Beyond amyloid and tau: New targets in developing dementia treatments

Alzheimer’s disease is the most common form of dementia. Although its exact cause is unknown, for many years scientists have believed that a protein called beta-amyloid was responsible. Recently, this amyloid hypothesis has been questioned, and there has been a huge upsurge in dementia research. Here, we round up the latest findings, look at possible advances in diagnosis, and ask: Where next for Alzheimer’s research and treatment?

There are several forms of dementia, of which Alzheimer’s disease is the most common. According to the World Health Organisation (WHO), there are currently 55 million people worldwide with dementia, and of these between 30 and 40 million are likely to have Alzheimer’s.

With an ageing population around the world, the number of people with dementia is rising rapidly. The Alzheimer’s Association estimates that 6.7 million people in the United States have Alzheimer’s disease, but by 2050, that number is predicted to almost double to 12.7 million.

Although Alzheimer’s is the most common form of dementia, its exact cause still eludes researchers. For several years, most have regarded the beta-amyloid hypothesis as the most likely explanation, but recently, this has been called into question.

So, is beta-amyloid the cause of Alzheimer’s, or are there other changes that may lead to this disease that is the seventh most common cause of death worldwide? This question has been the subject of much recent research.

Beta-amyloid and tau

Beta-amyloid is a peptide formed from a larger protein, called amyloid precursor protein (APP). APP is a type 1 membrane glycoprotein that is involved in the development and function of nerve cells, signaling, and transport within cells.

When enzymes cut APP into smaller molecules, beta-amyloid monomers are one of the products. These monomers are likely to be important in maintaining the health of nerve cells. The problems occur when beta-amyloid aggregates into fibrils and plaques, which many researchers believe play a large part in the development of Alzheimer’s.

The amyloid cascade hypothesis, first proposed in 1992, suggested that amyloid plaques were the first stage in the development of Alzheimer’s, leading to neurofibrillary tangles (tau tangles), cell loss, vascular damage, and dementia.

Tau is a protein that helps to stabilize the internal skeleton of nerve cells. In Alzheimer’s disease, an abnormal form of tau builds up, disrupting the internal skeleton and forming tangles. These tangles slow a person’s ability to think and remember.

“It is widely acknowledged that the cognitive symptoms due to Alzheimer’s disease correlate most closely with the predictable spread of tau protein in the brain.”

– Dr. Emer MacSweeney, CEO and consultant neuroradiologist at Re:Cognition Health

Questioning the amyloid hypothesis

Yet researchers have begun to question whether the amyloid cascade hypothesis is the best explanation for the development of Alzheimer’s disease.

New drugs that target beta-amyloid build-up have been shown to clear amyloid plaques, but none have yet succeeded in reversing Alzheimer’s symptoms. However, there is some evidence that they may slow cognitive decline, as Dr. MacSweeney told Medical News Today.

“The FDA [Food and Drug Administration] approval of lecanemab, in January this year, confirmed a correlation between the removal of amyloid protein from the brain and slowing of the progression of cognitive decline in individuals with mild cognitive impairment (MCI) and mild dementia due to Alzheimer’s disease,” she noted.

However, the relationship between amyloid and Alzheimer’s is not entirely clear. Although there appears to be a correlation between plaques and dementia, many people who showed no signs of dementia have significant amyloid pathology on post-mortem examination.

Recently, in another blow to the hypothesis, scientists questioned the veracity of images in a 2006 paper that was thought to provide firm evidence for the theory. This paper, published in Nature, showed that when young rats were injected with a particular beta-amyloid, beta-amyloid-56, they developed memory deficits.

Although the paper has been cited more than 2,000 times, because it has been suggested that images may have been manipulated, the findings of the paper are now disputed.

However, Dr. MacSweeney believes that work should continue on drugs that target beta-amyloid: “Many new treatments in development, currently, continue to focus on toxic amyloid protein and it is likely medications will come to market that provide an even more effective reduction in rate of cognitive decline than lecanemab.”

Perhaps beta-amyloid is part of the explanation, but it is looking less likely that it can fully explain the development of Alzheimer’s.

What is under investigation?

A recent study reinforced evidence for the involvement of beta-amyloid but proposed a different mechanism of action.

Its findings suggested that beta-amyloid was causing two proteins to bind together, activating genes that then stimulate the accumulation of tau. The researchers identified a drug that could disrupt this process, suggesting a possible treatment pathway.

Another study has suggested that cognitive decline might be triggered by the dysfunction of astrocytes — glial cells that make up the majority of cells in the human central nervous system (CNS), and help maintain the correct environment for nerve cells. The study suggests that abnormal immune activity in astrocytes may cause cognitive deficits in dementia.

