Neuroscience

Do the brains of different people listening to the same piece of music actually respond in the same way? An imaging study by Stanford University School of Medicine scientists says the answer is yes, which may in part explain why music plays such a big role in our social existence.

(Image: Anthony Ellis)

The investigators used functional magnetic resonance imaging to identify a distributed network of several brain structures whose activity levels waxed and waned in a strikingly similar pattern among study participants as they listened to classical music they’d never heard before. The results will be published online April 11 in the European Journal of Neuroscience.

"We spend a lot of time listening to music — often in groups, and often in conjunction with synchronized movement and dance," said Vinod Menon, PhD, a professor of psychiatry and behavioral sciences and the study’s senior author. "Here, we’ve shown for the first time that despite our individual differences in musical experiences and preferences, classical music elicits a highly consistent pattern of activity across individuals in several brain structures including those involved in movement planning, memory and attention."

The notion that healthy subjects respond to complex sounds in the same way, Menon said, could provide novel insights into how individuals with language and speech disorders might listen to and track information differently from the rest of us.

The new study is one in a series of collaborations between Menon and co-author Daniel Levitin, PhD, a psychology professor at McGill University in Montreal, dating back to when Levitin was a visiting scholar at Stanford several years ago.

To make sure it was music, not language, that study participants’ brains would be processing, Menon’s group used music that had no lyrics. Also excluded was anything participants had heard before, in order to eliminate the confounding effects of having some participants who had heard the musical selection before while others were hearing it for the first time. Using obscure pieces of music also avoided tripping off memories such as where participants were the first time they heard the selection.

The researchers settled on complete classical symphonic musical pieces by 18th-century English composer William Boyce, known to musical cognoscenti as “the English Bach” because his late-baroque compositions in some respects resembled those of the famed German composer. Boyce’s works fit well into the canon of Western music but are little known to modern Americans.

Next, Menon’s group recruited 17 right-handed participants (nine men and eight women) between the ages of 19 and 27 with little or no musical training and no previous knowledge of Boyce’s works. (Conventional maps of brain anatomy are based on studies of right-handed people. Left-handed people’s brains tend to deviate from that map.)

While participants listened to Boyce’s music through headphones with their heads maintained in a fixed position inside an fMRI chamber, their brains were imaged for more than nine minutes. During this imaging session, participants also heard two types of “pseudo-musical” stimuli containing one or another attribute of music but lacking in others. In one case, all of the timing information in the music was obliterated, including the rhythm, with an effect akin to a harmonized hissing sound. The other pseudo-musical input involved maintaining the same rhythmic structure as in the Boyce piece but with each tone transformed by a mathematical algorithm to another tone so that the melodic and harmonic aspects were drastically altered.

The team identified a hierarchal network stretching from low-level auditory relay stations in the midbrain to high-level cortical brain structures related to working memory and attention, and beyond that to movement-planning areas in the cortex. These regions track structural elements of a musical stimulus over time periods lasting up to several seconds, with each region processing information according to its own time scale.

Activity levels in several different places in the brain responded similarly from one individual to the next to music, but less so or not at all to pseudo-music. While these brain structures have been implicated individually in musical processing, their identifications had been obtained by probing with artificial laboratory stimuli, not real music. Nor had their coordination with one another been previously observed.

Notably, subcortical auditory structures in the midbrain and thalamus showed significantly greater synchronization in response to musical stimuli. These structures have been thought to passively relay auditory information to higher brain centers, Menon said. “But if they were just passive relay stations, their responses to both types of pseudo-music would have been just as closely synchronized between individuals as to real music.” The study demonstrated, for the first time, that those structures’ activity levels respond preferentially to music rather than to pseudo-music, suggesting that higher-level centers in the cortex direct these relay stations to closely heed sounds that are specifically musical in nature.

The fronto-parietal cortex, which anchors high-level cognitive functions including attention and working memory, also manifested intersubject synchronization — but only in response to music and only in the right hemisphere.

