For decades researchers have focused their attacks against Alzheimer’s on two proteins, amyloid beta and tau. Their buildup in the brain often serves as a defining indicator of the disease. Get rid of the amyloid and tau, and patients should do better, the thinking goes.
But drug trial after drug trial has failed to improve patients’ memory, agitation and anxiety. One trial of a drug that removes amyloid even seemed to make some patients worse. The failures suggest researchers were missing something. A series of observations and recently published research findings have hinted at a somewhat different path for progression of Alzheimer’s, offering new ways to attack a disease that robs memories and devastates the lives of 5.7 million Americans and their families.
One clue hinting at the need to look further afield was a close inspection of the 1918 worldwide flu pandemic, which left survivors with a higher chance of later developing Alzheimer’s or Parkinson’s. A second inkling came from the discovery that the amyloid of Alzheimer’s and the alpha-synuclein protein that characterizes Parkinson’s are antimicrobials, which help the immune system fight off invaders. The third piece of evidence was the finding in recent years, as more genes involved in Alzheimer’s have been identified, that traces nearly all of them to the immune system. Finally, neuroscientists have paid attention to cells that had been seen as ancillary—“helper” or “nursemaid” cells. They have come to recognize these brain cells, called microglia and astrocytes, play a central role in brain function—and one intimately related to the immune system.
All of these hints are pointing toward the conclusion that both Alzheimer’s and Parkinson’s may be the results of neuroinflammation—in which the brain’s immune system has gotten out of whack. “The accumulating evidence that inflammation is a driver of this disease is enormous,” says Paul Morgan, a professor of immunology and a member of the Systems Immunity Research Institute at Cardiff University in Wales. “It makes very good biological sense.”
The exact process remains unclear. In some cases the spark that starts the disease process might be some kind of insult—perhaps a passing virus, gut microbe or long-dormant infection. Or maybe in some people, simply getting older—adding some pounds or suffering too much stress could trigger inflammation that starts a cascade of harmful events.
This theory also would explain one of the biggest mysteries about Alzheimer’s: why some people can have brains clogged with amyloid plaques and tau tangles and still think and behave perfectly normally. “What made those people resilient was lack of neuroinflammation,” says Rudolph Tanzi, a professor of neurology at Harvard Medical School and one of the leaders behind this new view of Alzheimer’s. Their immune systems kept functioning normally, so although the spark was lit, the forest fire never took off, he says. In Tanzi’s fire analogy, the infection or insult sparks the amyloid match, triggering a brush fire. As amyloid and tau accumulate, they start interfering with the brain’s activities and killing neurons, leading to a raging inflammatory state that impairs memory and other cognitive capacities. The implication, he says, is that it is not enough to just treat the amyloid plaques, as most previous drug trials have done. “If you try to just treat plaques in those people, it’s like trying to put out forest fire by blowing out a match.”
Lighting the Fire
One study published earlier this year found gum disease might be the match that triggers this neuroinflammatory conflagration—but Tanzi is not yet convinced. The study was too small to be conclusive, he says. Plus, he has tried to find a link himself and found nothing. Other research has suggested the herpes virus could start this downward spiral, and he is currently investigating whether air pollution might as well. He used to think amyloid took years to develop, but he co-authored a companion paper to the herpes one last year, showing amyloid plaques can literally appear overnight.
It is not clear whether the microbes—say for herpes or gum disease—enter the brain or whether inflammation elsewhere in the body triggers the pathology, says Jessica Teeling, a professor of experimental neuroimmunology at the University of Southampton in England. If microbes can have an impact without entering the brain or spinal cord—staying in what’s called the peripheral nervous system—it may be possible to treat Alzheimer’s without having to cross the blood–brain barrier, Teeling says.
Genetics clearly play a role in Alzheimer’s, too. Rare cases of Alzheimer’s occurring at a relatively young age result from inheriting a single dominant gene. Another variant of a gene that transports fats in brain cells, APOE4, increases risk for more typical, later-onset disease. Over the last five years or so large studies of tens of thousands of people have looked across the human genome for other genetic risk factors. About 30 genes have jumped out, according to Alison Goate, a professor of neurogenetics and director of the Loeb Center for Alzheimer’s Disease at Icahn School of Medicine at Mount Sinai in New York City. Goate, who has been involved in some of those studies, says those genes are all involved in how the body responds to tissue debris—clearing out the gunk left behind after infections, cell death and similar insults. So, perhaps people with high genetic risk cannot cope as well with the debris that builds up in the brain after an infection or other insult, leading to a quicker spiral into Alzheimer’s. “Whatever the trigger is, the tissue-level response to that trigger is genetically regulated and seems to be at the heart of genetic risk for Alzheimer’s disease,” she says. When microglia—immune cells in the brain—are activated in response to tissue damage, these genes and APOE get activated. “How microglia respond to this tissue damage—that is at the heart of the genetic regulation of risk for Alzheimer’s,” she says.
