A Turning Point In Alzheimer's Care

After decades of hard-fought research, a new era of treatment, care and diagnostics are on the horizon.

In This Briefing

A Peculiar Disease

Alzheimer’s disease was first introduced to the scientific community on November 4th, 1906, when Dr. Alois Alzheimer presented a lecture about "a peculiar disease” at a psychiatric conference in Tubingen, Germany. There, he described the unsettling case of Auguste Deter.

Auguste worked as a seamstress from an early age. In her twenties, she married her husband, Karl, gave birth to a lovely daughter, and spent many happy years building a warm and loving family life. But everything changed once Auguste reached middle age. 

Her symptoms were subtle at first, harmless enough for Karl to overlook. A lost thought. A misplaced pen. A forgotten task. Unfortunately, Auguste’s symptoms worsened from there. Her memory faded. More carelessness crept into her routine. Casual conversations with Karl and her daughter constantly sputtered, spiraled and fell apart. Once symptoms were bad, Auguste’s condition continued to deteriorate. She forgot how to cook. She lost her sense of direction around the house. She developed insomnia and cried hysterically throughout the night. 

Over time, Auguste’s mind devolved into paranoia. Family. Neighbors. Strangers. Everyone appeared inexplicably suspicious or threatening in her eyes. Eventually, Auguste’s condition became too overwhelming for Karl to manage on his own. He took her to the hospital, where a doctor recommended her admission into a psychiatric institution. Karl agreed. After 28 years of marriage, he entrusted his wife’s care to a team of medical professionals.

Dr. Alzheimer met Auguste at Frankfurt's psychiatric hospital and conducted regular physical and cognitive exams to assess her health. He often asked a series of questions and recorded her responses. The following transcript describes one of their documented exchanges during Auguste's first week at the hospital:

Dr. Alois Alzheimer (left) and Auguste Deter (right)

“What is your name?” he asks.

“Auguste,” she says.

“Last name?”

“Auguste.”

“What is your husband’s name?”

“Auguste, I think.”

“Your husband?”

She looks as if she does not understand the question. “Ah, my husband.”

“Are you married?” he asks.

“To Auguste.”

“Mrs. D?”

“Yes, yes, Auguste D.”

“How long have you been here?”

“Three weeks.”

He shows her a pencil. “What is this?”

“A pen.”

During lunchtime, Dr. Alzheimer sits with Auguste while she is eating cauliflower and pork.

“What are you eating?” he asks.

“Spinach,” she says, while chewing her meat.

A moment passes.

“What are you doing?” he asks.

She answers, “Potatoes. Horseradish.”

Later on, he examines her writing ability.

“Can you write “Mrs. Auguste D”?” he asks.

She writes “Mrs.” and stops.

He repeats. “Can you write “Mrs. Auguste D”?”

Auguste does not continue writing. Instead, she mumbles, “I have lost myself,” repeatedly.

Auguste spent the last five years of her life in the hospital. With each passing day, she descended further into the depth of her disease. On April 8th, 1906, she passed away at the age of 55.

Auguste was a unique patient for Dr. Alzheimer. He was familiar with dementia cases from his time at psychiatric hospitals, but these patients typically remained asymptomatic until their 70s or 80s. With Karl's permission, Dr. Alzheimer performed an autopsy on Auguste's brain and observed distinctive abnormalities: significant brain atrophy, large clumps of plaques between neurons, and ropelike tangles inside neurons. He hypothesized Auguste had a rare form of "presenile dementia," which led to the recognition and diagnosis of more cases with similar characteristics months later. Dr. Alzheimer's findings ultimately inspired his boss, Emil Kraepelin, to coin the term "Alzheimer's disease" in a subsequent book.

An Era of Scientific Progress

Years passed. During this time, the global population experienced a sudden and sustained increase in life expectancy as the result of advances in medicine, public health, and living standards. Beyond the growing accessibility to clean water, sanitation and better hygiene, double blind and randomized control trials were designed for the first time and quickly became standard clinical protocols, which allowed researchers to observe the effects of treatments with far greater reliability. The electron microscope was also invented, enabling scientists to study brain cells and other microorganisms with unprecedented detail. There were countless other scientific breakthroughs throughout this era, and yet, Alzheimer’s disease was largely overlooked — as was research into symptoms of aging in general. The prevailing view among scientists was that memory loss was a normal, unavoidable aspect of aging, and there was little incentive to investigate or challenge a force of nature.

