Alzheimer’s disease (AD) is a complex illness whose symptoms and timeline vary widely among individuals. Although some people with AD progress rapidly from mild cognitive impairment (MCI) to severe dementia, many others continue to live independently for years. And while certain biomarkers appear to be consistent across cases, AD’s underlying biological mechanisms are hotly debated — as are theories of effective treatment.
Even the disease’s cause remains a subject of intense controversy. Some researchers place the blame squarely on aging, while others believe AD is primarily a neurological disease, an immune-system disorder, a genetic syndrome, or a dysfunction of the cardiovascular system. Other experts think AD has a gastrointestinal component, or may involve malfunctioning digestive processes within individual cells — while many believe that a true Unified Theory of Alzheimer’s Disease (UTAD) will have to incorporate and explain all these factors.
And while most physicians agree that AD involves aggregations of beta-amyloid and tau proteins in the brain, it’s unclear what roles these proteins play in the disease. Therapies targeting beta-amyloid plaques and tau tangles are widely prescribed to people with Alzheimer’s, yet these treatments frequently fail to relieve the disease’s symptoms — raising questions about whether amyloid and tau protein accumulations are truly causes of AD, or are merely effects or biomarkers of some as-yet undiscovered core mechanism.
Due to these perplexing clinical findings, doctors and researchers continue to explore alternate approaches to AD diagnosis and treatment. Some have reported promising results from simple modifications to diet and lifestyle, while others emphasize mental stimulation and aerobic exercise. Particularly intriguing results have emerged from the field of vascular therapy, which uses external counterpulsation (ECP) technology developed at Harvard University to stimulate body-wide blood flow — measurably improving cognitive performance in people with mild AD.
Here, we’ll examine the evidence for and against several of the most widespread theories of AD’s pathology, along with today’s leading approaches to Alzheimer’s treatment.
What causes Alzheimer’s disease?
The beta-amyloid buildup hypothesis blames AD on amyloid plaques in the brain.
For the past 25 years, the most predominant Alzheimer’s hypothesis has been that the disease is caused by the buildup of beta-amyloid peptides: proteins that suffocate and kill brain cells when they accumulate in thick deposits known as plaques. Beta-amyloid protein is produced naturally in brain cells called neurons, though its normal function is unclear. In a healthy brain, beta-amyloids are rapidly broken down and removed — but as people age, their ability to dissolve these proteins decreases, leading to the aggregation of amyloid plaques.
In the 1980s, beta-amyloid plaques were identified in the brains of people who had died from Alzheimer’s — and studies throughout the 1990s appeared to indicate that these protein aggregations were linked to the brain-wide neurotoxicity and cell death observed in autopsies of AD patients. Some researchers also believe amyloid plaques lead to the accumulation of tau protein tangles (see below), which could make them a likely culprit for the root cause of Alzheimer’s.
However, while the beta-amyloid hypothesis remains a popular one, many recent studies indicate that amyloid plaques are unlikely to be a direct cause of AD. For example, amyloid deposits are also found in the brains of people who don’t have the disease; and plaques transferred from people with Alzheimer’s into mouse brains have not been observed to cause AD symptoms. In fact, after more than 20 years of research, no one has yet been able to prove that beta-amyloid plaques kill neurons at all — a fact that casts serious doubt on this hypothesis’s central claim.
The tau-protein tangle hypothesis targets a different type of protein accumulation.
Like beta-amyloids, tau proteins are produced by healthy neurons, which use them to help maintain the stability of their axons (white-matter fibers that connect neurons to one another). In the 1990s, researchers studying amyloid plaques discovered that the brains of many people with Alzheimer’s also contained unusually large tangles of tau proteins. Today, as experts become increasingly skeptical of the beta-amyloid hypothesis, many have turned their attention to tau pathology as a more likely cause of AD.
A growing body of evidence indicates that tau pathology is strongly correlated with the range and extent of cognitive symptoms in people with Alzheimer’s. Brain-imaging studies, for example, have found that the spatial distribution of tau tangles is closely linked to the patterns of neurodegeneration observed in individuals with AD — in fact, the spread of tau pathology throughout the brain follows the same overall route as the disease itself. Furthermore, researchers have demonstrated that tau tangles directly harm neurons in a variety of ways.
Although tau-based treatments for AD remain in the early stages, several therapies targeting tau pathology appear to improve cognitive function in people with the disease. As a result, the tau hypothesis is now attracting considerable attention within the research community.
The lysosomal storage hypothesis focuses on intracellular digestion problems.
Since 2019, a new line of research has targeted a biological mechanism that may underlie the formation of both beta-amyloid and tau protein plaques. While proteins in a healthy brain would ordinarily be absorbed into cells and broken down in their lysosomes (tiny digestive organelles), certain spontaneous changes in a protein’s structure could make it indigestible to cells — which would cause the protein to build up in those cells’ lysosomes until the organelles finally rupture, releasing a dense sludge of protein plaque that might spread throughout the brain.