But APOE4 and other genes are part of the genome for life, so why do Alzheimer’s and Parkinson’s mainly strike older people? says Joel Dudley, a professor of genetics and genomics, also at Mount Sinai. He thinks the answer is likely to be inflammation, not from a single cause for everyone but from different immune triggers in different individuals.
Newer technologies that allow researchers to examine a person’s aggregate immune activity should help provide some of those answers, he says. Cardiff’s Morgan is developing a panel of inflammatory markers found in the blood to predict the onset of Alzheimer’s before much damage is done in the brain, a possible diagnostic that could point to the need for anti-inflammatory therapy
A similar inflammatory process is probably also at play in Parkinson’s disease, says Ole Isacson, a professor of Neurology at Harvard Medical School. Isacson points to another early clue about the role of inflammation in Parkinson’s: people who regularly took anti-inflammatory drugs like ibuprofen developed the disease one to two years later than average. Whereas other researchers focused exclusively on genetics, Isacson found the evidence suggested the environment had a substantial impact on who got Parkinson’s.
In 2008–09, Isacson worked with a postdoctoral student on an experiment trying to figure out which comes first in the disease process: inflammation or the death of dopamine-producing neurons, which make the brain chemical involved in transmitting signals among nerve cells. The student first triggered inflammation in the brains of some rodents with molecules from gram-negative bacteria and then damaged the neurons that produce dopamine. In another group of rodents, he damaged the neurons first and then introduced inflammation. When inflammation came first, the cells died en masse, just as they do in Parkinson’s disease. Blocking inflammation prevented their demise, they reported in The Journal of Neuroscience.
Other neurodegenerative diseases also have immune connections. In multiple sclerosis, which usually strikes young people, the body’s immune system attacks the insulation around nerve cells, slowing the transmission of signals in the body and brain.
The spinal fluid of people with MS include antibodies and high levels of white blood cells, indicating the immune system is revved up—although it is not clear whether that immune system activation is the cause or result of MS, says Mitchell Wallin, who directs the Veterans Affairs Multiple Sclerosis Centers of Excellence. People with antibodies to the Epstein–Barr virus in their systems, especially if they caught the virus in late adolescence or early adulthood run a higher risk of developing MS—supporting the idea that an infection plays a role in MS.
Thanks to newer medications and improvements in fighting infections, people with MS are now living longer. This increased longevity puts them at risk for neurological diseases of aging, including Alzheimer’s and Parkinson’s, Wallin says. Lack of data has left it unclear whether people with MS are at the same, higher or lower risk for these diseases than the general population. “How common it is, we’re just starting to explore right now,” Wallin says.
It will be years before the concept of a neuroinflammatory can be fully tested, but there are already some relevant drugs in development. One start-up, California-based INmune Bio, recently received a $1-million grant from the Alzheimer’s Association to advance XPro1595, a drug that targets neuroinflammation. The company is beginning its first clinical trial this spring, treating 18 patients with mild to moderate-stage Alzheimer’s who also show signs of inflammation. The company plans to test blood, breath by-products and cerebral spinal fluid as well as conduct brain scans to look for changes in inflammatory markers. That first trial will just explore if XPro1595 can safely bring down inflammation and change behaviors such as depression and sleep disorders. Company CEO and co-founder Raymond Tesi says he expects to see those indicators improve, even in a short, three-month trial.
The best way to avoid Alzheimer’s is to prevent it from ever starting, which might require keeping brain inflammation to a minimum, particularly in later life. Preventative measures are already well known: eat healthy foods, sleep well, exercise regularly, minimize stress and avoid smoking and heavy drinking.
You can’t do anything about your genetics but living a healthy lifestyle will help control your inheritance, says Tanzi, who, along with Deepak Chopra, wrote a book on the topic, The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life. “It’s important to get that set point as high as possible.”
Frailty is associated with a higher risk of both Alzheimer’s disease and its crippling symptoms, a new study shows.
“By reducing an individual’s physiological reserve, frailty could trigger the clinical expression of dementia when it might remain asymptomatic in someone who is not frail,” said study leader Dr. Kenneth Rockwood, a professor at Dalhousie University in Halifax, Canada.
