The Amyloid Hypothesis of Alzheimer’s: Are we on the right track?

The Amyloid Hypothesis Of Alzheimer’s

According to estimates, the global dementia population will grow from roughly 57 million in 2019 to 153 million by 2050 [1]. About 60–70% of these cases are due to Alzheimer’s. After age 65, its prevalence doubles every five years, increasing the burden on aging communities in terms of both human distress and healthcare expenses [2].

Nearly all current Alzheimer’s treatments only deal with the cognitive and behavioral symptoms of the disease, not their underlying causes. There is still no known means to stop the illness, let alone cure it.

The Amyloid Hypothesis

The amyloid hypothesis was the primary origin story for the disease for over 30 years [3]. It argues that this sticky protein causes a series of changes in the brain which disturb synapses, produce inflammation, kill nerve cells, and cause gradually increasing dementia.

However, contradicting evidence from brain-imaging studies over the last decade, with a lengthy string of disappointing failures in anti-amyloid medication and vaccination trials, has led to a gradual issue for the amyloid theory.

Beta-amyloid with another protein, tau, are primarily responsible for brain changes associated with Alzheimer’s. According to the amyloid hypothesis, beta-amyloid starts the cascade of degenerative alterations decades before symptoms appear. The two proteins may cooperate to create dementia.

An enzyme breaks down the larger molecule, the amyloid precursor protein (APP), which is essential for the central nervous system’s development and the survival of nerves following injury, to produce soluble units of beta-amyloid.

According to the theory, problems arise when beta-amyloid generates more quickly than its removal from the brain. Insoluble plaques can form when many units group together to produce poisonous, free-floating “oligomers,” which spread.

What evidence supports the theory

However, there hasn’t been any firm evidence to support the amyloid theory. The best evidence for Alzheimer’s disease up until recently came from genetics, which connected genes to the production and processing of amyloid [4].

For instance, people with Down syndrome frequently experience Alzheimer’s in their 40s or earlier. The gene for APP is present on chromosome 21, which has an extra copy that causes Down syndrome. It means that those with Down syndrome make a lot of beta-amyloid.

The gene variations that provide this additional risk either increase overall beta-amyloid synthesis or enhance the production of a particularly sticky type of beta-amyloid that is more likely to clump together. Early-onset Alzheimer’s disease can also run in families.

What evidence contradicts the theory

The amyloid theory faces significant obstacles despite these genetic smoke signals [5]. The discovery that some older individuals without dementia have massive plaque buildup in their brains while others with clinical Alzheimer’s symptoms have little or no plaque was one of them. In fact, a far stronger correlation exists between symptoms getting worse and tau fibril distribution across the brain.

This data has led some neuroscientists to assert that Alzheimer’s doesn’t have a single original cause but develops as the result of two or more loosely connected causal chains of events [6].

A slew of disappointing failures of beta amyloid-targeting medicines — both monoclonal antibodies and vaccinations — appeared to support this viewpoint [7][8]. Several medications were successful in removing amyloid plaques from the brain. However, they did not slow cognitive deterioration.

The conclusion was that beta-amyloid was a result of the disease rather than its cause. Some others argued that stress and declining immunity caused infectious organisms like the herpes simplex virus, which had remained dormant for years, to reactivate in aged brains [9]. According to this view, beta-amyloid—which has antimicrobial properties—was only a defense mechanism, whereas pathogens, directly or indirectly through inflammation, damaged nerves.

Some blamed the gum disease-causing Porphyromonas gingivalis bacteria, which has also been discovered in Alzheimer’s patient’s brains. The bacterium produces destructive enzymes known as gingipains that may encourage the development of tau tangles [10].

The trials targeting beta-amyloid

The previously approved medications for beta-amyloid

In June 2021, the FDA authorized aducanumab, an anti-amyloid treatment, despite problems with the amyloid hypothesis and against the advice of its own advisory council. The medication, a monoclonal antibody, removes amyloid. However, experts found contradictory results from two identical clinical trials.