But as the world's population continued to age, sentiments began to shift. A growing percentage of society required constant support for daily tasks like washing, dressing, and eating, and families and caregivers bore an intense physical, emotional and financial burden. Healthcare systems were ill-prepared to alleviate this crescendoing pressure, and a crisis was festering. In response, the United States Congress established the National Institute on Aging (NIA) in 1974. Under the NIA's auspices, resources and research funding flowed into targeted projects with a goal to improve the health and well-being of older adults.

Soon after, Alzheimer's disease was identified as the most common cause of dementia rather than as a rare form of dementia as Dr. Alzheimer suspected. In the subsequent years, a series of studies fundamentally reshaped science’s understanding of the disease. The first deterministic gene for Alzheimer's was identified. Many people were not displaying meaningful signs of cognitive decline well into their 80s and 90s. Simultaneously, the brains of young and elderly patients with Alzheimer's appeared identical, indicating the disease’s onset is not solely dependent on a person’s age. The infamous plaques and tangles Dr. Alzheimer and his contemporaries described decades earlier were structurally identified: the plaques were accumulated clusters of misfolded beta-amyloid proteins and the tangles were bundles of tau proteins. Through these findings, the scientific community made a groundbreaking realization: dementia symptoms are not an inevitability of old age, and Alzheimer’s may be a treatable disease.

A microscopic image of amyloid plaques (left) and a neuron with tau tangles (right)

The Toll of Aging

A generation of researchers have come and gone since these discoveries. Although the field has deepened its understanding of dementia since the NIA's founding, effective treatments for Alzheimer's remain elusive. As a result, global deaths from Alzheimer's and other forms of dementia increased by 122% between 2000 and 2019, rising to the 7th leading cause of death worldwide in the process. In contrast, cardiovascular disease is the world's leading cause of death, and its number of deaths has decreased by 1% over the same period.

Meanwhile, the physical, emotional, and financial strain to support an aging population that led to the NIA's creation has only intensified over time. While the complete personal and societal burden of Alzheimer's is difficult to determine, the measurable and immeasurable costs are immense. 

A family with a 75-year-old diagnosed with Alzheimer's dementia in the United States may incur over $500,000 USD (net $250,000+ USD) worth of lifetime care costs. This price far exceeds the retirement savings of most Americans and may even be conservative, since calculations struggle to fully account for the impact on family caregivers' time, health, and employment.

For instance, there were approximately 18.4 billion hours of unpaid care for dementia patients in 2023 in the United States alone, which contributed to an estimated economic value of $350 billion USD. Moreover, the demands of unpaid care intensify over time, as elderly family members require more supervision and support as their disease progresses. This may eventually lead to conflicts with work responsibilities, which can directly impact a caregiver's income, create more distress, and exacerbate problems in their own health. In fact, studies indicate the chronic stress from caring for family members negatively impacts people’s sleep, which worsens their performance at work and increases their risk of developing chronic health conditions like high-blood pressure.

All these indirect and unpaid care costs do not even address the direct care costs for Alzheimer’s and other dementia, which are projected to surpass $360 billion USD in 2024 in the United States alone. Barring a medical breakthrough to prevent, delay, or alter the course of Alzheimer's disease, direct costs in the United States are expected to exceed $1 trillion USD by 2050.

Family Ties

Less than 6% of Alzheimer’s cases are people under the age of 65. When an onset case is identified, a foreboding issue beneath the surface often explains the abnormality. This was the case when Walter Jennings was diagnosed with the disease at 58 in the early 1980s. 

Within three years, four of Walter’s younger siblings also developed dementia symptoms as they approached their 60th birthdays. However, since everyone in the Jennings family was developing Alzheimer’s at a young age, clinicians and relatives alike assumed it was normal or circumstantial. Except for Walter's daughter, Carol. The astute schoolteacher from Nottingham, England was troubled by her family’s history. Her resolve to understand why the disease’s scourge struck her father and so many beloved aunts and uncles motivated her to write. 

'I… think my family could be of use.' she penned

On a separate sheet of paper, she illustrated her ancestry. 'Actually, I am the daughter of Walter, who you will see from the family tree is sixty-three years old and has Alzheimer's, as does his sister, Audrey… Please contact me if you think we could be of help.'

