Beyond Profound Autism - Towards More Useful Ways to Classify Autism

 

A new paper continues to refine the concept of Profound Autism to define how should we describe autistic people who require lifelong, round-the-clock care. 

Developing a consensus research definition for profound autism using a modified Delphi method

 

Using a modified Delphi process involving researchers, clinicians, caregivers and autistic individuals, the authors developed a consensus research definition of profound autism. Their goal is admirable. By encouraging researchers to use a common definition, studies become easier to compare and the subgroup with the greatest support needs is less likely to be overlooked.

I welcome that goal, but …

 

Research definition or clinical reality?

The authors are careful to emphasise that "profound autism" is intended as a research definition rather than a new clinical diagnosis.

That distinction is important.

Researchers need consistent definitions so that studies include comparable participants. A research definition helps ensure that one study of "profound autism" is investigating a similar population to another.

Parents, however, have often been asking for something completely different.

Many families caring for autistic people who require lifelong support argue that the autism spectrum has become so broad that it no longer communicates the reality of their child's disability. They are looking for terminology that helps explain prognosis, support needs and, in some countries, eligibility for services.

A research-only definition does not solve those problems.

Indeed, by combining autism severity, intellectual disability and adaptive functioning into a single category, it may create new sources of confusion outside the research setting.

 

This is in marked contrast to Asperger's syndrome. In 1994, Asperger's syndrome was introduced into the DSM-IV as a recognised clinical diagnosis, not merely as a research category. It was used by clinicians, educators and families to describe a distinctive presentation of autism. When it was removed in 2013 and absorbed into the broader diagnosis of Autism Spectrum Disorder, the spectrum expanded to encompass individuals ranging from those living entirely independently to those requiring lifelong, round-the-clock care.

It is therefore unsurprising that researchers are once again looking for ways to subdivide this very broad spectrum.

However, unlike Asperger's syndrome, profound autism is not intended to become a clinical diagnosis. It is a tool for research, not for clinical practice.

Perhaps what is really needed are two complementary frameworks:

·        A research framework that allows scientists to compare studies using consistent and well-defined populations.

·        A clinical framework that describes an individual's autism severity, intellectual ability, adaptive functioning, language, medical complications and support needs separately.

The second approach may be far more useful for families because it paints a richer and more accurate picture of the individual than any single label ever could.

The authors deserve credit for recognising that the current autism spectrum has become too broad for many research questions and their perseverance. Whether "profound autism" is the best way to address that problem remains open to debate, but they have undoubtedly started an important conversation.

How Has the Diagnosis Changed?

It is easy to forget how much the diagnosis of autism has changed over the past quarter of a century.

In 2000, clinicians were still using the DSM-IV classification, which recognised several distinct pervasive developmental disorders: Autistic Disorder, Asperger's syndrome and PDD-NOS (Pervasive Developmental Disorder – Not Otherwise Specified).

To receive a diagnosis of Autistic Disorder, a child had to meet at least six diagnostic criteria spanning social interaction, communication and restricted or repetitive behaviours, with symptoms present before three years of age. Most children diagnosed with Autistic Disorder had significant language delay, many had intellectual disability, and a large proportion required substantial lifelong support.

By contrast, individuals with average or above-average intelligence and no clinically significant language delay were generally diagnosed with Asperger's syndrome, while those who showed autistic features but did not fully satisfy the criteria for either diagnosis often received a diagnosis of PDD-NOS.

This changed dramatically in 2013 when DSM-5 replaced these separate diagnoses with a single diagnosis of Autism Spectrum Disorder (ASD). The intention was to improve diagnostic consistency, recognising that there were no clear biological boundaries separating the previous categories. However, the consequence was the creation of an exceptionally broad diagnostic spectrum.

Today, the same diagnosis encompasses people living entirely independently—including university professors, engineers, scientists and other professionals—as well as individuals who cannot communicate verbally, require assistance with every aspect of daily living and need lifelong, round-the-clock care.

This historical perspective helps explain why researchers are once again attempting to identify meaningful subgroups within autism. In many respects, the proposal for profound autism represents an effort to recover some of the distinctions that were lost when Asperger's syndrome and PDD-NOS were merged into a single spectrum. 

Why do we need a better classification of autism?

Autism has become an extraordinarily broad diagnosis.

At one end of the spectrum are university professors, software engineers, airline pilots and people who require little or no formal support.

At the other end are individuals who cannot communicate verbally, cannot dress or feed themselves, may have epilepsy, severe gastrointestinal disease, self-injurious behaviour and require lifelong supervision.