Interestingly, the structures involved included the right-brain counterparts of two important structures in the brain’s left hemisphere, Broca’s and Geschwind’s areas, known to be crucial for speech and language interpretation.

"These right-hemisphere brain areas track non-linguistic stimuli such as music in the same way that the left hemisphere tracks linguistic sequences," said Menon.

In any single individual listening to music, each cluster of music-responsive areas appeared to be tracking music on its own time scale. For example, midbrain auditory processing centers worked more or less in real time, while the right-brain analogs of the Broca’s and Geschwind’s areas appeared to chew on longer stretches of music. These structures may be necessary for holding musical phrases and passages in mind as part of making sense of a piece of music’s long-term structure.

"A novelty of our work is that we identified brain structures that track the temporal evolution of the music over extended periods of time, similar to our everyday experience of music listening," said postdoctoral scholar Daniel Abrams, PhD, the study’s first author.

The preferential activation of motor-planning centers in response to music, compared with pseudo-music, suggests that our brains respond naturally to musical stimulation by foreshadowing movements that typically accompany music listening: clapping, dancing, marching, singing or head-bobbing. The apparently similar activation patterns among normal individuals make it more likely our movements will be socially coordinated.

"Our method can be extended to a number of research domains that involve interpersonal communication. We are particularly interested in language and social communication in autism," Menon said. "Do children with autism listen to speech the same way as typically developing children? If not, how are they processing information differently? Which brain regions are out of sync?"

The age at which a child with autism is diagnosed is related to the particular suite of behavioral symptoms he or she exhibits, new research from the University of Wisconsin-Madison shows.

Certain diagnostic features, including poor nonverbal communication and repetitive behaviors, were associated with earlier identification of an autism spectrum disorder, according to a study in the April issue of the Journal of the American Academy of Child and Adolescent Psychiatry. Displaying more behavioral features was also associated with earlier diagnosis.

"Early diagnosis is one of the major public health goals related to autism," says lead study author Matthew Maenner, a researcher at the UW-Madison Waisman Center. "The earlier you can identify that a child might be having problems, the sooner they can receive support to help them succeed and reach their potential."

But there is a large gap between current research and what is actually happening in schools and communities, Maenner adds. Although research suggests autism can be reliably diagnosed by age 2, the new analysis shows that fewer than half of children with autism are identified in their communities by age 5.

One challenge is that autism spectrum disorders (ASD) are extremely diverse. According to the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition - Text Revision (DSM-IV-TR), the standard handbook used for classification of psychiatric disorders, there are more than 600 different symptom combinations that meet the minimum criteria for diagnosing autistic disorder, one subtype of ASD.

Previous research on age at diagnosis has focused on external factors such as gender, socioeconomic status, and intellectual disability. Maenner and his colleagues instead looked at patterns of the 12 behavioral features used to diagnose autism according to the DSM-IV-TR.

He and Maureen Durkin, a UW-Madison professor of population health and pediatrics and Waisman Center investigator, studied records of 2,757 8-year- olds from 11 surveillance sites in the nationwide Autism and Developmental Disabilities Monitoring Network, run by the Centers for Disease Control and Prevention (CDC). They found significant associations between the presence of certain behavioral features and age at diagnosis.

"When it comes to the timing of autism identification, the symptoms actually matter quite a bit," Maenner says.

In the study population, the median age at diagnosis (the age by which half the children were diagnosed) was 8.2 years for children with only seven of the listed behavioral features but dropped to just 3.8 years for children with all 12 of the symptoms.

The specific symptoms present also emerged as an important factor. Children with impairments in nonverbal communication, imaginary play, repetitive motor behaviors, and inflexibility in routines were more likely to be diagnosed at a younger age, while those with deficits in conversational ability, idiosyncratic speech and relating to peers were more likely to be diagnosed at a later age.

These patterns make a lot of sense, Maenner says, since they involve behaviors that may arise at different developmental times. The findings suggest that children who show fewer behavioral features or whose autism is characterized by symptoms typically identified at later ages may face more barriers to early diagnosis.