A snapshot of the letter Carol Jennings wrote in 1986

Carol sent her letter to St. Mary's Hospital in London, where a group of scientists posted a newsletter advertisement requesting to hear from families with two or more members affected by Alzheimer's disease. The team suspected early-onset was influenced by familial genetics and was searching for evidence, hoping a breakthrough in rare cases will offer clues about how Alzheimer's develops in most cases. 

Dozens of people wrote to them, many with intriguing stories worth consideration. But when the researchers read Carol’s letter, they responded immediately. They wanted to learn more – talk to the family, collect blood samples. Through persistence and persuasion, Carol convinced 39 relatives to participate in the team’s investigative study. The scientists spent the next five years sequencing the genes of the Jennings, sifting through their DNA with painstaking detail, searching for any differences between those who had Alzheimer's and those who did not. 

Their determination led to a momentous discovery. Amongst the human body’s 3.1 billion base pairs of genetic code was a singular mistake. A molecule on chromosome 21 was amiss. The error impacts the amyloid precursor protein (APP) gene and leads to an overproduction of beta-amyloid proteins. Every person who inherits the gene mutation invariably develops Alzheimer’s disease, and they have a 50% chance of passing on the variant gene to each of their children.

One molecular mistake followed by a genetic coin toss. This is all it takes to unravel the delicate balance of an otherwise healthy life, to ravage a genealogy with a disease. 

The scientific community celebrated the research team’s achievement when they published their findings in Nature’s 1991 journal. Gene Mutation That Causes Alzheimer's Is Found, said The New York Times; Family links offer hope of Alzheimer's disease cure, read The Times in London. There are only a few hundred extended families worldwide who carry deterministic Alzheimer’s mutations, and the Jennings family is one of society’s earliest known examples. Dr. Alzheimer did not realize it at the time, but a 2012 study found Auguste also carried a deterministic gene for the disease, albeit a different genetic variant than what the Jennings have.

The article about the APP gene discovery from The Times in London, February 16th, 1991

The Amyloid Cascade Hypothesis

The following year, Dr. John Hardy and his colleague Dr. David Allsop expanded upon their team’s groundbreaking APP gene mutation discovery by proposing the amyloid cascade hypothesis. They theorized that excessive amyloid is the primary cause of Alzheimer's; the clinical symptoms patients experience from the disease are downstream events to amyloid oversaturating the brain and disrupting neuronal activity. 

Although their initial hypothesis underemphasized important details, such as how amyloid specifically triggers a cascade of neurodegenerative effects, it presented one key advantage over other, less prominent hypotheses at the time: it allowed scientists to make testable predictions about the disease's trajectory and evolution based on the presence of a single molecule. Occam's Razor suggests the simplest explanation is often the best choice when faced with competing ideas, and the clarity of Dr. Hardy and Dr. Allsop’s hypothesis was alluring compared to alternatives with more complexity and just as many unanswered questions. 

Then another breakthrough, less than three years later, irrevocably tipped the scales towards the amyloid cascade hypothesis. A group of researchers from Athena Neurosciences in San Francisco injected a human APP gene mutation into mice embryos. The mice born with the mutation struggled to navigate mazes and complete simple cognitive activities at earlier ages than mice without the APP gene variant. Upon autopsy, the brains of the transgenic mice revealed amyloid plaques yet surprisingly few tau tangles.

While this did not prove the amyloid cascade hypothesis, it provided corroborating evidence and introduced a new paradigm of research for scientists to explore an analog of Alzheimer’s in lab animals. For a growing constituency of families, caregivers and medical experts desperate to overcome Alzheimer’s disease, Athena Neurosciences’ innovation became the catalyst for funding agencies and pharmaceutical companies to concentrate their resources on developing anti-amyloid treatments.

The newspaper article about the first transgenic mice from The New York Times, February 15th, 1995

Between 1999 - 2009, the number of new clinical trials targeting Alzheimer's disease skyrocketed from 10 to 120. Between 2002 - 2012, 48% of drugs under development and 65% of clinical trials primarily targeted beta-amyloid proteins.

Treatment strategies largely fell into one of three categories: prevent the body from overproducing beta-amyloid proteins, stop the protein from clustering together into hazardous plaques, or remove existing amyloid proteins from the brain and body.

If only treating Alzheimer’s was so simple. 