Although these individuals all satisfy the behavioural criteria for autism spectrum disorder, they clearly do not represent the same clinical condition.

When research studies combine such diverse populations under one diagnostic label, interpreting the results becomes increasingly difficult. A treatment that benefits one subgroup may have no effect—or even be harmful—in another.

Recognising this enormous heterogeneity is one of the greatest strengths of the new paper.

 

The proposed definition of profound autism

After two rounds of expert consultation, the Delphi panel proposed that profound autism should be defined by several key characteristics.

The individual should:

• meet the diagnostic criteria for autism spectrum disorder
• be at least eight years old
• require continuous adult supervision to ensure health, safety and wellbeing
• demonstrate adaptive functioning well below age expectations

and also have either:

• severe intellectual impairment (typically reflected by an IQ below 50), or
• minimal verbal communication, consisting mainly of single words or fixed phrases used to communicate basic needs.

Importantly, this is intended as a research definition, not a new clinical diagnosis.

The intention is not to create another subtype of autism but to ensure that studies investigating those with the highest support needs are describing comparable populations.

That is an entirely reasonable objective.

 

What the Paper Gets Right

Several aspects of the paper deserve praise.

First, it openly acknowledges that autism is not one disorder.

The current autism spectrum encompasses people with enormously different abilities, medical problems, educational outcomes and support requirements.

Recognising that these individuals should not always be analysed together is long overdue.

Secondly, the authors move away from relying solely on IQ.

Instead, they give much greater emphasis to adaptive functioning—the practical skills needed for everyday life.

Being able to dress, wash, communicate needs, recognise danger, prepare food or manage daily routines often determines independence far more than an IQ score.

In many ways, adaptive functioning is a better measure of the help a person actually requires.

Finally, the authors recognise that research involving those with the greatest support needs has declined over recent decades.

That imbalance deserves to be corrected.

 

Where I think the definition falls short

Although I agree with the motivation behind the paper, I am less convinced by the solution.

My concern is that the proposed definition combines three different concepts into a single label:

• autism severity
• intellectual disability
• adaptive functioning

These are related, but they are not identical.

A person may have extremely severe autistic symptoms while having an IQ of 120.

Another may have equally severe autistic symptoms together with profound intellectual disability.

A third may have only moderate autistic features but such poor adaptive functioning that lifelong supervision is still required.

These individuals have very different developmental trajectories, medical needs and treatment priorities.

Grouping them together under one behavioural label risks obscuring those important differences.

 

James Coplan's alternative framework

More than twenty years ago, pediatric neurologist James Coplan proposed a remarkably elegant way of thinking about autism prognosis. I wrote about it in my book on page 90.

Instead of asking a single question—

"How severe is the autism?"

—he separated prognosis into independent dimensions.

His framework considered:

• severity of autistic features
• intellectual ability
• age

 

 

 

 

 

His diagrams illustrate two children who initially appear equally autistic.

Child A has profound intellectual disability.

Child B has normal intelligence.

Both improve with age and both still have autism. But child B’s intelligence allows him to break up the troubling aspects of autism into smaller more manageable pieces. Child A never manages to overcome these barriers and remains disabled.

Their long-term outcomes become completely different.

The difference is not autism alone.

It is autism combined with intellectual disability.

I have always thought this framework was one of the clearest ways of explaining why prognosis varies so enormously across the autism spectrum.

If I were updating Coplan's model today, I would start with a fourth independent dimension, adaptive functioning. Later we can add some additional dimensions to narrow down sub-groups of autism.

 

 

 

 

Autism severity is not the same as IQ

One recurring source of confusion is the assumption that severe autism automatically means low intelligence. It does not.

Many autistic people experience severe sensory difficulties, severe social disability and marked repetitive behaviours while having average, or even exceptionally high, IQ.

Conversely, many autistic people also have severe intellectual disability.

These are different dimensions.

This distinction matters because one reason the term "profound autism" has generated debate is that many autistic people with severe autistic symptoms but normal intelligence feel it reinforces the misconception that intellectual disability is simply part of autism, rather than a common but separate co-occurring condition.

The authors of the Delphi paper were clearly aware of this problem.

Interestingly, the expert panel could not reach consensus on the most appropriate IQ threshold.

An IQ below 50 received the greatest support but still failed to reach the predefined level required for formal consensus.

That illustrates just how difficult it is to reduce a complex clinical picture to a single number.

 

The taboo of low IQ

One recurring issue when discussing autism today is the reluctance to talk openly about impaired cognitive function, or low IQ.