But they also indicate that more screening may not always lead to early diagnoses for everyone.

"Increasing the intensity of screening for autism might lead to identifying more children earlier, but it could also catch a lot of people at later ages who might not have otherwise been identified as having autism," Maenner says.

Most people are so attuned to the nuances of social interaction that they can detect clues to mental illness while playing a strategy game with someone they have never met.

That was the finding of a team of scientists led by Read Montague, director of the Human Neuroimaging Laboratory at the Virginia Tech Carilion Research Institute. The researchers discovered that healthy people and those with borderline personality disorder displayed different patterns of behavior while playing an online strategy game, so much so that when healthy players played people with borderline personality disorder, they gave up on trying to predict what their partners would do next.

For their large neuroimaging study, the scientists used a multiround social interaction game, the investor-trustee game, to study the level of strategic thinking in 195 pairs of subjects. In each pair, one player played the investor and the other the trustee. The investor chose how much money to send the trustee, and the trustee in turn decided how much to return to the investor. Profit required the cooperation of both players.

“This classic tit-for-tat game allows us to probe people’s responses to the social gestures of others,” said Montague, who also directs the Computational Psychiatry Unit, an academic center that uses computational models to understand mental disease. “It further allows us to see how people form models of one another. These insights are important for understanding a range of mental illnesses, as the ability to infer other people’s intentions is an essential component of healthy cognition.”

The scientists classified the investors according to varying levels of strategic depth of thought. The healthy subjects fell into three categories: about half simply responded to the amount the other player sent; about one-quarter built a model of their partner’s behavior; and the remaining quarter considered not just their model of their partner, but also their partner’s models of them. 

Not surprisingly, the depth-of-thought style of play correlated with success, with the players who looked deeper into interactions making considerably more money than those who played at a shallow level.

When healthy subjects played people with borderline personality disorder, though, they were far less likely to exhibit depth of thought.

“People with borderline personality disorder are characterized by their unstable relationships, and when they play this game, they tend to break cooperation,” said Montague. “The healthy subjects picked up on the erratic behavior, likely without even realizing it, and far fewer played strategically.”

Notably, the functional magnetic resonance imaging of the subjects’ brains revealed that each category of player showed distinct neural correlates of learning signals associated with differing depths of thought. The scientists used hyperscanning, a technique Montague invented that enables subjects in different brain scanners to interact in real time, regardless of geography. Hyperscanning allows scientists to eavesdrop on brain activity during social exchanges in scanners, whether across the hallway or across the world.

“We’re always modeling other people, and our brains have a substantial amount of neural tissue devoted to pondering our interactions with other people,” Montague said. “This study is a start to turning neural signals into numbers – not just theory-of-mind arguments, but actual numbers. And when we can do that across thousands of people, we should start to gain insights into psychopathologies – what circuits are involved, what brain regions are engaged, and how injuries, congenital disorders, and genetic defects might play into psychiatric illness.”

Montague believes the study represents a significant contribution to the field of computational psychiatry, which seeks to bring computational clout to efforts to understand mental dysfunction. “Traditional psychiatric categories are useful yet incomplete,” said Montague, who delivered a TEDGlobal talk on the growing field of computational psychiatry last year. “Computational psychiatry enables us to redefine with a new lexicon – a mathematical one – the standard ways we think about mental illness.”

Computationally based insights may one day help psychiatry achieve better precision in diagnosis and treatment, Montague said. But until scientists have the right instruments, they cannot even begin to make those connections.

“The exquisite sensitivity that most people have to social gestures gives us a valuable opening,” Montague said. “We’re hoping to invent a tool – almost a human inkblot test – for identifying and characterizing mental disorders in which social interactions go awry.”

Newborn babies’ immune system development and levels of vitamin D have been found to vary according to their month of birth, according to new research.

The research, from scientists at Queen Mary, University of London and the University of Oxford, provides a potential biological basis as to why an individual’s risk of developing the neurological condition multiple sclerosis (MS) is influenced by their month of birth. It also supports the need for further research into the potential benefits of vitamin D supplementation during pregnancy.