The Price of Failure

Despite best efforts, an astonishing 98% of all experimental Alzheimer's drugs failed in later-stage clinical studies between 2004 - 2021. Later-stage failures come at significant opportunity costs for future research, because the average Alzheimer’s drug development program takes 13 years to complete and costs an estimated $5.7 billion USD to fund from initial drug discovery to clinical approval. As a result, private enterprises spent an estimated $42.5 billion USD between 1995 - 2021 on Alzheimer's clinical research, yet only six new drugs were approved by the United States’ Food and Drug Administration (FDA). One drug was discontinued shortly after its approval, leaving five active medications to represent a costly, multi-decade time period. Furthermore, the five remaining drugs only address symptoms of Alzheimer’s like mood swings and memory loss, rather than redress the underlying neurobiology of the disease.

These lackluster results lag far behind estimates for clinical trials in other therapeutic areas. For instance, cancer research and development costs an estimated $800 million before FDA approval and takes 7-10 years for programs to complete.

A Diagnostic Dilemma

The main reason why Alzheimer's trials take longer, cost more and fail at a higher rate than other research areas is because it is difficult to identify eligible patients. Most trials are designed to treat patients with little or no cognitive dysfunction to measure if medications delay or slow down the progression of the disease. But the challenge with enrolling participants for early intervention trials is multi-faceted. 

It is hard to classify asymptomatic Alzheimer's cases because many elderly people with normal cognitive function have abnormal amounts of amyloid plaques in their brains. Would these individuals eventually develop dementia symptoms if enough time passed? How far in advance do asymptomatic patients need to start medication to change the course of an eventual symptomatic case? 5 years may be too short to register a meaningful impact, but dedicating resources for 10 or 20 years to test a single drug is less viable and just as risky.

It is also difficult to diagnose early-stage Alzheimer's because cognitive decline and amyloid deposits do not linearly correlate with disease progression. How do researchers make consistent diagnoses amidst so much variance in disease symptoms and beta-amyloid deposits?

In particular, it is laborious to distinguish Alzheimer’s disease from other types of dementia, since many people with symptoms have wide-ranging amounts of beta-amyloid in their brains. Thus, when symptoms arise, it is often the result of multiple, confounding factors. For example, Alzheimer's often coexists with other types of dementia. When a person has brain changes associated with more than one type of dementia, their condition is known as mixed dementia, and studies suggest mixed dementia is the norm rather than the exception for people with Alzheimer’s symptoms. For instance, a 2017 study autopsied 447 people who were previously diagnosed with Alzheimer’s, and 82% of the deceased had mixed dementia. Scientists craft elaborate physical and cognitive tests to capture nuance and account for clinical minutiae, but they are imperfect and cannot determine with certainty which symptoms are due to which dementia. 

As a result, the only definitive way to diagnose an Alzheimer’s case in the 20th century was through an autopsy, and this limitation led to patient misdiagnosis during trial enrollment. In fact, a number of postmortem studies throughout the 2010s found 15% - 30% of trial participants in the 20th century and early 2000s were misdiagnosed with Alzheimer's dementia. It is so improbable to prove clinical significance with such an overwhelming design flaw — it may as well be a statistical impossibility. In hindsight, these trials were doomed to fail.

It took until 2004 for the misfortunes of Alzheimer’s diagnostics to brighten. A research team at the University of Pittsburgh developed a compound to enter the brain through the bloodstream and attach itself to beta-amyloid proteins. The compound’s fluorescent color lit up in PET imaging scans and helped scientists locate amyloid plaques in living people for the first time. 

Shown are PET scans that track tau (top row) and beta-amyloid (left) from two normal older adults (left and middle) and one patient with Alzheimer’s disease (right). The normal older adult on the left has no brain amyloid plaques and minimal tau. The normal older adult in the middle has amyloid spread throughout the brain as well as some tau in a portion of their brain. In the Alzheimer’s patient, amyloid and tau are spread through the brain. Credit Michael Schöll/UC Berkeley

The Pittsburgh team’s breakthrough renewed the scientific community’s vigor and pursuit of anti-amyloid treatments. Biological assessments to enroll in trials. Better study designs. More reliable clinical results. Critical pieces to solve the Alzheimer’s puzzle began to fall into place.