Also supporting the involvement of astrocytes is another study, from South Korea, which suggests that reactive astrocytes excessively absorb acetate in models of Alzheimer’s disease and that this elevated uptake is associated with reduced cognitive function.

Alzheimer’s risk factors and health stressors

As the hunt goes on for treatments for Alzheimer’s disease, another key goal of the research is to identify factors that increase a person’s risk, so these can be addressed to try and mitigate that risk.

“It’s critical that doctors caring for middle-aged and older adults look both beyond and before the deposition of amyloid and tau in the brain. We now know of literally dozens of health stressors that lead to neurodegenerative dementias.”

– Dr. David Merrill, adult and geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA

More than twice as many women as men are affected by Alzheimer’s disease, and although this has often been explained by the greater longevity of women, researchers have also investigated whether hormones may affect risk.

A new study has found that early menopause is associated with elevated levels of tau in the brain, particularly in women who delay the start of hormone therapy (HRT).

As those in this study with a later menopause or earlier start of HRT did not have the same increase in tau, this could suggest that estrogen has a protective effect against Alzheimer’s disease.

But there may be other explanations for the greater prevalence of Alzheimer’s disease in women — the APOE e4 gene variant, which increases dementia risk and is carried by around 15% to 25% of people, seems to have more effect in women than men.

Other studies have suggested that some medications, such as those used for sleep, and frequent microbial infections are associated with an increased Alzheimer’s disease risk.

And Dr. MacSweeney explained that there are many avenues still to be investigated. “The understanding of this disease, which is not likely to be one disease entity, is becoming increasingly sophisticated with multiple diagnostic biomarkers and numerous new types of potential treatments, aimed at many different components of the disease etiology,” she told us.

“These new avenues of research include [a] focus on potential new treatments involving epigenetic, neuro-inflammatory, immune-mediated mechanisms,” she added.

Recent developments in diagnosis

One way to help slow the progress of Alzheimer’s disease is by diagnosing the condition early, so that exposure to common risk factors can be modified. Early diagnosis also means treatment can be started to help manage symptoms. And there has been much progress in the hunt for rapid, less-invasive methods of diagnosing Alzheimer’s disease earlier.

Recent studies have identified several biomarkers in the blood that may indicate Alzheimer’s disease. One study found a connection between levels of a sugar molecule, glycan, in the blood, and tau, which might predict Alzheimer’s disease up to 10 years before symptom onset.

Another identified phosphorylated tau as a possible predictor. Yet another study, which found significant changes in the retinas of people who had died with Alzheimer’s disease, suggests that retinal screening might be a noninvasive method of detecting the early stages of Alzheimer’s.

Potential new treatments

In addition to the new medications that target amyloid plaques, other therapies under investigation are showing promise.

In a study in mice, researchers identified that nerve cells in the mammillary body were particularly susceptible to neurodegeneration and they could reverse resulting memory impairments by treating them with a drug that is now used to treat epilepsy.

Dr. MacSweeney agreed that mammillary bodies were worth further investigation:

“Similar findings have been elucidated in humans, and Tsai’s lab is now working on further defining how the lateral neurons of the mammillary body are connected to other parts of the brain, to figure out how it forms memory circuits and how to then design very targeted new treatments for Alzheimer’s disease, to prevent progression of symptoms and, ideally, to prevent symptoms developing in the first place.”

This area of the brain has also been the focus of research into deep brain stimulation to alleviate Alzheimer’s disease symptoms.

Although this treatment generally involves inserting electrodes into the brain, a new noninvasive method called chemogenetics showed promise in a mouse model, prompting calls for further research into its potential.

One avenue of research includes the identification of drug targets that could mimic its beneficial effects in people with Alzheimer’s disease.

The molecule mRNA might be another target in combating Alzheimer’s disease. A study from China recently found that modifying mRNA in mice helped improve the cognitive symptoms of Alzheimer’s disease.

The outlook for Alzheimer’s disease

“Dementia can be solved, but it won’t be from targeting a single health factor. We need to leave no stone unturned for each individual at risk for Alzheimer’s, optimizing sub-optimal factors throughout life and into old age. This gives us each the best odds of achieving successful aging free of the chronic disability associated with AD and other neurodegenerative dementias.”

— Dr. David Merrill

There may not yet be a cure for Alzheimer’s disease but, with the renaissance of research efforts focused on this disorder, the outlook will likely become brighter for the many people affected by it.

Perhaps the last word should go to Dr. Maria C. Carrillo, chief science officer of the Alzheimer’s Association.

“As with any renaissance, the invigoration of the Alzheimer’s and dementia field comes with vigorous debate and disagreement, those who cling on to established ideas and those who seek to smash the status quo,” said Dr. Carrillo.

“This debate and disagreement [are] essential in research, and as a community, we must be grounded in evidence to drive our progress,” she emphasized.

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