Around 100,000 people in the UK have MS, a disabling neurological condition which results from the body’s own immune system damaging the central nervous system. This interferes with the transmission of messages between the brain and other parts of the body and leads to problems with vision, muscle control, hearing and memory. 

The development of MS is believed to be a result of a complex interaction between genes and the environment.

A number of population studies have suggested that the month you are born in can influence your risk of developing MS. This ‘month of birth’ effect is particularly evident in England, where the risk of MS peaks in individuals born in May and drops in those delivered in November. As vitamin D is formed by the skin when it is exposed to sunlight, the ‘month of birth’ effect has been interpreted as evidence of a prenatal role for vitamin D in MS risk.

In this study, samples of cord blood – blood extracted from a newborn baby’s umbilical cord – were taken from 50 babies born in November and 50 born in May between 2009 and 2010 in London.

The blood was analysed to measure levels of vitamin D and levels of autoreactive T-cells. T-cells are white blood cells which play a crucial role in the body’s immune response by identifying and destroying infectious agents, such as viruses. However some T-cells are ‘autoreactive’ and capable of attacking the body’s own cells, triggering autoimmune diseases, and should be eliminated by the immune system during its development. This job of processing T-cells is carried out by the thymus , a specialised organ in the immune system located in the upper chest cavity.

The results showed that the May babies had significantly lower levels of vitamin D (around 20 per cent lower than those born in November) and significantly higher levels (approximately double) of these autoreactive T-cells, compared to the sample of November babies.

Co-author Dr Sreeram Ramagopalan, a lecturer in neuroscience at Barts and The London School of Medicine and Dentistry, part of Queen Mary, said: “By showing that month of birth has a measurable impact on in utero immune system development, this study provides a potential biological explanation for the widely observed “month of birth” effect in MS. Higher levels of autoreactive T-cells, which have the ability to turn on the body, could explain why babies born in May are at a higher risk of developing MS.

“The correlation with vitamin D suggests this could be the driver of this effect. There is a need for long-term studies to assess the effect of vitamin D supplementation in pregnant women and the subsequent impact on immune system development and risk of MS and other autoimmune diseases.”

The research letter is published today in the journal JAMA Neurology.

Research from Western University and Lawson Health Research Institute sheds new light on a gene called ATRX and its function in the brain and pituitary. Children born with ATRX syndrome have cognitive defects and developmental abnormalities. ATRX mutations have also been linked to brain tumors.

Dr. Nathalie Bérubé, PhD, and her colleagues found mice developed without the ATRX gene had problems in in the forebrain, the part of the brain associated with learning and memory, and in the anterior pituitary which has a direct effect on body growth and metabolism. The mice, unexpectedly, also displayed shortened lifespan, cataracts, heart enlargement, reduced bone density, hypoglycemia; in short, many of the symptoms associated with aging. The research is published in the Journal of Clinical Investigation.

Ashley Watson, a PhD candidate working in the Bérubé lab and the first author on the paper, discovered the loss of ATRX caused DNA damage especially at the ends of chromosomes which are called telomeres. She investigated further and discovered the damage is due to problems during DNA replication, which is required before the onset of cell division. Basically, the ATRX protein was needed to help replicate the telomere.

Working with Frank Beier of the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry, the researchers made another discovery. “Mice that developed without ATRX were small at birth and failed to thrive, and when we looked at the skeleton of these mice, we found very low bone mineralization. This is another feature found in mouse models of premature aging,” says Bérubé, an associate professor in the Departments of Biochemistry and Paediatrics at Schulich Medicine & Dentistry, and a scientist in the Molecular Genetics Program at the Children’s Health Research Institute within Lawson. “We found the loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary, resulting in systemic defects similar to those seen in aging.”

The researchers say the lack of ATRX in the anterior pituitary caused problems with the thyroid, resulting in low levels of a hormone called insulin-like growth factor-one (IGF-1) in the blood. There are theories that low IGF-1 can deplete stores of stem cells in the body, and Bérubé says that’s one of the explanations for the premature aging.