But alas. PET scans are scarce and require specialized equipment. There are only a few thousand machines scattered throughout the world yet millions of people with Alzheimer’s. Aside from the exorbitant costs to use PET scans, it is simply not possible to test every patient with such a vast discrepancy in supply and demand. Spinal fluid tests were able to address some of the field's enormous diagnostic gaps, but these tests are invasive, so patients are more hesitant to have the procedure. As a result, a striking 36% of failed phase 3 Alzheimer's drug trials between 2004 - 2021 did not screen participants for amyloid plaques or tau tangles for enrollment. 

Necessary, But Insufficient

It is apparent the amyloid cascade hypothesis struggled with systemic challenges for much of its history, which prevents the research field from forming a clear consensus about the topic. Nonetheless, a 2021 meta-analysis compared the results of 14 prominent Alzheimer’s trials and reached an unsurprising conclusion: reducing excessive beta-amyloid does not “substantially improve cognition.” In one phase 3 trial example, a drug reduced concentrations of beta-amyloid by more than 90% and still failed to show functional changes in patients.

While a body of evidence still supports a strong relationship between beta-amyloid and Alzheimer's, the relationship is more complex than the original amyloid cascade hypothesis proposed. Amyloid is closely associated with Alzheimer's, but scientists have yet to prove it causes the disease, and there is a big difference between association and causation. Amyloid may be a necessary component to develop Alzheimer’s, but it does not appear to be sufficient by itself to cause the disease.

Unfortunately, because of the limited commercial success amassed by Alzheimer’s trials, Pfizer, Johnson & Johnson and several other pharmaceutical companies curtailed investments to treat the disease over the years, leaving much of the financial research and development to the public and non-profit sectors.

Trials and Triumphs

Despite a disheartening history, the turmoils experienced from the field’s predominant era of anti-amyloid treatments are worth celebrating. The pantheon of scientific achievements sit atop a mountain of failed experiments because success in science is an iterative process. It requires ingenuity, tenacity, trial and error, and a willingness to learn from past mistakes to build something better in the future. Researchers endure frustration and families experience grief throughout the process, but their dedication spurs the momentum for critical research to reach new heights.

It is remarkable to see the FDA approve three new Alzheimer's drugs in the past five years after a historical 98% failure rate. While the clinical results of recent drug approvals are modest, they address the neurology of the disease rather than the surface-level symptoms of dementia. In this sense, the milestones of Aduhelm (aka Aducanumab), Leqembi (aka Lecanemab) and Kisunla (aka Donanemab) are more meaningful than previous Alzheimer's drug approvals. Also, after many years of anti-amyloid experiments, the research field is finally ready to explore more creative treatment solutions. In 2016, 56% of Alzheimer's clinical trials focused on beta-amyloid, but by 2024, the number dropped to 16%. This newfound diversity in clinical trials is a strength and a sign of encouragement for the direction of future research. 

Neural Communication 101

Since beta-amyloid plaques and tau tangles do not tell the full story of Alzheimer's dementia, learning more about how neurons function and malfunction may unravel the disease’s mysteries.

Neurons are specialized cells that share information throughout the body through a series of electrical and chemical signals. Tens of billions are concentrated in the brain, and billions more are scattered throughout the spinal cord and peripheral nervous system to form a dynamic meshed network. The following basic sequence describes how neurons communicate with each other:

A stimulus occurs

The process begins when a neuron’s sensory receptors experience an initial stimulus from its environment or bodily functions. These senses can range from taste, touch and temperature, to pain, light, sound, smell and more. 

The stimulus turns into an electrical signal

Afterwards, the stimulated neuron initiates an electrical signal to share the information it received with nearby neurons by passing its message down to the slender, elongated edges of its cell, known as its axons

The electrical signal turns into a chemical signal 

When the electrical signal reaches the ends of a neuron’s axons, its message is translated into a chemical signal and released as neurotransmitters

The chemical signal passes to the next neuron

These neurotransmitters then cross the synapse – an intercellular junction for proteins and other molecules to move from one cell to another – in order to reach the next neuron in the communication chain. After crossing the synapse, the neurotransmitters bind to dendrites, which are branching, tree-like receptors at the edges of adjacent neurons.

The chemical signal turns back into a electrical signal

As the neurotransmitters bind to dendrites, their chemical message translates back into an electrical signal to pass through the cell body of the new neuron. This intricate electrochemical communication cycle repeats itself until the initial message reaches the brain or another part of the body to interpret and react to the information. 

