take proactive steps to manage their personal risk factors.

The underlying mechanisms of the disease are equally intricate. While amyloid plaques and tau tangles often dominate discussions, Alzheimer’s-affected brains exhibit a range of additional issues. These include the breakdown of the blood-brain barrier, increased oxidative stress, mitochondrial dysfunction, disrupted glucose metabolism, damaged microglia, impaired serotonin signaling, and inflammation.

Exploring New Theories

Because amyloid plaques are a hallmark of the disease, they have frequently been viewed as critical contributors to Alzheimer’s pathology. Indeed, the amyloid cascade hypothesis is supported by several observations: plaques are closely associated with Alzheimer’s, specific genetic risk factors relate to plaque processing, and their accumulation leads to considerable neural damage.

However, not all correlations are straightforward. Some individuals with high plaque levels remain largely unaffected by the disease, while treatments targeting plaques have not produced the anticipated results.

This doesn’t invalidate the amyloid cascade hypothesis, but it does indicate a need for refinement and a broader consideration of other factors at play in Alzheimer’s disease. Here are two emerging models worth discussing.

Lipid Invasion Model

This theory begins with the blood-brain barrier (BBB). Essentially, the lipid invasion model posits that the breakdown of the BBB permits lipids from the bloodstream to infiltrate the brain, causing various forms of damage, including Alzheimer's. These lipids behave differently from the brain’s resident lipids.

Many known Alzheimer’s risk factors also compromise the integrity of the BBB. Consequently, the hypothesis suggests that free fatty acids and large lipoproteins can enter the brain. While these molecules are harmless in moderation, an overload can lead to oxidative stress, mitochondrial dysfunction, and neuroinflammation. Large lipoproteins can also hinder recycling processes, resulting in plaques and tangles.

Importantly, the lipid invasion model does not dismiss previous theories. Instead, it complements both the cholinergic and amyloid hypotheses along with other lipid and BBB-related explanations. However, further empirical validation is necessary.

Autoimmune Disorder Perspective

Another recent proposition is that Alzheimer’s disease may exhibit characteristics of an autoimmune disorder. While this concept isn’t entirely new, prior research has generally concentrated on traditional autoimmunity linked to autoantibodies and adaptive immune responses. Current data, however, aligns more with Alzheimer’s being a brain-centric autoimmune disorder focused on innate immunity.

In simplified terms, damage from trauma, infection, or pollution triggers the release of amyloid-beta—a key player in the innate immune response. This overproduction of amyloid-beta can lead to neuron damage, further exacerbating the cycle of neuronal death and amyloid-beta release.

In their research, the authors screened over 1,100 molecules to find those that might help regulate this excessive amyloid response. Notably, several identified compounds were tryptophan metabolites, which is significant given that tryptophan levels typically decline with age and drop even more in Alzheimer’s patients. A second screening also revealed plant-derived phenylalanine metabolites as potential therapeutic targets.

As with the lipid invasion model, additional research is essential, but progress is being made.

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Chapter 2: The Role of Inflammation in Alzheimer’s Disease

This video, titled "Deciphering Neurodegeneration: Inflammation, Immune Response, and Alzheimer's," explores how inflammatory processes and the immune response contribute to the complexities of Alzheimer’s disease.

In "Inflammatory and Immune Function in Alzheimer's Disease," the video delves into the intricate relationship between inflammation and the progression of Alzheimer's, highlighting key immune mechanisms involved.