A new study by an international team of researchers suggests that there are at least four distinct forms of Alzheimer's disease, each of which attacks a different part of the brain. The findings, published in Nature Medicine, may be the foundation for a new understanding of a disease which is expected to affect millions of people in the coming decades.
The leading hypothesis on the mechanism of Alzheimer's is that the disease is caused by unusual aggregation and spread of the tau protein in the brain. While there is still debate over if the strange behavior of these proteins is the cause of Alzheimer's or merely a symptom of the disease, the spread of such proteins can be used to identify the condition.
The authors reviewed the positron emission tomography (PET) data of 1,143 people. The PET images allowed the scientists to view where in the brain tau proteins were building up. An algorithm was applied to this data which was able to categorize the patterns in the images. In those brains with tau protein abnormalities, there were four distinct variations in how they manifested in the brain as seen below:
The four different Alzheimer's subtypes identified by the study. Areas in warmer colors had higher concentrations of tau proteins. The progression of the disease was related to the region of the brain that was most impacted. Image: Jacob Vogel
Four types of Alzheimer's disease
This could mean that there are four subtypes of Alzheimer's, each with different affected areas of the brain, symptoms, and prognoses. The authors described them as follows:
Type one is characterized by the tau protein spreading within the temporal lobe, impacting memory. This type was observed in 33% of Alzheimer's cases.
Type two is the inverse of type one in many ways. The tau protein spreads primarily in the cerebral cortex rather than in the temporal lobe. Patients with this variation have fewer memory problems than those with type one but more difficulties with planning and performing actions. This type appeared in 18% of cases.
Type three targets the visual cortex, the part of the brain that processes visual information. Those with this variant had particular difficulty with orientation, movement, and processing sensory information. This type occurred in 30% of cases.
Type four features the protein spreading in the left hemisphere of the brain and seems to principally affect language ability. This manifested in the remaining 19% of cases.
Major implications
Beyond the differences in symptoms and pathology, the prognosis of each subtype appears to differ. After reviewing the long-term data of the patients, it appears that people with the third subtype have the slowest rate of mental decline, while those with the fourth endured a much steeper rate of facility loss.
Study co-author Oskar Hansson of Lund University in Sweden, commented on the findings in a press release:
"We identified four clear patterns of tau pathology that became distinct over time. The prevalence of the subgroups varied between 18 and 30 percent, which means that all these variants of Alzheimer's are actually quite common and no single one dominates as we previously thought. The varied and large databases of tau-PET that exist today, along with newly developed methods for machine learning that can be applied to large amounts of data, made it possible for us to discover and characterize these four subtypes of Alzheimer's. However, we need a longer follow-up study over five to ten years to be able to confirm the four patterns with even greater accuracy."
If the authors are correct, a more accurate Alzheimer's diagnosis may help provide specialized treatment to future patients.
It can be hard to conceptualize the total damage caused by Alzheimer's. The neurodegenerative disease is a leading cause of death in the U.S., killing more than 100,000 people each year. And as Alzheimer's progresses in the brain it not only erodes memory but also causes troubling symptoms like agitation, paranoia, and aggression.
These burdens fall not only on patients but also on their loved ones, doctors, and caregivers. Economically, the cost of caring for Alzheimer's patients hit an estimated $305 billion in 2020, according to a report from the Alzheimer's Association. And that figure doesn't include an estimated $244 billion in unpaid caregiving provided by family and friends.
The number of Alzheimer's patients in the U.S. is expected to double by 2050, affecting about 14 million people. That's one reason why hospitals and health professionals are already working to bolster how they care for the elderly and Alzheimer's patients. It takes 15 years to develop new treatments, so today's research needs adequate funding.
"Caring for our older adults is a big responsibility, one that we take great pride in," said Michael Dowling, president and CEO of Northwell Health. "Our aging population will face health issues, including and especially Alzheimer's, that will require the right care at the right time. That's why we have increased our services, including at Glen Cove Hospital, and research at the Feinstein Institutes for Medical Research."
... the real suffering comes from the changes that happen in the personality...
What causes Alzheimer’s disease?
While the costs of Alzheimer's are clear, its exact causes remain frustratingly mysterious. Currently, there's no cure for the disease, nor treatments that stop its progression.
"Alzheimer's is this brain problem, and everyone sort of knows what's probably causing the problem, but nobody's been able to do anything about it," said Dr. Jeremy Koppel, a geriatric psychiatrist and co-director of the Litwin-Zucker Alzheimer Research Center.