“This indicates that a ‘frail brain‘ might be more susceptible to neurological problems like dementia as it is less able to cope with the pathological burden,” he added.
The study included 456 adults in Illinois, aged 59 and older, who did not have Alzheimer’s when first enrolled in the Rush Memory and Aging Project. They underwent annual assessments of their mental and physical health, and their brains were examined after they died.
By their last assessment, 53 percent of the participants had been diagnosed with possible or probable Alzheimer’s disease.
Overall, 8 percent of the participants had significant Alzheimer’s disease-related brain changes without having been diagnosed with dementia, and 11 percent had Alzheimer’s but little evidence of disease-related brain changes.
Those with higher levels of frailty were more likely to have both Alzheimer’s disease-related brain changes and symptoms of dementia, while others with substantial brain changes, but who were not frail, had fewer symptoms of the disease.
After adjusting for age, sex and education, the researchers concluded that frailty and Alzheimer’s disease-related brain changes independently contribute to dementia, though they could not prove that frailty caused Alzheimer’s and its symptoms.
The investigators also said there was a significant association between frailty and Alzheimer’s-related brain changes after they excluded activities of daily living from the frailty index and adjusted for other risk factors such as stroke, heart failure, high blood pressure and diabetes.
The study was published Jan. 17 in The Lancet Neurology journal.
“This is an enormous step in the right direction for Alzheimer’s research,” Rockwood said in a journal news release. “Our findings suggest that the expression of dementia symptoms results from several causes, and Alzheimer’s disease-related brain changes are likely to be only one factor in a whole cascade of events that lead to clinical symptoms.”
Understanding frailty could help predict and prevent dementia, Dr. Francesco Panza, from the University of Bari Aldo Moro in Italy, wrote in an accompanying editorial.
Leaky blood vessels in the brain may be an early sign of Alzheimer’s disease, researchers say.
They followed 161 older adults for five years and found that those with the most severe memory declines had the greatest leakage in their brain’s blood vessels, regardless of whether the Alzheimer’s-related proteins amyloid and tau were present.
The findings could help with earlier diagnosis of Alzheimer’s and suggest a new drug target for slowing down or preventing the disease, according to the researchers from the University of Southern California.
“The fact that we’re seeing the blood vessels leaking, independent of tau and independent of amyloid, when people have cognitive [mental] impairment on a mild level, suggests it could be a totally separate process or a very early process,” said study senior author Dr. Berislav Zlokovic. He is director of the Zilkha Neurogenetic Institute at the university’s Keck School of Medicine in Los Angeles.
“That was surprising, that this blood-brain barrier breakdown is occurring independently,” Zlokovic added in a university news release.
The blood-brain barrier prevents harmful substances from reaching brain tissue. In some people, this barrier weakens with age.
“If the blood-brain barrier is not working properly, then there is the potential for damage,” explained study co-author Arthur Toga, who is director of the Stevens Neuroimaging and Informatics Institute at Keck.
“It suggests the vessels aren’t properly providing the nutrients and blood flow that the neurons need. And you have the possibility of toxic proteins getting in,” Toga said.
“The results were really kind of eye-opening,” said study first author Daniel Nation, an assistant professor of psychology. “It didn’t matter whether people had amyloid or tau pathology; they still had cognitive impairment.”
The findings were published recently in the journal Nature Medicine.
The next step in this research is to determine how soon mental decline occurs after damage to brain blood vessels.
The number of Americans with Alzheimer’s is expected to nearly triple to about 14 million by 2060, according to the U.S. Centers for Disease Control and Prevention.
‘Alzheimer’s disease is a disease of the medial temporal lobe’. These are words that one of us remembers vividly from a particularly interesting undergraduate lecture nearly 25 years ago, and similar statements have been heard many times in many lecture theatres since. Countless studies have indeed shown that medial temporal lobe atrophy is predictive of the development of Alzheimer’s dementia, and that this relates to changes in episodic memory. However, the medial temporal lobe is not always the first brain region to diminish in volume in Alzheimer’s disease, and cognitive impairment does not always begin with episodic memory dysfunction. Alzheimer’s disease has a range of presentations, each with well described behavioural characteristics and an associated pattern of atrophy that can be visualized with MRI. As well as the typical episodic memory-medial temporal lobe profile, individuals may present with predominant visuospatial impairment (posterior cortical atrophy), with profound language deficits (logopenic aphasia) or with frontal signs (Benson et al., 1988; Gorno-Tempini et al., 2011; Ossenkoppele et al., 2015). The increasing use of biomarkers such as CSF analysis and amyloid PET (Figure 1) is enabling clinicians to better identify patients with variants of Alzheimer’s disease in memory clinics (Carswell et al., 2018), and allowing greater understanding of how these syndromes relate to each other. Furthermore, the use of such biomarkers, in combination with comprehensive behavioural testing and longitudinal scanning, in large research cohorts has enabled researchers to explore atrophy patterns and cognitive profiles in mild cognitive impairment in addition to Alzheimer’s dementia (Zhang et al., 2016). In this issue of Brain, ten Kate and co-workers have taken this approach further by using a data-driven cluster analysis to identify subtypes in multiple Alzheimer’s disease dementia cohorts, and then attempting to group biomarker-positive individuals with prodromal Alzheimer’s disease into these subtypes (ten Kate et al., 2018).