In a healthy body, the weblike circuitry of the nervous system blossoms as it orchestrates all sorts of information to seamlessly traverse the brain and body. But this intricacy comes at a cost. 

Dimensions of Neurodegeneration

Neurons cannot repair or replace themselves as easily as damaged skin, bone, and most other types of cells. One reason is that the brain and nervous system use protective measures to prevent most outside entities from reaching them. As a result, they depend on massive amounts of redundancy to persist through potential problems rather than rely on outside organs for help. But as the body ages, damage accumulates, inefficiency creeps in, and their communication protocols falter. Aside from physical injuries, several underlying factors contribute to neural dysfunction and decline over time. 

The following is a simplified, non-exhaustive overview:

Protein Dysfunction: Abnormal protein structures or intolerable amounts of proteins are created or clumped together to disrupt normal neural processes. For instance, clusters of beta-amyloid interfere with neuron-to-neuron communication at synapses. Inside neurons, tau tangles prevent nutrients and other essential molecules from entering or exiting cells.

Autophagy Dysfunction: Neurons fail to recycle and remove waste or other unnecessary components in their cell. Over time, the accumulated waste disrupts neural function.

Oxidative Stress: The structural foundation of a neuron is damaged by toxic oxygen molecules when the body cannot adequately regulate its energy production and immune system.

Inflammatory Response: The immune system's overactive or misdirected response to an injury, irritation, or infection damages neural tissue.

Axonal & Neurotransmitter Issues: Neurons cannot effectively send or receive electrochemical signals, which impacts their ability to communicate with one another.

Vascular Issues: Blood flow problems deprive neurons of oxygen and essential nutrients to function normally. Poor blood flow can also make it harder for neurons to flush away unwanted molecules from their cells.

Most of these factors entwine and interplay with one another. While compelling arguments can be made to explain what sequence of events happens first, second or third, decoding the technicalities of the brain is one of the most complex questions for a scientist to answer. 

Ultimately, these interconnected biological issues fester for years, until early symptoms are apparent in the afflicted and intractable for modern medicine. In the case of Alzheimer’s dementia, pathological changes are believed to occur 20 years or more before symptoms arise. 

Cognitive changes from Alzheimer’s disease erode away the brain, just as the effects of Parkinson’s, Huntington's and other neurodegenerative diseases manifest and debilitate over long time periods. The silver lining is the similarities between these diseases create an opportunity for breakthroughs in one area to potentially benefit the broader field of neurodegeneration. Though as the domain’s collective efforts progress, one thing remains clear: neurodegenerative diseases like Alzheimer's are not a normal part of aging. Older age is the greatest risk factor for Alzheimer’s, but it does not cause Alzheimer’s dementia by itself.

Genetics and family history are two other major risk factors for Alzheimer’s. Like aging, they are non-modifiable, and partially explains why the disease is so hard to treat. A growing body of evidence suggests certain lifestyle choices can influence modifiable risk factors and reduce a person's likelihood to develop Alzheimer's dementia. In fact, The Lancet’s 2020 Commission report about dementia prevention, intervention and care mentions up to 40% of dementia cases may be attributable to modifiable risk factors. 

Paths for Resilience

There are potentially dozens of risk factors relevant to Alzheimer’s disease, but lifestyle studies have key limitations. These types of studies can show an association between a lifestyle choice and an outcome, but they can rarely prove cause and effect because it is not possible for researchers to control for all variables in a person’s daily schedule. 

Furthermore, it is unlikely that some modifiable risk factors will ever be fully tested in randomized control trials for practical or ethical reasons. Sleep illustrates an example. Too much sleep can cause muscle atrophy, bedsores and other issues. On the other hand, too little sleep is a well-known threat to physical and mental health. But to definitively assess the impact of sleep on Alzheimer's risk may require tens of thousands of people to experience too much or too little sleep for many years. The logistical challenges and moral dilemmas are prohibitive.

Nevertheless, the following section focuses on some modifiable risk factors with substantial supportive evidence identified in The Lancet’s 2020 Commission report, the World Health Organization’s (WHO) 2019 recommendations to reduce the risk of cognitive decline and dementia, and the National Academy of Medicine’s (NAM) 2015 report about Cognitive Aging. 

Cardiovascular Health

Diabetes, high blood pressure and high cholesterol increase the risk of cardiovascular disease. They also increase the risk of Alzheimer's because the health of the heart and blood vessels affect the health of the brain. 