In January 2023, the FDA’s clearance of another anti-amyloid antibody, lecanemab, marked the emergence of real hope. It was the first clinical experiment to demonstrate that focusing on amyloid oligomers that float freely can halt cognitive deterioration in people with early Alzheimer’s.

Although the medicine slowed the decline by 27% over 18 months, the therapeutic effect was small.

The Lilly Trial: A new hope?

Last month, the manufacturer of another monoclonal, donanemab, issued a press release with better news [11]. According to its clinical trial, the medication resulted in a 35% slower rate of cognitive decline over 18 months in individuals with early-stage dementia than the placebo, as well as a 40% slower rate of decrease in their ability to do daily tasks like handling money.

How do scientists explain the failure of numerous earlier experiments using such comparable drugs? They assert that either the treatment term was too brief, the doses were too low, or the studies did not begin early enough during the disease. Monoclonals can result in brain swelling or minor bleeding as a side consequence of removing plaque, which completely justifies the warning. However, the more recent monoclonals work to reduce these side effects. Additionally, they may be more effective at halting the production and spread of hazardous oligomers by focusing on a sweet spot in the beta-amyloid molecule.

The most recent studies support the need to halt plaque spread before it leads to the development of tau tangles inside neurons, the next stage of the illness. Neuroscientists had no idea that cells like microglia, which are the brain’s own immune cells, would be a hidden factor in the illness process that could explain the apparent irregularities in brain imaging studies when the amyloid theory was originally put forth. Numerous genetic factors influence how well they work to prevent the production and spread of amyloid oligomers.

Challenges remain

Numerous obstacles still exist. In the most recent trials, patients’ symptoms did not actually get better or even stop getting worse; monoclonals only slowed down the disease. Furthermore, screening for illness indicators – a difficult task in and of itself — will be critical to reaping the benefits of these medications because the treatments must begin before the toxic effects of tau take effect.

Other difficulties include exorbitant prices and the requirement to set up specialized treatment facilities for routine infusions. Vaccines focused on beta-amyloid oligomer removal would be less expensive and probably safer if they could successfully activate our own immune system. A few are still under development. The condition, it turns out, includes a variety of controllable risk factors, such as social isolation, cardiovascular disease, gut bacteria, and sleep apnea.

Although the causes of Alzheimer’s may be straightforward, the course of the disease’s development is far from it.


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  4. Haass, C. and Selkoe, D., 2022. If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?. PLoS biology, 20(7), p.e3001694.
  5. Kametani, F. and Hasegawa, M., 2018. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Frontiers in neuroscience, 12, p.25.
  6. Chételat, G., 2013. Aβ-independent processes—rethinking preclinical AD. Nature Reviews Neurology, 9(3), pp.123-124
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  11. Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. Lilly. Published Online: 3rd May, 2023. Accessed: 4th August, 2023.
  12. Kingsland. J. Do we finally know what causes Alzheimer’s? Freethink. Published Online: 27th May, 2023. Accessed: 4th August, 2023.

How to tell when a person with dementia is nearing the end of their life

How To Tell When A Person With Dementia Is Nearing The End Of Their Life

When a loved one has late-stage dementia, knowing what to anticipate might be helpful. The loss of a loved one can be a difficult notion to grasp and comprehend. Understanding what is ahead can help you prepare both mentally and physically.

Knowing when a dementia patient is on the verge of passing away can be challenging. Early signs of the dying process may include indications of late-stage dementia and a rapid decline in the patient’s condition.

How long will someone with dementia live?

Although dementia is a life-limiting illness, it is exceedingly challenging to predict how long a person with dementia will live. Several factors influence this.

It may be easier to predict how long someone will live and how they will die if they also have another illness that may shorten their life (such as cancer or heart failure).

An individual can die from another illness at any stage of dementia. As a result, people might pass away before their dementia symptoms get severe.