Amyloid PET scan in Alzheimer’s disease. Colour image of an amyloid PET scan from a patient with increasing episodic memory impairment. There is loss of grey/white matter differentiation in multiple regions strongly suggestive of widespread amyloid deposition. Courtesy of Dr Zarni Win.
The authors identified four atrophy subtypes in a dataset of patients with dementia imaged with a single scanner in Amsterdam, before validating these subtypes in a separate cohort of patients from Amsterdam as well as individuals with dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. In addition to the ‘classical’ medial-temporal-predominant atrophy group with memory and language dysfunction, they found three other clusters: a posterior atrophy group with poor executive function/attention and poor visuospatial function, a group with mild atrophy with relatively better cognition, and a subtype with diffuse cortical atrophy and intermediate cognitive features (Table 1). Critically, age, biomarker profile and other features formed part of the defining characteristics. For example, the mild atrophy group was relatively young with the highest CSF tau levels, whereas patients in the medial-temporal atrophy group were older, and had the greatest burden of vascular lesions and the lowest CSF tau levels. The authors applied their classification to over 600 individuals with prodromal Alzheimer’s disease (from the Amsterdam Dementia Cohort and from the ADNI) and found that the four subgroups manifested subtle differences in their rate and profile of cognitive decline.
This important study by ten Kate et al. builds on previous work and provides further evidence for an intermediate subtype of Alzheimer’s dementia that does not strongly conform to a specific set of cognitive features. Furthermore, the data suggest that the mapping between CSF biomarkers and cognitive profile is not straightforward, and that particular molecular biomarker characteristics may relate to specific cognitive features rather than there being a one-to-many mapping (Husain, 2017). The study also adds to recent work by Dong and co-workers (2017), suggesting that subtypes exist at the prodromal stage. However, it should be noted that around 21% of prodromal subjects in the current study showed a match to more than one subtype, and that the proportion of subjects in each group was different for the prodromal dataset versus the Alzheimer’s disease dementia subsets. In particular, a larger proportion (55%) of the prodromal patients belonged to the milder atrophy group. Thus, one issue that deserves further evaluation is whether the different subtypes observed in the prodromal Alzheimer’s disease population may represent points on the same trajectory, rather than distinct patient groups. ten Kate et al. suggest that the biomarker profiles from their study indicate that this is not the case, and their account would be in keeping with longitudinal data previously published by Zhang and colleagues (2016). However, it is still possible that a significant proportion of individuals with Alzheimer’s disease show longitudinal crossover between subtypes (i.e. mild to diffuse or mild to medial-temporal), whereas other individuals (e.g. parieto-occipital) remain ‘true-to-subtype’ for a much longer period.
Another aspect of the study that must be considered is that, although the cluster analysis employed by the authors is data-driven and unbiased, it can only work with the cohort data that are available; hence the conflation of attention and executive function into a single neuropsychological domain in this study. It is possible that datasets with more detailed cognitive measures might allow better definition of existing subtypes and the identification of more disease clusters. An additional area that is likely to be of particular interest is the neuropsychiatric symptom profile in prodromal Alzheimer’s disease. Recent research suggests that symptoms such as agitation, anxiety, appetite changes and depression can occur at the earliest pathological stages of the disease (Ehrenberg et al., 2018). Exactly how these psychiatric symptoms map onto each of the four subtypes described by ten Kate and colleagues is of great interest. Moreover, although the classification in the current study included the presence of white matter hyperintensities on MRI, the datasets do not include systematic information regarding comorbidities. Particularly in older individuals, further knowledge concerning co-existing conditions such as diabetes and hypertension is likely to throw light on the pathogenesis and development of Alzheimer’s disease. Specifically, knowing whether certain subtypes are more likely to suffer from one or more of these conditions may further inform our understanding of the variable rate of progression across subtypes (Li et al., 2011). The lectures will keep becoming more complicated, and even more interesting.