But in recent decades, researchers have zeroed in on likely contributors to the disease. The brains of Alzheimer's patients reliably show two abnormalities: build-ups of proteins called abnormal tau and beta-amyloid. As these proteins accumulate in the brain, they disrupt healthy communication between neurons. Over time, neurons get injured and die, and brain tissue shrinks.
Still, it's unclear exactly how these proteins, or other factors such as inflammation, may drive Alzheimer's.
"We are dealing with very complicated components," said Dr. Philippe Marambaud, a professor at the Feinstein Institutes and co-director of the Litwin-Zucker Alzheimer Research Center. "The actual culprit is not clearly defined. We know there are three possible culprits [tau, beta-amyloid, inflammation]. They're working in concert, or maybe in isolation. We don't know precisely."
Many Alzheimer's researchers have spent years developing therapies that target beta-amyloid, which can accumulate to form plaques in the brain. The Alzheimer's Association writes:
"According to the amyloid hypothesis, these stages of beta-amyloid aggregation disrupt cell-to-cell communication and activate immune cells. These immune cells trigger inflammation. Ultimately, the brain cells are destroyed."
Unfortunately, clinical trials of therapies that target beta-amyloid haven't been effective in treating Alzheimer's.
Anti-tau immunotherapies: The holy grail of Alzheimer’s?
In brains with Alzheimer's disease, tau proteins lose their structure and form neurofibrillary tangles that block communication between synapses.
Credit: Adobe Stock
At the Feinstein Institutes, Dr. Marambaud and his colleagues have been focusing on the lesser-explored Alzheimer's component: abnormal tau.
In healthy brains, tau plays several important functions, including stabilizing internal microtubules in neurons. But in the brains of Alzheimer's patients, a process called phosphorylation changes the structure of tau proteins. This blocks synaptic communication.
Dr. Marambaud said there are good reasons to think anti-tau therapies may effectively treat Alzheimer's.
"The main argument around why [anti-tau therapies] could be more beneficial is that we've known for a very long time that tau pathology in the brain of the Alzheimer's patient correlates much better with the disease progression, and the loss of neuronal material in the brain," compared to beta-amyloid, Dr. Marambaud said.
"The second strong argument is that there are inherited dementias, called tauopathies, which are caused by mutations in the gene coding for the tau protein. So, there is a direct genetic link between dementia and tau pathology."
To better understand how this protein interacts with Alzheimer's, Dr. Marambaud and his colleagues have been developing immunotherapies that target abnormal tau.
Immunotherapies, such as vaccines, typically target infectious diseases. But it's also possible to use the body's immune system to prevent or treat some non-infectious diseases. Scientists have recently succeeded in treating certain forms of cancer with immunotherapies, for example.
"We have developed a series of monoclonal antibodies, which are basically the therapeutics that are required when you want to do immunotherapy," Dr. Marambaud said.
Currently, Feinstein Institutes researchers are conducting promising ongoing clinical trials with anti-tau antibodies, some of which are in phase III trials under the Food and Drug Administration. Patients receive these therapies intravenously over several hours and would undergo multiple rounds of treatment. It's similar to chemotherapy.
In the short term, it's more likely that anti-tau therapies would help to stabilize Alzheimer's, not cure it.
"Just stabilization of the disease's progression will save a huge societal, but also financial, burden," Dr. Marambaud said. "As research progresses, we would improve upon these stabilization approaches to make them more and more efficacious."
Even if anti-tau therapies don't prove to be the holy grail of Alzheimer's treatments, they could potentially alleviate severe behavioral symptoms of the disease, and potentially illuminate some of the mechanisms behind psychosis.
Alzheimer’s and psychosis
Credit: Getty Images
When most people think of Alzheimer's, they tend to focus on the erosion of memory. But the darkest effects of the disease are often psychotic symptoms like agitation, aggression and paranoia, according to Dr. Koppel, who, in addition to researching Alzheimer's, spent decades treating Alzheimer's patients as a clinician.
"My research focus comes out of 20 years of sitting with Alzheimer's families and listening to what the primary issue is," said Dr. Koppel. "It's never memory. It starts out with memory as a diagnostic issue. But the real suffering comes from the changes that happen in the personality and the belief system that make Alzheimer's patients" ostracized or even become violent toward their loved ones.
At the Feinstein Institutes, Dr. Koppel's research focuses on alleviating Alzheimer's-related psychotic symptoms through anti-tau immunotherapies.
"It's our hypothesis that abnormal tau proteins in the brain somehow, downstream, impact the way that people think," Dr. Koppel said. "And the impact that it has is this paranoid, agitated, psychotic phenotype."