Exposure to the anesthetic agent isoflurane increases “programmed cell death” of specific types of cells in the newborn mouse brain, reports a study in the April issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

With prolonged exposure, a common inhaled anesthesia eliminates approximately two percent of neurons in the cortex of newborn mice. Although its relevance to anesthesia in human newborns remains to be determined, the study by Dr George K. Istaphanous and colleagues of Cincinnati Children’s Hospital Medical Center provides unprecedented detail on the cellular-level effects of anesthetics on the developing brain.

Isoflurane Exposure Increases ‘Programmed Death’ of Brain Cells
In the study, seven-day-old mice were exposed to isoflurane for several hours. After exposure, sophisticated examinations were performed to assess the extent of isoflurane-induced brain cell death, including the specific types, locations, and functions of brain cells lost.

Isoflurane exposure led to widespread increases programmed cell death, called apoptosis, throughout the brain. Although cell loss was substantially higher after isoflurane exposure, the cell types lost were similar to the cells lost in the apoptosis that is part of normal brain maturation. In both cases, mainly neurons were lost. Neurons are the cells that transmit and store information.

The rate of cell death in the superficial cortex—the thick outer layer of the brain—was at least eleven times higher in isoflurane-exposed animals than seen with normal brain maturation. Overall, approximately two percent of cortical neurons were lost after isoflurane exposure. Astrocytes, another major type of cortical brain cells, were less affected by anesthetic exposure.

Relevance to Anesthesia in Human Newborns Is Unclear—For Now
A growing body of evidence suggests that isoflurane and similar anesthetics may have toxic effects on brain cells in newborn animals and humans. “However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized,” according to Dr Istaphanous and colleagues.

The new study provides detailed information on the extent and types of brain cell loss resulting from prolonged isoflurane exposure in newborn mice. It’s unclear whether the two percent brain cell loss induced in the experiments would lead to any permanent damage—in previous studies, newborn isoflurane-exposed mice showed no obvious brain damage long after the exposure.

It can’t be assumed that isoflurane causes similar patterns of cellular damage in human newborns requiring general anesthesia, Dr Istaphanous and coauthors emphasize. Some studies have linked early-life exposure to anesthesia and surgery to later behavioral and learning abnormalities. Other studies have found no adverse affects on children exposed to anesthetics during vulnerable times of brain development. Further research on the selective nature and molecular mechanisms of isoflurane-induced brain cell death would be needed to determine the relevance of the experimental findings, if any, to human infants undergoing anesthesia.

One of the most controversial topics in neurology today is the prevalence of serious permanent brain damage after traumatic brain injury (TBI). Long-term studies and a search for genetic risk factors are required in order to predict an individual’s risk for serious permanent brain damage, according to a review article published by Sam Gandy, MD, PhD, from the Icahn School of Medicine at Mount Sinai in a special issue of Nature Reviews Neurology dedicated to TBI.

About one percent of the population in the developed world has experienced TBI, which can cause serious long-term complications such as Alzheimer’s disease (AD) or chronic traumatic encephalopathy (CTE), which is marked by neuropsychiatric features such as dementia, Parkinson’s disease, depression, and aggression. Patients may be normal for decades after the TBI event before they develop AD or CTE. Although first described in boxers in the 1920s, the association of CTE with battlefield exposure and sports, such as football and hockey, has only recently begun to attract public attention.  

"Athletes such as David Duerson and Junior Seau have brought to light the need for preventive measures and early diagnosis of CTE, but it remains highly controversial because hard data are not available that enable prediction of the prevalence, incidence, and individual risk for CTE," said Dr. Gandy, who is Professor of Neurology and Psychiatry and Director of the Center for Cognitive Health at Mount Sinai. "We need much more in the way of hard facts before we can advise the public of the proper level of concern."