Brain. 2018;141(12):3285-3287. © 2018 Oxford University Press
New research provides novel insight into the shape-shifting nature of tau proteins, in findings that may aid in the development of therapies to stabilize the protein before it has the ability to aggregate and contribute to Alzheimer’s disease (AD).
Researchers from UT Southwestern’s O’Donnell Brain Institute in Dallas, Texas, found that tau proteins can convert from an inert form to a misfolded form that seeds the growth of toxic aggregates that contribute to the pathology of AD.
“We think of this as the Big Bang of tau pathology. This is a way of peering to the very beginning of the disease process,” lead investigator Marc Diamond, PhD, director of UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases, said in a statement.
The results, published online July 10 in eLife, contradict the belief that tau is an intrinsically disordered protein with no distinct form, the researchers note.
“Although tau monomer has been considered to be natively unstructured, our findings belie this assumption and suggest that initiation of pathological aggregation could begin with conversion of tau monomer from an inert to a seed-competent form,” the investigators write.
The researchers purified and characterized the two distinct forms of tau from recombinant sources and human AD brain. They observed that the inert form is nontoxic, is stable for long periods, and does not easily aggregate.
The seed-competent form helps convert inert tau into misfolded tau that forms toxic aggregates by seeding or self-assembly. Tau can slowly change from the inert to the seed-competent form.
“The identification of distinct and stable forms of tau monomer, including some that are uniquely seed-competent, bears directly on how we understand the initiation of protein aggregation in tauopathies,” the researchers note.
“Personally, I think that this is the biggest thing that we have done because it offers fundamental and important insight into tau that has immediate implications for therapy and diagnosis,” Diamond told Medscape Medical News.
If it’s possible to detect seed-competent tau in healthy people, “we could anticipate disease, and that’s been a major goal of our center — to develop diagnostic tests that could be applied to a healthy population, analogous to the way we use hemoglobin A1c to detect early diabetes,” said Diamond.
In terms of therapeutics, “it may be possible to develop therapies to target only the bad forms of tau that are building up as opposed to all tau. If the protein has two different defined structures, then you can envision making small molecules that stick to the normal or good form of tau and stabilize it before it converts to the bad form,” he added.
“It is known that small molecules can bind to the inert conformation of proteins that are prone to misfolding, and thus prevent the conformational change that leads to amyloid diseases,” Jeffery Kelly, PhD, from The Scripps Research Institute, La Jolla, California, notes in an accompanying editorial published with the study.
“For example, transthyretin is another protein with two ways of folding, and whose toxic conformation damages various nervous systems, as well as the heart. However, drugs known as kinetic stabilizers can slow down the degenerative process by increasing the population of the properly folded conformation,” Kelly explains.
He notes that three placebo-controlled clinical trials have shown that small molecules, such as the drugs tafamidis and diflunisal, can bind to the nonpathogenic form of transthyretin and stabilize it, “which prevents the protein from converting into the conformation that initiates aggregates and leads to degenerative pathologies,” Kelly writes.
“This suggests that it should be possible to fashion similar kinetic stabilizers for the tau protein and offer better treatment for diseases such as Alzheimer’s.”
This research was funded by the National Institutes of Health, Rainwater Charitable Foundation, and Effie Marie Cain Endowed Scholarship. Diamond and Kelly have disclosed no relevant financial relationships.
In people who are genetically predisposed to develop Alzheimer’s disease (AD), notable changes occur in tau peptides decades before the estimated age of symptom onset — a fact that offers potentially important pieces of the complex puzzle of how AD progresses, new research suggests.
“For the first time, we demonstrate that the phosphorylation status of the tau protein measured in the CSF [cerebrospinal fluid] appears to track distinct stages of the Alzheimer’s disease cascade in DIAD [dominantly inherited Alzheimer’s disease], as measured by both estimated years to symptom onset as well as by neuroimaging biomarkers that sequentially change as dementia approaches,” said first author Nicolas Barthélemy, PhD, Department of Neurology, Washington University, St. Louis, Missouri.
Tau peptides have a basic role in functions of the central nervous system, but in their hyperphosphorylated form, they are also key components of AD tangles, Barthélemy noted.
He presented the findings here at ANA 2018: 143rd Annual Meeting of the American Neurological Association.