Supporting this hypothesis is research on chronic traumatic encephalopathy (CTE), a degenerative disease that involves the accumulation of abnormal tau. CTE, common among professional football players, also causes psychotic symptoms like agitation, aggression and paranoia.
What's more, research shows that as Alzheimer's patients accumulate more abnormal tau in their brains, as measured through cerebrospinal fluid, they exhibit more psychotic symptoms, and are more likely to die sooner than patients with less abnormal tau.
Given these strong connections between psychosis and abnormal tau, Dr. Koppel and his colleagues hope that anti-tau immunotherapies will alleviate psychosis in Alzheimer's patients, who currently lack safe and effective treatment options and are often given medication that is meant to alleviate psychosis in people with schizophrenia.
"We are giving medications to Alzheimer's patients that hasten their cognitive decline and lead to bad outcomes, like stroke and sudden death," Dr. Koppel said. "Nonetheless, the schizophrenia medications do treat some of the psychotic symptoms and aggressive behavior related to Alzheimer's disease, and for many families this is crucial. We just don't have many options, and we desperately need more."
Beyond treating Alzheimer's patients, anti-tau immunotherapies may shed light on other mental illnesses.
"Alzheimer's may give us a window into what happens in the brain that makes people psychotic," Dr. Koppel said. "Once you have a biologic treatment for psychosis that gets at an underlying pathophysiology, believe me, you could look at schizophrenia in new ways. Maybe it's not going to be tau, but it may be a paradigm for treating mental illness."
The future of Alzheimer’s treatments
Dr. Marambaud said the long-term goal of anti-tau immunotherapies is to prevent Alzheimer's. But that's currently impossible because scientists lack the biomarkers and diagnostic tools needed to detect the disease before cognitive symptoms appear. It could take decades before prevention becomes possible, if it ever does.
In the short term, stabilizing Alzheimer's is a more realistic goal.
"Our hope is that the treatments will be aggressive enough so that we can at least stabilize the disease in patients identified to be already affected by dementia, with cognitive tests that can be done by the clinicians," Dr. Marambaud said. "And even better, maybe reduce the cognitive impairments."
Dr. Marambaud said he encourages the public not to lose faith.
"Be patient. It's a very complicated disease," he said. "A lot of labs are really committed to making a difference. Congress has also realized that this is a huge priority. In the past five years, [National Institutes of Health] funding has increased tremendously. So the scientific field is working very hard. The politicians are behind us in funding this research. And it's a complicated disease. But we will make a difference in the years to come."
In the meantime, the Alzheimer's Association notes that physical activity and a healthy diet can reduce the chances of developing Alzheimer's, though more large-scale studies are needed to better understand how these factors interact with the disease.
"Many of these lifestyle changes have been shown to lower the risk of other diseases, like heart disease and diabetes, which have been linked to Alzheimer's," the association wrote. "With few drawbacks and plenty of known benefits, healthy lifestyle choices can improve your health and possibly protect your brain."
Just a few years ago, it was not unusual to run into people bragging about being multitaskers. You may also have found such people difficult to work with as they momentarily tuned out of chats or otherwise drifted away for a few frustrating moments. Recent research has found that multitasking actually means paying insufficient attention to, and doing a lousy job with, multiple things at once.
Now a new study from Stanford published in the journal Nature asserts that multitasking is even worse than that — it prevents young people from remembering what they've done and seen, especially when they're flipping from screen to screen.
It's akin to finding an object and realizing you have no memory of putting it there. It's a weird experience, but doing something when you're not paying attention — because you're not really present — can wind up feeling a lot like never having done it at all.
Information in, duh out
Credit: F8studio/Adobe Stock
The Stanford study looked specifically at the effect of "media multitasking" on memory. Media multitasking is moving continually between screen-based activities: texting, checking Instagram, or watching a TikTok video, for example. The research suggests that these experiences may not quite stick.
Even though we continually devour information, "As we navigate our lives, we have these periods in which we're frustrated because we're not able to bring knowledge to mind, expressing what we know," the study's senior investigator Anthony Wagner tells Stanford News. "Fortunately," he adds, "science now has tools that allow us to explain why an individual, from moment to moment, might fail to remember something stored in their memory."
Apt pupils
Credit: H_Ko/Adobe Stock
The researchers recruited 80 subjects, ages 18 to 26. As these individuals participated in experimental exercises, researchers tracked their lapses in attention by monitoring their posterior alpha power brain wave activity and changes to the sizes of their pupils.
Lead author Kevin Madore explains, "Increases in alpha power in the back of your skull have been related to attention lapses, mind wandering, distractibility and so forth. We also know that constrictions in pupil diameter — in particular before you do different tasks — are related to failures of performance like slower reaction times and more mind wandering."