A healthy heart pumps sufficient amounts of blood, and healthy blood vessels pass oxygen and nutrient-rich blood to the brain. The relationship between cardiovascular health and brain health is strong insofar as some autopsy studies observe up to 80% of people with Alzheimer's disease also have cardiovascular disease.

As such, smoking, obesity, stress and other factors to increase the risk of cardiovascular disease are associated with higher risks of dementia. Likewise, factors to decrease the risk of cardiovascular disease are associated with lower risks of dementia.

Movement, exercise and physical activity are examples. However, researchers do not yet know if specific types of physical activity are more effective than others to decrease Alzheimer's risk. 

Sleep

Inadequate or low quality sleep is another risk factor with several active studies. 

Sleep helps the brain remove excessive amounts of beta-amyloid and other harmful substances. Therefore, experts believe poor sleep limits the brain’s ability to remove toxins, which may increase the risk of Alzheimer’s dementia. Moreover, poor sleep may interfere with blood flow and other important processes the brain relies on to strengthen memory and attention.

Furthermore, the relationship between sleep and Alzheimer’s dementia may be bidirectional. Not only may poor sleep increase the risk of Alzheimer’s, but brain changes from the disease may also increase the risk of poor sleep. For example, once beta-amyloid and tau proteins pollute the brain, they may disrupt sleep cycles and lead to low quality sleep. The pathogens are not removed because of a poor night’s sleep, which perpetuates a vicious, downward spiral.

Diet

Diet is another modifiable risk factor with active studies. Current evidence suggests a heart-healthy diet may help protect the brain from Alzheimer’s. A possible explanation is a heart-healthy diet has an association with better cardiovascular health, and the relationship between heart health and brain health is meaningful. 

For reference, a heart-healthy diet emphasizes fruits, vegetables, whole grains, fish, chicken, nuts, legumes and healthy fats like olive oil. These diets limit saturated fats, red meat, sugar and processed foods. Thus far, no single food, beverage, ingredient, vitamin or supplement is known to prevent or cure Alzheimer's dementia.

Education and Employment

Researchers report people with more years of formal education develop Alzheimer’s at lower rates than people with fewer years of formal education. The reasons why are inconclusive. Experts suspect formal education may help brains form strong, adaptive neural connections. If so, then many years of formal education in early life may help brains sustain higher cognitive function in mid and late life to delay potential disease symptoms. 

Employment is another important factor to keep in mind. It is possible that people with more years of formal education are more likely to work in jobs with more cognitive stimulation than people with fewer years of formal education. If so, then such jobs may do more to build resilient neural connections and stave off Alzheimer’s dementia than people’s direct years of formal education. 

Both factors probably play important roles, which is why the relationship between education, employment and Alzheimer’s disease is still under investigation.

Social and Cognitive Engagement

Likewise, studies suggest social activities and recreational cognitive engagement may support brain health and reduce the risk of Alzheimer’s. The association between social connection, cognitive engagement and the disease is nuanced, though the evidence indicates they help the brain build and sustain neural connections.

However, it is possible people voluntarily disengage from hobbies, social activities and other worthwhile pastimes as they experience Alzheimer’s symptoms. If so, then the relationship between these activities and Alzheimer’s may also be somewhat bidirectional, like sleep. 

For example, once beta-amyloid and tau proteins infect the brain, book clubs and crossword puzzles may be less enjoyable because of memory and attention issues caused by Alzheimer’s dementia. The brain’s neural connections weaken with less time to nourish cognition, which allows the disease to spread and deepen its roots.

Air Pollution

A notable field of research includes efforts to understand how exposure to environmental toxicants can increase dementia risk. This includes but is not limited to known carcinogens such as lead, mercury and arsenic, as well as emergent fields like the impact of pesticides and air pollution. One major research domain with prominent results involves fine particulate matter (PM), which consists of tiny solid particles and liquid droplets from dust, fires and fuel emissions. 

PM2.5 is particulate matter with a diameter of 2.5 microns or smaller. The lungs can inhale these small particles and pass the pollutants through to the bloodstream. As a result, PM2.5 shows adverse health impacts in many studies. For instance, in 2019, the United States' Environmental Protection Agency released an extensive report where they mention long-term exposure to PM2.5 is “likely to be causal” to “nervous system effects.” Moreover, studies specific to dementia find higher long-term exposure to PM2.5 is associated with more brain atrophy, worse cognitive decline and higher rates of the onset of dementia symptoms.