Defining AD Status
The investigators used mass spectrometry imaging to better understand when increased phosphorylation begins to occur in tau peptides in individuals who carry the genetic mutation for AD. They evaluated normal and phosphorylated tau peptides in the CSF of 115 participants in the Dominantly Inherited Alzheimer Network (DIAN). All patients were still asymptomatic.
The researchers assessed 405 samples from DIAD mutation carriers, representing four tau sites, T181, S202, T205 and T217, and compared them with 639 CSF samples from 234 cross-sectional participants.
Among DIAD mutation carriers, phosphorylation occurred on peptides at the T217 site as much as 21 years prior to the estimated age of onset, as well as 2 years prior to β-amyloid deposition observed with Pittsburgh compound-B positron-emission tomography (PiB-PET).
Increases in total tau levels and in the phosphorylation rate at the T205 site were observed much closer to symptom onset among DIAD mutation carriers.
Levels of T217 hyperphosphorylation were strongly associated with mean cortical β-amyloid deposition on PiB-PET in the asymptomatic carriers of mutations (P < .0001), whereas rates of phosphorylation on the T205 area were inversely associated with numerous cortical areas of fluorodeoxyglucose metabolism (P < .05) and atrophy (P < .01).
“We found that CSF tau T217 hyperphosphorylation is strongly associated with amyloidosis,” Barthélemy said.
“The findings indicate that tau phosphorylation can define Alzheimer’s disease status…by using site-specific changes,” he added.
Furthermore, there is “phosphorylation modification on T205 closer to symptom onset, brain atrophy, and hypometabolism,” Barthélemy said.
“This work allows us to evaluate the association of PET tau imaging with new CSF tau biomarkers and improve method sensitivity to monitor more phosphorylated sites in CSF,” he said.
“Staging the Disease”
Asked by Medscape Medical News to comment, ANA President David M. Holtzman, MD, professor and chair of neurology at Washington University, St. Louis, Missouri, said the findings add to the understanding of the mechanisms that may underlie the earliest stages of AD.
“What they showed was that one form of the tau protein that has a certain phosphorylation site starts to accumulate and increases. It’s present all the time, but it goes higher about 20 years before symptoms start, and it’s probably due to the fact that amyloid is leading to the release of that protein from nerve cells,” Holtzman said.
“Interestingly, the study also showed different phosphorylation changes, but not until right about when the Alzheimer’s symptoms are coming on. So there are these different molecular effects on tau that are useful at staging the disease,” he said.
The insights of these patterns could have therapeutic implications, he added.
“We’re seeing that one effect occurs very early, well before the start of symptoms, and the other occurs much later. So that could be very useful for monitoring the effects of therapy if you’re targeting that molecule, for example,” Holtzman explained.
“Or maybe if you’re presymptomatic, the patterns could help tell you where you are along the time course. So that is really important if we want to test treatments that delay the disease,” he added.
“We want to know when we’re treating people, so some things might be more effective as a primary prevention really early, or some may be okay for later,” said Holtzman. “That’s why I think these are really important findings.”
Iron is known to be toxic to brain cells, and tiny magnetic iron particles (magnetite) are thought to be involved in the development of neurological disorders. Now, for the first time, we have identified the abundant presence of these highly reactive particles in human brains.
Previous studies have suggested that there are increased amounts of magnetite in Alzheimer’s-affected brains, and that these particles may be linked with the development of the disease. We wondered if this increased brain magnetite might come from inhaling polluted air.
Very small, round particles made out of magnetite (called magnetite nanospheres) are abundant in city air pollution. They are formed at high temperatures and condense as iron-rich droplets as they cool. These particles range in diameter from less than 5nm (nanometres) to more than 100nm (for comparison an HIV is 120nm in diameter) and are often found together with pollution particles made out of other metals.
Vehicles are a major source of these magnetite nanospheres. They are created by fuel combustion (especially diesel), iron wear from the engine block and frictional heating from brake pads. In addition to some occupational settings, high concentrations of magnetite pollution nanoparticles may be produced indoors by open fires or poorly-sealed stoves used for cooking or heating.
Larger magnetite particles can be more than 10 micrometres in diameter (about the size of a cloud water droplet) and come from industrial sources, such as power stations, but only magnetite pollution particles that are smaller than 200nm can enter the brain directly by being breathed in through the nose. They can then travel through the nerve cells of the olfactory bulb (see illustration).