This is not an entirely new phenomenon. In 1973 the IQ threshold traditionally associated with what was then called mental retardation (now intellectual disability) became more stringent. Whereas an IQ below about 80 had been used previously, the emphasis shifted to an IQ below 70, approximately two standard deviations below the population mean. Although this appears to be a relatively small numerical change, it reduced the proportion of the population meeting the criterion from roughly 16% to about 2.3% today.

Today we seem to be moving in opposite directions. The diagnostic boundaries for autism and ADHD have broadened considerably, while the definition of intellectual disability become narrower.

Unfortunately, IQ has become an uncomfortable subject. Rather than asking why some children have impaired cognitive development—and whether it might be prevented or treated—we often focus on finding more acceptable terminology, such as intellectual disability or learning difficulty. Changing the name may reduce stigma, but it does not change the underlying biology.

IQ is not determined by genetics alone. It is influenced by prenatal health, nutrition, education, environmental factors and many medical conditions. The remarkable increase in average IQ observed in countries such as South Korea over the past several decades demonstrates that cognitive performance can improve substantially across a population as living conditions, health and education improve.

South Korea provides one of the world's clearest examples of how environmental factors can influence measured cognitive ability. During the country's rapid economic development, researchers documented exceptionally large gains in IQ test performance—around 7–8 points per decade for cohorts born between 1970 and 1990. These gains are far too rapid to be explained by genetics and instead reflect the powerful effects of improved nutrition, healthcare, education and childhood development.

Average IQ in sub-Saharan Africa is reported to be around 80, but it is not a politically correct subject to discuss.

Perhaps the most encouraging development is the growing recognition that some forms of intellectual disability are treatable. This indeed ended up being one of the goals of my son’s autism therapy.

I was surprised to later discover the excellent Treatable-ID.org project, which catalogues hundreds of inherited metabolic and genetic disorders in which early diagnosis and targeted treatment can prevent or reduce intellectual disability. The database is not yet complete, but it highlights how understanding the biology of cognitive impairment can lead to meaningful interventions.

Parents often face a difficult dilemma. When applying for educational or social support, they may need to provide evidence that their child has intellectual disability. Yet, understandably, they also want to emphasise their child's strengths and abilities. That tension can make honest discussions about cognitive ability surprisingly difficult.

Ultimately, our goal should not simply be to find kinder terminology. It should be to understand why intellectual disability develops and, wherever possible, to prevent or treat it.

 

CARS, IQ and Adaptive Functioning Measure Different Things

One lesson from this discussion is that we should stop expecting a single measurement to describe everything.

Autism researchers already have well-established tools for measuring different aspects of an individual's condition.

The Childhood Autism Rating Scale (CARS) is widely used in clinical trials to quantify the severity of autistic symptoms. It allows researchers to determine whether a treatment has reduced the core behavioural features of autism.

IQ tests measure cognitive ability.

Adaptive behaviour scales, such as the Vineland Adaptive Behavior Scales, measure how well a person functions in everyday life.

Language assessments measure communication.

These are not competing measurements.

They answer different questions.

 

Question	Measurement Tool	What It Isolates
How severe are the autistic features?	CARS (Childhood Autism Rating Scale)	Core behavioral features & symptom severity
How well does the brain solve problems?	IQ Tests	Cognitive and intellectual ability
How independently can the person function?	Vineland (Adaptive Behavior Scales)	Practical, real-world everyday life skills
How well can they communicate?	Language Assessment	Structural and functional communication levels

 

No single score can replace the others.

For example, two children may both have a CARS score of 46, indicating similarly severe autistic symptoms.

One may have an IQ of 110.

The other an IQ of 35.

Their autism severity is similar.

Their prognosis is not.

Likewise, two people with identical IQs may have very different adaptive functioning. One may travel independently and prepare meals, while another may require constant supervision because of poor judgement or inability to communicate in dangerous situations.

Each measurement adds a different piece of the puzzle.

Although adaptive functioning may ultimately predict support needs better than IQ, IQ remains a concept that most people readily understand. Saying that someone has an IQ below 50 immediately conveys severe cognitive impairment. Saying that adaptive functioning is "three standard deviations below the mean" is scientifically precise but far less intuitive.

For parents, describing an eight-year-old as having adaptive skills comparable with those of an eighteen-month-old child may actually communicate the situation more clearly, even though psychologists generally avoid age-equivalent scores because of their statistical limitations.

Rather than trying to compress all of these dimensions into a single label, we should recognise that each contributes valuable information.

 

What About Self-Injury and Aggression?