A person in the final stages of dementia may deteriorate gradually over several months. Typically, at this time, they will:

  • become more feeble
  • experience infections and falls more frequently
  • have trouble swallowing, eating, and drinking
  • more likely to require immediate medical attention
  • become less mobile
  • more sleep
  • Talk less frequently.

A person with advanced dementia is more likely to have a compromised immune system. As a result, individuals are more likely to contract infections, which in some situations may be chronic. Pneumonia brought on by an infection is one of the most typical causes of death for dementia patients.

A person with advanced dementia may exhibit signs that indicate they are on the verge of passing away, yet they may still be able to function for several months. Planning and putting in place measures for someone’s passing become quite challenging due to this unpredictability.

What are the symptoms that a person with dementia is approaching the end of their life?

Knowing when a dementia patient is approaching the end of their life can help with providing the appropriate care. It can be challenging to determine the exact moment, though.

This unpredictability can significantly affect how the person feels and how their family, friends, and caregivers feel.

Late Stage Dementia

Your loved one with dementia will eventually enter the late stages of the disease. This stage is also known as advanced dementia or end-stage dementia. Their symptoms become acute at this point.

The person will experience difficulties performing routine tasks, including showering, getting dressed, eating, and using the restroom. They might not be able to walk or sit up without assistance and constantly require care. At this stage, they would become bedridden.

Additionally, they could lose their capacity to talk and make facial emotions like a smile. Seeing this transformation can be very difficult for family members.

Signs of late-stage dementia

Some later-stage dementia symptoms may indicate the patient is nearing the end of life. These include:

  • speech confined to single, potentially meaningless words or sentences
  • having trouble understanding what is being stated to them
  • needing assistance with most daily tasks
  • eating less and experiencing swallowing issues
  • bowel and bladder incontinence
  • having trouble sitting up, difficulty walking or standing, and becoming bedbound.

A person with dementia is likely nearing the end of their life if they exhibit most or all of these symptoms. They could also be very feeble, suffer from recurring infections, or have pressure ulcers (or bedsores).

Signs of the dying process

More changes are typical as a person’s condition deteriorates, and they are just days or hours away from dying. A person might:

  • deteriorate at a faster rate than before
  • become unconscious
  • be incapable of swallowing
  • become restless and agitated
  • develop an uneven breathing pattern
  • have breathing that sounds chesty or rattling
  • have chilly feet and hands.

These changes are common during the dying process, and the person is frequently unaware of what is happening.

What assistance may medical professionals offer at this point?

Healthcare providers can explain these changes to you so you comprehend what is happening.

Medical personnel might intervene to lessen the patient’s suffering. If the patient cannot swallow, they can administer medication via skin patches, small injections, or syringe pumps, which deliver a constant flow of medication through a tiny needle under the patient’s skin. Consult your general practitioner or another qualified healthcare provider about this.

How can you manage dementia end-of-life symptoms of your loved one?

It’s crucial for caregivers to closely monitor their loved one for pain or discomfort because people with advanced dementia frequently have trouble speaking. Some examples of such symptoms include moaning or shouting, restlessness or an inability to fall asleep, grimacing, or sweating. It can also be a sign that you should contact a hospice or palliative care provider for assistance with pain management.

Hospice can offer a hospital bed or other equipment to raise the head if a person with end-stage dementia has problems sitting up without help.

Families may find it most difficult when a loved one with dementia loses the ability to swallow or eat. Because a person with dementia cannot comprehend the advantages of IV drips or feeding tubes, they frequently get extremely agitated and try to remove them, resulting in further discomfort and infection risk. Instead, concentrate on keeping the person at ease.


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Your Gut May Influence Your Risk of Alzheimer’s: Study

Your Gut May Influence Your Risk Of Alzheimer’s

A recent study relates the risk of Alzheimer’s to the gut microbiome. People with early indicators of the disease exhibited similar gut microbiome compositions that differed from those without early symptoms of the disorder.