The blood-brain barrier – the protective cell wall that prevents harmful substances entering the brain – doesn’t protect against this type of nasal entry, so these small particles can enter the brain relatively unimpeded. After nanoparticles enter these olfactory areas, they can spread to other parts of the brain, including the hippocampus and cerebral cortex, which are regions affected in Alzheimer’s disease.
The presence in the brain of magnetite might trigger events leading to neurodegenerative disease. Magnetite contains a mix of two types of iron, called ferric and ferrous iron. Ferrous iron has been shown to be an effective catalyst for the production of very reactive and damaging molecules called “reactive oxygen species”. Brain damage due to these types of molecules is known to occur very early in the course of Alzheimer’s disease.
A key change in the brain in this disease is the formation of “senile plaques”, which are clumps of abnormal protein found between nerve cells. Magnetite particles have been found to be directly associated with these senile plaques, and to enhance the toxicity of the protein that is found in the centre of each one.
To examine if magnetite from external sources might exist in human brains, we used magnetic, electron microscopic and other techniques to examine brain samples from 37 cadavers – aged three to 92 years at time of death – who had lived in Mexico City or in Manchester, UK. We found that many of the highly magnetic brain samples were from people under the age of 40 from Mexico City who had been exposed to high levels of air pollution, and in older Manchester cases (over 65 years at death) with moderate to severe Alzheimer’s disease.
Most of the magnetite particles in the brain samples were spherical and different in size and shape from the magnetite particles that naturally occur in people and animals. They ranged in diameter from 5nm to 150nm and were found together with nanoparticles containing other metals, such as platinum, nickel and cobalt, which would not occur naturally in the brain. We also extracted the magnetite particles from the brains using an enzyme. The enzyme dissolved the brain tissue and left the magnetite particles intact. These particles were then extracted using a magnet. The particles were a striking match for the magnetite nanospheres found in air pollution.
Since less than 5% of cases of Alzheimer’s disease are directly inherited, it is likely that the environment plays a major role in the disease. Because of their combination of being very tiny, known to be toxic to brains, and very commonly found in air pollution, magnetite pollution nanoparticles need to be examined as a possible risk for brain disease, including Alzheimer’s. If a link to human health is discovered, this would have major implications for laws limiting exposure to this type of air pollution.
Scientists have been studying the link between amyloid plaques and Alzheimer’s disease for over 20 years, but a growing number of experts are questioning this prevailing hypothesis. Thomas J. Lewis, Ph.D. has been leading the call to change the way the medical community looks at, and treats, Alzheimer’s disease. And according to this Alzheimer’s expert, the notion that amyloid plaque is the sole cause of Alzheimer’s disease is nothing more than a myth, peddled by the profit-seeking pharma industry for their own financial gain.
Dr. Lewis is the CEO and founder of RealHealth Clinics, and has spent years researching and developing alternative treatments for the condition. Despite the fact that amyloid plaques and the “amyloid cascade” hypothesis have been the cornerstone of Alzheimer’s disease research for decades, Lewis believes that other forces are at play. Other experts have also begun to question the amyloid dogma — and for good reason.
Amyloid plaques and Alzheimer’s disease
As sources explain, the current accepted theory about Alzheimer’s goes like so: Beta amyloid, a protein fragment, accumulates in the brain and forms clumps of amyloid plaque. This plaque is believed to destroy synapses, cause nerve cell death and ultimately, impair brain function.
The theory sounds good on paper, but as Dr. Lewis explains, there are some glaring problems with this hypothesis.
And as sources report, more than 100 amyloid-targeting drugs have been tested in the treatment of Alzheimer’s disease; all have failed. Researchers have even tried using these drugs in milder cases of dementia, still to no avail. Now, rather than admit their prevailing theory is wrong, Big Pharma is looking to employ totally healthy people as their guinea pigs. If amyloid plaques were the problem, the drugs should have offered at least some benefit. Further, giving healthy people drugs to prevent a disease they don’t have, ultimately, won’t even provide substantiating proof of concept, anyways — not that a lack of convincing evidence has ever stopped Big Pharma before.
100% organic essential oil sets now available for your home and personal care, including Rosemary, Oregano, Eucalyptus, Tea Tree, Clary Sage and more, all 100% organic and laboratory tested for safety. A multitude of uses, from stress reduction to topical first aid. See the complete listing here, and help support this news site.
More, Dr. Lewis explained at a recent summit, there are many cases of Alzheimer’s disease in which no amyloid plaques are present. This alone is a bit of a red flag; after all, if the plaques are the only thing that causes Alzheimer’s, they should be present in all patients.
This finding, at the very least, suggests that there is more than one cause of Alzheimer’s.