Recent experiments have shown that certain interactions between naturally occurring brain chemicals can produce structural modifications in proteins like beta-amyloid and tau; and that cells’ digestive enzymes would be unable to latch onto the resulting altered molecules. However, the lysosomal hypothesis is so new that no one has yet been able to observe such modified proteins in the brain of an actual person with Alzheimer’s. Much more investigation is needed before this hypothesis can be verified or disproven — and even if it turns out to be valid, the roles of beta-amyloid and tau deposits in AD still remain unclear.
The vascular hypothesis suggests that AD’s root cause may be circulatory.
Although the vascular hypothesis of Alzheimer’s disease (VHAD) was first proposed more than 25 years ago, it’s begun to attract greater attention recently. Today, a growing number of experts agree that hypoperfusion (decreased blood flow) likely plays a central role in AD pathology. Dysfunction of the body’s circulatory (or vascular) system reduces the flow of oxygen and other nutrients to cells, and prevents the effective removal of cellular waste products — creating a bodily environment in which widespread neurodegeneration becomes a significant risk.
Disturbances in cerebral blood flow (CBF) are already widely recognized as key biomarkers for Alzheimer’s; and clinicians increasingly use cerebral hypoperfusion as a preclinical predictor of the disease. These close linkages between circulatory problems and AD symptoms suggest that early vascular interventions can strengthen CBF and delay cognitive decline — a conclusion that’s backed up by several recent studies.
As researchers develop a clearer understanding of vascular risk factors in AD, circulatory diagnostic methods may enable doctors to diagnose the disease much sooner, while vascular therapies may even help prevent certain symptoms altogether.
Many hypotheses also include factors like diet, exercise, social activity and genetics.
The uniqueness of each patient’s Alzheimer’s pathology means that the disease may be triggered by different combinations of causes in different people. For this reason, most hypotheses of AD acknowledge that diet, exercise, cognitive stimulation, social interaction, genetics, and numerous other factors interact in complex ways to influence the disease’s symptoms, severity and timeline in any given individual.
For example, numerous studies have found that a heavy intake of sugar and red meat significantly raises a person’s risk of developing AD. A sedentary lifestyle with minimal exercise weakens blood flow throughout the entire body, limiting cells’ ability to fight off degeneration. Loneliness and boredom are both linked with faster rates of cognitive decline. And while genetics are unlikely to be the disease’s primary cause, certain “risk genes” do correlate with a higher likelihood of developing Alzheimer’s at some point in life.
Although none of these factors may be the root mechanism behind AD, they all increase a person’s risk of developing severe symptoms sooner — while interventions in each of these areas have been shown to delay cognitive decline, protect against dementia, and preserve quality of life; sometimes for years after an initial Alzheimer’s diagnosis. In fact, simple lifestyle changes can reduce an individual’s risk of ever developing AD by as much as 53 percent.
What’s the most effective Alzheimer’s treatment?
Beta-amyloid therapies attract major investment, but many clinical trials have failed.
Over the past 20 years, many millions of dollars have been invested in the development of AD therapies specifically targeting beta-amyloid proteins. These drugs span a wide range of treatment vectors, from protein translation inhibitors designed to prevent cells from making beta-amyloids, to monoclonal antibodies (mAbs) that work to clear away amyloid plaques. However, the vast majority of these therapies have failed to deliver their intended results in clinical trials — in fact, some have made patients’ symptoms even worse.
For example, the anti-amyloid antibody drug Bapineuzumab provided “no significant clinical benefit,” while causing harmful side effects such as vasogenic edema (fluid accumulation in the brain). The monoclonal antibodies aducanumab, solanezumab, crenezumab and gantenerumab all failed to meet their clinical trial goals. The amyloid production inhibitor avagacestat, meanwhile, provided no measurable improvement in cognitive function, and the inhibitor semagacestat actually resulted in a worsening of functional ability.
Failures like these have forced manufacturers to cut their losses by ending clinical trials early, leading numerous doctors and research experts to conclude that “this approach is not working.” Today, many clinicians remain skeptical of new beta-amyloid drugs — and of the amyloid hypothesis in general.
Tau protein therapies for Alzheimer’s also continue to fail in most clinical trials.
As evidence for the tau-protein tangle hypothesis continues to mount, Alzheimer’s drug developers are increasingly shifting their investment dollars toward tau therapies. Similarly to beta-amyloid drugs, most therapies targeting tau tangles take the forms of monoclonal antibodies and protein translation inhibitors. But whereas beta-amyloid therapies are typically given to people who already have mild-to-moderate AD, tau-targeting drugs are often administered in the disease’s earlier stages, with the aim of “stopping Alzheimer’s before it starts.”