As participants viewed a set of object images onscreen, they were tasked with classifying each image according to pleasantness or size. This was followed by a 10-minute break, after which they were presented with another set of images. They were asked to identify these images as either being new or having already been seen. This allowed the researchers to assess each individual's memory.
Participants also filled out questionnaires that described their media multitasking habits, and they were asked to state the degree to which they could successfully engage with multiple activities simultaneously.
Taking all this information together, the researchers found that people less able to sustain attention and those who reported being heavy media multitaskers both performed more poorly at memory tasks.
Says Madore, "We can't say that heavier media multitasking causes difficulties with sustained attention and memory failures, though we are increasingly learning more about the directions of the interactions."
Strengthening your memory
Wagner notes the key to all this may lie in other research that looks at how we prepare to remember what we wish to learn. He suggests remembering occurs most successfully when it's goal-oriented, when we're ready to store something in our minds.
"While it's logical that attention is important for learning and for remembering, an important point here is that the things that happen even before you begin remembering are going to affect whether or not you can actually reactivate a memory that is relevant to your current goal," says Wagner.
With this in mind, he says, paying attention to your attentiveness may help you stay aware and prepared to store new memories of what you're currently experiencing.
Likewise, he suggests it may be possible to develop memory hacks that can enhance our capacity to remember. He cites the idea of attention training in which eye sensors alert their wearer to attention lapses as they occur, allowing the person to consciously refocus each time their mind wanders.
While the current study explores the memories of young people, its insights may broadly apply. "We have an opportunity now," Wagner concludes, "to explore and understand how interactions between the brain's networks that support attention, the use of goals and memory relate to individual differences in memory in older adults both independent of, and in relation to, Alzheimer's disease."
Doctors have suspected for some time that white spots appearing in MRI brain scans are associated with cognitive decline. However, the relationship between the number and size of spots and the likelihood of dementia has been mostly a judgment call. Now, a new study from New York University's Grossman Medical Center proposes the first standardized, objective measurement tool designed to predict cognitive decline when considered alongside other factors.
The study is published in the journal Academic Radiology.
White spots and educated guesses
The white spots, or "hyperintensities," are brain lesions—fluid-filled holes in the brain believed to have been left behind by the breaking down of blood vessels that had previously provided nourishment to brain cells.
Prior to the new research, the quantity of white spots was assessed using an imprecise three-point scale indicating ascending likelihoods of dementia: A minimal number of spots was considered as level 1, a medium number of spots level 2, and a great number of them level 3.
How the new measurements were derived
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The team of researchers from NYU's Langone's Center for Cognitive Neurology and Alzheimer's Disease Research Center were led by Jingyun "Josh" Chen. They analyzed 72 MRI scans from a national database of older people taken as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The scans were mostly of white people over age 70, and there were a roughly equivalent number of men and women. Some had normal brain function, some were presenting moderate cognitive decline, and some had severe dementia.
Without knowing each individual's diagnosis, the researchers analyzed the white spots in their scans. While the team counted each scan's lesions, the innovation they introduced was the production of a 3D measurement for each lesion's fluid volume. The measurement was derived by measuring a lesion's distance from opposite sides of the brain.
Measurements of 0 milliliters (mL) were assessed for areas without white spots, with other white spots coming up as containing 60 mL of fluid. Chen's team predicted that volumes over 100 mL could signify severe dementia.
"Amounts of white matter lesions above the normal range should serve as an early warning sign for patients and physicians," Chen told NYU Langone Health NewsHub.
When the team compared the likely diagnoses derived from their calculations against the individuals' medical records, they found that their predictions were correct about 7 out of 10 times.
The researchers compiled their formulas into an online tool that's available to physicians for free via GitHub. The researchers plan to further refine and test it using an additional 1,495 brain scans representing a more diverse group of individuals from the ADNI database.
The new tool and its limits
Chen notes that white spots alone may not tell the entire story of an individual's cognitive decline or the onset of dementia. Other factors must be considered as well, including memory loss, hypertension, and brain injuries.
Nonetheless, says senior investigator Yulin Ge, "Our new calculator for properly sizing white matter hyperintensities, which we call 'bilateral distancing,' offers radiologists and other clinicians an additional standardized test for assessing these lesions in the brain, well before severe dementia or stroke damage."
Having an objective means of measuring white hyperintensities will allow physicians not only to get a better handle on the association between white spots and dementia, but also to track the spots alongside changes to a person's tau and beta-amyloid proteins, two chemicals implicated in Alzheimer's disease and dementia.