Even more interesting is the finding that amyloid plaque is often present in the brains of individuals not affected by Alzheimer’s disease.
As Dr. Lewis notes further, research by Harvard University has shown that beta amyloid is actually part of the immune system response. This, he posits, could mean that amyloid plaques may actually play a protective role in the brain. Instead of causing Alzheimer’s, the accumulation of beta amyloid may be a sign that something else is going awry.
So, the drugs designed to target the “cause” of Alzheimer’s do nothing to actually help treat the disease, and studies have indicated that amyloid plaque, at the very least, is not the only factor that contributes to it, either. It is no wonder that experts like Dr. Lewis propose that perhaps another factor is at play.
Indeed, it would seem that like other conditions, Alzheimer’s disease can be triggered by an array of causes. Dr. Lewis notes, however, that inflammation is virtually always present. He posits that environmental toxins, stress, poor nutrition, lack of sleep and bacterial and viral infections can all play a role in the onset of the disease.
Research has shown that prescription drugs and vaccines can also contribute to the development of Alzheimer’s. All things considered, it’s clear that the way mainstream medicine currently looks at Alzheimer’s disease is misguided. You can learn more at Dementia.news.
Sources for this article include:
Researchers have categorized Alzheimer’s disease into six distinct conditions based on cognitive function at the time of diagnosis and genetic data demonstrating biological differences across groups.
The findings represent “an important result on the road to personalized medicine,” write Dr. Paul Crane of the University of Washington School of Medicine in Seattle and colleagues in a report online December 4 in Molecular Psychiatry.
“Clinicians have noted a lot of variation in the cognitive profiles of people presenting with Alzheimer’s disease for many years,” Dr. Crane told Reuters Health by email. “A ‘relative deficits’ approach to differential diagnosis has characterized typical clinical neuropsychological practice.”
“We were curious as to whether this clinical framework could prove useful in characterizing heterogeneity among people with typical late-onset Alzheimer’s disease,” he said.
In previous studies, the group used cognitive tests to subdivide people with late-onset Alzheimer’s disease into different groups. The current study “looks specifically at genetic data to see whether there is genetic (biological) support for this particular way of categorizing people with typical late-onset Alzheimer’s disease,” Dr. Crane said.
The researchers studied information from five studies involving 4,050 patients with late-onset Alzheimer’s (mean age, 80; 61% women), including 2,431 with single nucleotide polymorphism (SNP) data.
Individuals were assigned to cognitively defined subgroups on the basis of their relative performance in memory, executive functioning, visuospatial functioning, and language at the time of diagnosis. Genotype frequencies for each subgroup were compared with those from cognitively normal elderly controls.
The team focused on the APOE gene and SNPs with more extreme odds ratios than those previously reported for Alzheimer’s disease. They found substantial variation across studies in the proportions of people in each subgroup. However, in each study, higher proportions of people in the subgroup with isolated substantial relative memory impairment had at least one APOE-e4 allele.
Overall, across subgroups, “we found 33 SNPs scattered through the genome with a strong association with one of the cognitively defined subgroups,” Dr. Crane said. “Few of these SNPs had previously been identified as being interesting in Alzheimer’s disease.”
“These data provide strong support for the biological coherence of subgroups produced by our categorization scheme,” the authors state. “Each subgroup we analyzed has extreme ORs at novel SNPs that were consistent across multiple independent samples.”
“Even with the relatively small sample sizes from these studies, the large effect sizes at common SNPs produced p values that are close to genome-wide significance,” they concluded.
“A lot more work needs to happen downstream of our initial findings,” Dr. Crane noted, “but each of these 33 SNPs represents some underlying biology that makes people susceptible to one specific subtype of Alzheimer’s disease,” he said. “Each one thus represents a possible novel target for future work.”
In the future, he said, clinicians “may see different treatments recommended on the basis of cognitively-defined subgroups, but we are not there yet.”
Dr. Keith Fargo, Alzheimer’s Association Director of Scientific Programs and Outreach, commented, “This seems to be a reasonable approach — trying to identify subgroups of people with Alzheimer’s who have different clinical presentations, and associate those with specific genetic variants.”
“Whether it is clinically useful or not remains to be seen,” he said, after the findings have been replicated and additional studies have been done in larger, more diverse populations.
“Looking to the future, it is possible that we may soon be able to treat people with Alzheimer’s disease based on their unique combination of genetics, medical history, risk factors and more,” he said. “This kind of research may be getting us closer to this future of precision medicine for Alzheimer’s and other dementias.”