Led by Dr. Gandy, the authors evaluated the pathological impact of single-incident TBI, such as that sustained during military combat; and mild, repetitive TBI, as seen in boxers and National Football League (NFL) players to learn what measures need to be taken to identify risk and incidence early and reduce long-term complications.

Mild, repetitive TBI, as is seen in boxers, football players, and occasionally military veterans who suffer multiple blows to the head, is most often associated with CTE, or a condition called “boxer’s dementia.” Boxing scoring includes a record of knockouts, providing researchers with a starting point in interpreting an athlete’s risk. But no such records exist for NFL players or soldiers on the battlefield.

Dr. Gandy and the authors of the Nature Reviews Neurology piece suggest recruiting large cohorts of players and military veterans in multi-center trials, where players and soldiers maintain a TBI diary for the duration of their lives. The researchers also suggest a genome-wide association study to clearly identify risk factors of CTE. “Confirmed biomarkers of risk, diagnostic tools, and long-term trials are needed to fully characterize this disease and develop prevention and treatment strategies,” said Dr. Gandy.  

Amyloid imaging, which has recently been approved by the U.S. Food and Drug Administration, may be useful as a monitoring tool in TBI, since amyloid plaques are a hallmark symptom of AD-type neurodegeneration. Amyloid imaging consists of a PET scan with an injection of a contrast agent called florbetapir, which binds to amyloid plaque in the brain, allowing researchers to visualize plaque deposits and determine whether the diagnosis is CTE or AD, and monitor progression over time. Tangle imaging is expected to be available soon, complementing amyloid imaging and providing an affirmative diagnosis of CTE. Dr. Gandy and colleagues recently reported the use of amyloid imaging to exclude AD in a retired NFL player with memory problems under their care at Mount Sinai.  

Clinical diagnosis and evaluation of mild, repetitive TBI is a challenge, indicating a significant need for new biomarkers to identify damage, report the authors. Measuring cerebrospinal fluid (CSF) may reflect damage done to neurons post-TBI. Previous research has identified a marked increase in CSF biomarkers in boxers when the CSF is taken soon after a fight, and this may predict which boxers are more likely to develop detrimental long-term effects. CSF samples are now only obtained by invasive lumbar puncture; a blood test would be preferable.

"Biomarkers would be a valuable tool both from a research perspective in comparing them before and after injury and from a clinical perspective in terms of diagnostic and prognostic guidance," said Dr. Gandy. "Having the biomarker information will also help us understand the mechanism of disease development, the reasons for its delayed progression, and the pathway toward effective therapeutic interventions."

Currently, there are no treatments for boxer’s dementia or CTE, but these diseases are preventable. “With more protective equipment, adjustments in the rules of the game, and overall education among athletes, coaches, and parents, we should be able to offer informed consent to prospective sports players and soldiers. With the right combination of identified genetic risk factor, biomarkers, and better drugs, we should be able to dramatically improve the outcome of TBI and prevent the long-term, devastating effects of CTE,” said Dr. Gandy.

People in their 20s don’t have much on their middle-aged counterparts when it comes to some fine motor movements, researchers from UT Arlington have found.

In a simple finger-tapping exercise, study participants’ speed declined only slightly with age until a marked drop in ability with participants in their mid-60s.

Priscila Caçola, an assistant professor of kinesiology at The University of Texas at Arlington, hopes the new work will help clinicians identify abnormal loss of function in their patients. Though motor ability in older adults has been studied widely, not a lot of research has focused on when deficits begin, she said.

The journal Brain and Cognition will include the study in its June 2013 issue. It is already available online.

“We have this so-called age decline, everybody knows that. I wanted to see if that was a gradual process,” Caçola said. “It’s good news really because I didn’t see differences between the young and middle-aged people.”

Caçola’s co-authors on the paper are Jerroed Roberson, a senior kinesiology major at UT Arlington, and Carl Gabbard, a professor in the Texas A&M University Department of Health and Kinesiology.