However, the exact relationship between air pollution and Alzheimer's dementia is unclear. Air pollution may damage the body and trigger harmful physiological responses, thereby increasing the risk of Alzheimer's disease, but more studies need to examine if there is a direct association.

Socioeconomic Status

The studies from The Lancet, WHO and NAM allude to how socioeconomic factors affect human health, and these effects are profound. Life is different when people work in environments and live in neighborhoods with clean air instead of toxic air. Bodies are stronger when people eat nutritious food instead of junk food for every meal, when they drink clean water instead of water poisoned by carcinogens. Hearts are healthier when people relax in housing conditions with modern temperature controls, ventilation, and safe building materials instead of anguish in spaces with mold, asbestos, and infestations. Brains are calmer when people rest in quiet, soothing beds, when the racket of the outside world does not disturb a night's sleep.

The list goes on and on and on. In spite of the tremendous progress in public health since Dr. Alzheimer first met Auguste, more still needs to be done. Policymakers and organizational leaders alike can help countless constituents around the world if they enact measures to reduce hazardous environmental conditions through adequate funding, regulation, and oversight.

Overall, preventative care research for Alzheimer’s dementia is promising, but the field is nascent and early results are open to interpretation. More evidence is needed, though good evidence is more important than simply increasing the sheer quantity of research – large population samples, widely replicated studies, strong control parameters to isolate the impact of specific variables, and so forth. That said, few would dispute the benefits of consistent exercise, thought-provoking activities, and a full night's sleep. It is never too early or too late to make positive lifestyle changes to reduce chronic health risks. There is little to lose and much to gain as the years go by.

A Vial for Victory

Kisunla (aka Donanemab) joins its anti-amyloid predecessors as symbols of how far Alzheimer’s research and development has come. The drug also belongs to a new era of innovative technological advancements. Between gene therapies to reduce genetic risk factors for the disease, non-invasive wearable headset devices to attempt to slow down cognitive decline, and machine learning-based solutions to analyze and personalize treatments for optimal medication success, the research field is finally filled with an assortment of exciting solutions that may achieve astounding results for a forthcoming class of clinical trials. 

These developments are welcome signs. For if nothing else, the ensnares of mixed dementia, the entanglements of neurodegenerative disease pathology and the historical failures of anti-amyloid trials suggests a singular solution will not defeat Alzheimer’s dementia. Instead, a combination of treatments alongside a heart-healthy lifestyle likely need to work in tandem to contain the disease. 

Perhaps even more important than a variety of treatment strategies is the critical need for cheap, convenient, and reliable disease tests. No matter how promising a potential solution may be, it will not demonstrate clinical significance unless trial participants receive a trustworthy diagnosis.

Blood tests are the diagnostic gold standard in science, and for good reason. They are fast, accessible, affordable, and accurate. Clinicians worldwide rely on blood tests to monitor patient health in consistent ways, to detect dormant diseases years before serious problems arise and to track how people respond to specific treatments in near real-time. 

Just as cholesterol levels in blood indicate risk for cardiovascular disease, blood glucose levels signal risk for diabetes. Alzheimer’s and related dementia diseases are similar to these chronic medical conditions insofar as beta-amyloid, tau proteins, and other biological hallmarks reside in blood. Once scientists refine novel blood tests, dementia may become a manageable condition like diabetes, high-blood pressure and HIV/AIDS, and the field can enter a new medical era. 

There are over a dozen different Alzheimer’s blood tests at various stages of development. The field’s diagnostic landscape can transform for the better if blood tests perform on par with today’s PET scans and spinal fluid tests, which can correctly classify 90% - 95% of patients as either positive, negative or borderline cases. Some of the best preliminary blood tests already meet this high threshold, which implies the Alzheimer’s community is close to another major inflection point.

The next Alzheimer’s milestone to watch for will not be another FDA approval of the latest anti-amyloid du jour. Rather, it will be the first Alzheimer’s blood test the agency approves. When this happens, the field's recent renaissance in treatment strategies will approach their full potential, and humanity’s century-long struggle to achieve the unthinkable will climb one gigantic stride forward in pursuit of a long-awaited summit.

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