Yet unfortunately, as with beta-amyloid drugs, failures of tau therapies continue to stack up in clinical trials. In 2020, for example, the anti-tau antibody semorinemab proved unable to reduce adverse events in people with AD, forcing the manufacturer to admit that the mAb had failed to meet its clinical-trial endpoints. Development of the antibody zagotenemab was discontinued in 2021, after it failed to meet its trial goals for the fourth time in a row. And a 2020 survey of numerous tau drug candidates found that even the most promising clinical trials remain “highly debated” and “ongoing,” with no conclusive results.
At the same time, the field of tau therapy research is still quite young in comparison to that of beta-amyloid drug development. Several pharmaceutical companies currently have brand-new anti-tau antibodies in their research and trial pipelines, and the results of these mAb investigations may prove more positive.
Therapies targeting lysosomal dysfunction remain in the very early research stages.
The lysosomal hypothesis is the newest and most controversial theory of Alzheimer’s. Only in 2019 did researchers demonstrate that this hypothesis’s central mechanism was biologically possible, by showing that beta-amyloid and tau proteins could be spontaneously modified in ways that would make them indigestible to neurons. Since then, clinicians have expressed cautious excitement about the potential of lysosomes as a therapeutic target for Alzheimer’s — but research on lysosomal therapies has yet to progress beyond the theoretical stage.
In 2021, for example, a team at Huazhong University of Science and Technology proposed six possible targeting strategies for lysosome-focused therapies, including approaches focused on preventing acidification and preserving lysosomal membrane integrity. A research team at Yale University, by contrast, recently concluded that drug developers will need a much clearer understanding of lysosomes’ biochemistry and role in Alzheimer’s pathology before they can begin to identify promising candidate molecules for clinical trials.
At present, the lysosomal hypothesis continues to attract widespread research interest, and many experts believe lysosomes may represent viable targets for a new generation of AD therapies. But until lysosomal drugs start to reach the clinical trial stage, it’s impossible to know for sure how effective such therapies will turn out to be.
Vascular therapies like ECP are non-invasive and show significant promise.
Unlike the lysosomal and tau theories, the vascular hypothesis of Alzheimer’s has a long and distinguished pedigree dating back to the early 1990s. While researchers continue to debate whether vascular dysfunction is a cause or effect of Alzheimer’s, most agree that vascular pathology is intimately related to AD symptoms — and that stimulation of the circulatory system can delay cognitive decline by increasing blood flow throughout the brain and body.
For many years, the most popular vascular therapy was aerobic exercise, which clinicians frequently prescribe for early-stage Alzheimer’s, and for people who display preclinical risk factors for the disease. But unfortunately, this approach is highly dependent on patients’ willingness to participate, as well as their physical ability to perform the prescribed exercises. As a result, aerobics produce inconsistent levels of improvement in people with AD; and daily workouts become increasingly impractical as patients grow older and less physically active.
However, several teams of doctors have had success treating Alzheimer’s by stimulating the vascular system with Harvard’s FDA-cleared external counterpulsation (ECP) technology. Non-invasive ECP devices rhythmically compress patients’ limbs in synchronization with their cardiac cycles — and research shows that this approach strengthens body-wide blood flow and improves cognitive performance in people with mild AD. In fact, ECP may result in some of the same effects as an aerobic workout, and could provide many of the same benefits, too.
A comprehensive approach to treatment should address many different lifestyle factors.
The federal government’s National Plan to Address Alzheimer’s Disease has set a deadline of 2025 for effective prevention of AD. As a result, many researchers have shifted their focus from mitigation to early intervention — developing machine-learning algorithms that can predict the disease while it’s still in the preclinical stages, and designing cognitive training tools and brain-boosting dietary regimens that can delay or even prevent many AD symptoms. With intervention options like these, a growing number of AD experts are becoming increasingly optimistic about the possibility of overcoming Alzheimer’s within the coming decade.
Whether the future of Alzheimer’s research continues to focus on the beta-amyloid hypothesis, or pivots more toward tau-tangle investigations, or targets lysosomal dysfunction, or explores non-invasive vascular therapies — or all the above — tomorrow’s treatment approaches will likely involve a combination of interrelated techniques, from pharmaceutical prescriptions to memory-training apps, to aerobic exercise regimens, to vascular therapies like ECP.
In the ongoing search for a Unified Theory of Alzheimer’s Disease (UTAD), each of these factors will almost certainly turn out to play its own important role in our understanding of the mechanisms underlying AD, and in the development of integrated treatment plans that address each patient’s unique pathology with individually tailored combinations of therapies. The cutting edge of medicine is becoming increasingly personalized, holistic, and data-driven — and as the latest research makes clear, the field of Alzheimer’s treatment is certainly no exception.