The cause of Alzheimer’s disease is still a mystery to researchers because it is a complex ailment. According to a recent study, your gut bacteria may influence whether you get Alzheimer’s disease or not.

Researchers at Washington University School of Medicine have found that individuals with Alzheimer’s who are in the early stages of the disease – when brain changes have started but before cognitive symptoms are noticeable – have an assortment of bacteria in their intestines that are different from the gut bacteria of healthy individuals.

What is the new research about?

The scientists discovered that experiencing changes in gut bacterial populations may be an early sign of the disease. These alterations can sometimes develop years before the first indications of cognitive decline, such as memory loss and confusion.

The study, which examined the gut microbiome and composition of 164 senior citizens (aged 68 to 94) with normal cognitive function, was published in the journal Science Translational Medicine. To find those who might have early signs of Alzheimer’s, the researchers looked for the presence of the proteins amyloid and tau in the participants’ brains and had them take cognitive tests.

The scientists then compared the bacteria identified in the guts of 49 preclinical Alzheimer’s patients to those who did not show symptoms of Alzheimer’s proteins via fecal samples to determine if their microbiomes were distinct.

Researchers discovered that individuals with preclinical Alzheimer’s had distinct gut microbiomes from those who did not have the condition. In particular, individuals with preclinical disease frequently had larger quantities of bacteria responsible for degrading the amino acids arginine and ornithine, which contribute to protein synthesis. In general, those without preclinical Alzheimer’s had higher levels of microorganisms engaged in glutamate breakdown, which can preserve neurons.

The researchers also compared that information to risk factors such as a family history of Alzheimer’s, the participants’ age, genetics, and diabetes status, as well as brain images, to determine who was in the early stages of Alzheimer’s—and it was quite accurate.

The researchers stated that gut microbiome implications of preclinical Alzheimer’s neuropathology could help understand the disease’s etiology and find gut-derived markers of its risk.

How are the gut and brain connected?

Although your gut and brain are present in different regions of your body, research has revealed that they can influence one another. The gut-brain axis, which is essentially communication between your brain and gut, connects some activities in your intestine with your brain’s emotional and cognitive regions.

Here are some instances of your gut-brain axis in action: When you are stressed, you may experience diarrhea or constipation, or when you are nervous, you may experience butterflies in your stomach.

Researchers are still investigating how the gut-brain axis can affect a variety of disorders, including IBS (irritable bowel syndrome), depression, and obesity.

What connection exists between the gut and the brain in Alzheimer’s disease?

At this moment, nothing is certain. According to the co-author Beau M. Ances, it’s difficult to distinguish if the gut influences the brain or the brain influences the gut. That means it is unclear if the gut microbiota alterations are due to brain abnormalities or if the gut changes truly contribute to Alzheimer’s.

Some previous studies have also explored this connection.

  • According to a previous study, chronic inflammation in the brain can increase the likelihood of developing Alzheimer’s by triggering cell damage and death.
  • Another research has reported that high-fiber diets, including whole grains, fruits, and vegetables, may also help lower inflammation.
  • According to the National Institute on Aging (NIA), specific gut bacteria turn the fiber in these foods into substances known as short-chain fatty acids (SCFAs), which can reduce inflammation and may enhance animal memory.
  • A high-fiber diet, for example, changed the species of bacteria in the gut microbiome, increased the generation of SCFAs, and decreased the expression of some genes that govern inflammation in the brain, according to the findings of one mouse study published last year.

What’s next?

There are some ambiguities. The most recent study discovered that despite consuming essentially the same diet, persons with preclinical Alzheimer’s disease and those who were healthy had distinct gut microbes.

According to Dr. Ances, this research may eventually result in a diagnostic test that is more user-friendly and widely available.

People who have early signs of Alzheimer’s disease may also benefit from taking action to halt the disease’s course or perhaps prevent it.

In addition, Dr. Ances and his team have started a five-year follow-up research to determine whether variations in the gut microbiome are a cause or a consequence of the alterations in the brain that are characteristic of early Alzheimer’s.


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