The researchers based their work on the idea that before movements are made, the brain makes a mental plan. They used an evaluation process called chronometry that compares the time of test participants’ imagined movements to actual movements. Study participants – 99 people ranging in age from 18 to 93 – were asked to imagine and perform a series of increasingly difficult, ordered finger movements. They were divided into three age groups – 18-32, 40-63 and 65-93 – and the results were analyzed.

“What we found is that there is a significant drop-off after the age of 64,” Roberson said. “So if you see a drop-off in ability before that, then it could be a signal that there might be something wrong with that person and they might need further evaluation.”

The researchers also noted that the speed of imagined movements and executed actions tended to be closely associated within each group. That also could be useful knowledge for clinicians, the study said.

“The important message here is that clinicians should be aware that healthy older adults are slower than younger adults, but are able to create relatively accurate internal models for action,” the study said.

Caçola is a member of UT Arlington Center for Health Living and Longevity. She has published previous research on the links between movement representation and motor ability in children.

Researchers at Washington University School of Medicine in St. Louis have identified a new set of genetic markers for Alzheimer’s that point to a second pathway through which the disease develops.

Much of the genetic research on Alzheimer’s centers on amyloid-beta, a key component of brain plaques that build up in the brains of people with the disease.

In the new study, the scientists identified several genes linked to the tau protein, which is found in the tangles that develop in the brain as Alzheimer’s progresses and patients develop dementia. The findings may help provide targets for a different class of drugs that could be used for treatment.

The researchers report their findings online April 24 in the journal Neuron.

"We measured the tau protein in the cerebrospinal fluid and identified several genes that are related to high levels of tau and also affect risk for Alzheimer’s disease,” says senior investigator Alison M. Goate, DPhil, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry. “As far as we’re aware, three of these genes have no effect on amyloid-beta, suggesting that they are operating through a completely different pathway.”

A fourth gene in the mix, APOE, had been identified long ago as a risk factor for Alzheimer’s. It has been linked to amyloid-beta, but in the new study, APOE appears to be connected to elevated levels of tau. Finding that APOE is influencing more than one pathway could help explain why the gene has such a big effect on Alzheimer’s disease risk, the researchers say.

“It appears APOE influences risk in more than one way,” says Goate, also a professor of genetics and co-director of the Hope Center for Neurological Disorders. “Some of the effects are mediated through amyloid-beta and others by tau. That suggests there are at least two ways in which the gene can influence our risk for Alzheimer’s disease.”

The new research by Goate and her colleagues is the largest genome-wide association study (GWAS) yet on tau in cerebrospinal fluid. The scientists analyzed points along the genomes of 1,269 individuals who had undergone spinal taps as part of ongoing Alzheimer’s research.

Whereas amyloid is known to collect in the brain and affect brain cells from the outside, the tau protein usually is stored inside cells. So tau usually moves into the spinal fluid when cells are damaged or die. Elevated tau has been linked to several forms of non-Alzheimer’s dementia, and first author Carlos Cruchaga, PhD, says that although amyloid plaques are a key feature of Alzheimer’s disease, it’s possible that excess tau has more to do with the dementia than plaques.

“We know there are some individuals with high levels of amyloid-beta who don’t develop Alzheimer’s disease,” says Cruchaga, an assistant professor of psychiatry. “We don’t know why that is, but perhaps it could be related to the fact that they don’t have elevated tau levels.”

In addition to APOE, the researchers found that a gene called GLIS3, and the genes TREM2 and TREML2 also affect both tau levels and Alzheimer’s risk.

Goate says she suspects changes in tau may be good predictors of advancing disease. As tau levels rise, she says people may be more likely to develop dementia. If drugs could be developed to target tau, they may prevent much of the neurodegeneration that characterizes Alzheimer’s disease and, in that way, help prevent or delay dementia.

The new research also suggests it may one day be possible to reduce Alzheimer’s risk by targeting both pathways.

“Since two mechanisms apparently exist, identifying potential drug targets along these pathways could be very useful,” she says. “If drugs that influence tau could be added to those that affect amyloid, we could potentially reduce risk through two different pathways.”