One of the most surprising findings from the Delphi process is not what was included—but what was deliberately excluded.

The expert panel decided that self-injurious behaviour (SIB), aggression and other severe challenging behaviours should not form part of the definition of profound autism.

Their reasoning is understandable.

Although these behaviours are common among autistic people requiring lifelong care, they are not universal. Some profoundly disabled autistic people never become aggressive or self-injurious, while others with less severe intellectual impairment do.

From the perspective of defining a research population, that makes sense.

However, from the perspective of improving lives, I think something important risks being overlooked.

Self-injury and severe aggression are among the greatest causes of:

• family stress
• school exclusion
• psychiatric admission
• physical injury
• use of restrictive practices
• reduced quality of life

These behaviours are not simply unfortunate complications.

They are major clinical problems in their own right.

They also almost certainly represent important biological processes that deserve investigation.

Whether driven by pain, epilepsy, anxiety, executive dysfunction, sensory overload, catatonia, immune activation or other mechanisms, severe behavioural dysregulation should not disappear from autism research simply because it does not define a diagnostic subgroup.

Instead, it should become a major research priority.

 

Towards a Multidimensional Framework

Rather than inventing another umbrella label, I believe autism research would benefit from routinely describing individuals across several independent dimensions.

For example:

Dimension	Example measure
Autism severity	CARS-2
Intellectual ability	IQ
Adaptive functioning	Vineland
Language	Single words, phrases, fluent speech
Behaviour	Self-injury, aggression, catatonia
Medical complexity	Epilepsy, gastrointestinal disease, sleep disorder
Development	Age and developmental trajectory

 

This immediately creates a far richer description than any single label.

Instead of saying:

"This study included children with profound autism."

Researchers could report:

• Mean CARS score
• Mean IQ
• Mean adaptive functioning
• Language level
• Prevalence of epilepsy
• Frequency of self-injury
• Frequency of aggression
• Presence of regression
• Known genetic diagnoses

Readers would immediately understand precisely which population had been studied.

 

 

 

Then, for example, we have some Aspies with IBD (irritable bowel disease). The IBD does share a biological basis with their autism. Treat the IBD and watch their autism symptoms mellow.

The future lies in studying better subgroups

Perhaps the greatest opportunity is not to invent another autism label, but to identify clinically and biologically meaningful subgroups.

Many of these already exist.

Examples include:

• Autism with profound intellectual disability
• Autism with average or high intelligence
• Autism with severe self-injury
• Autism with severe aggression
• Autism with epilepsy
• Autism with catatonia
• Autism with developmental regression
• Autism associated with mitochondrial dysfunction
• Autism with severe gastrointestinal disease
• Autism with chronic sleep disorders
• Autism associated with immune dysregulation
• Autism following hypoxic brain injury
• Autism following congenital infection
• Autism associated with connective tissue disorders
• Autism associated with specific genetic syndromes such as SCN2A, SHANK3, CACNA1C, SCN8A, SYNGAP1, Phelan-McDermid syndrome, Rett syndrome, Fragile X syndrome, Tuberous Sclerosis Complex and many others.

 

Even these subgroups are not mutually exclusive.

A child may belong to several simultaneously.

That is perfectly acceptable.

The purpose is not to create dozens of new diagnoses.

The purpose is to identify people who are likely to share similar biology—and therefore similar treatment opportunities.

Interestingly, autism research is already moving in this direction.

Clinical trials increasingly recruit specific subgroups rather than "all autism."

Examples include:

• minimally verbal autism
• autism with epilepsy
• Fragile X syndrome
• Rett syndrome
• tuberous sclerosis
• Phelan-McDermid syndrome
• SCN2A-related autism

The field has already recognised that autism is biologically heterogeneous.

Perhaps our classification systems should catch up.

 

Precision medicine needs better descriptions

The real promise of precision medicine is not simply to identify ever smaller genetic subgroups.

It is to understand why individuals who satisfy the same behavioural diagnosis often have completely different biology.

One child may have mitochondrial dysfunction.

Another an ion channel disorder.

Another chronic neuroinflammation.

Another an underlying metabolic disease.

Another significant prenatal hypoxic brain injury.

Behaviour alone cannot distinguish these individuals.

Yet these biological differences may determine prognosis far more accurately than behavioural scores.

They may also determine which treatments are most likely to work.

The future of autism research therefore lies not in inventing broader behavioural labels but in combining behavioural assessment with genetics, neurobiology, metabolism, electrophysiology and careful clinical phenotyping.

That is the essence of precision medicine.

 

Conclusion

The new consensus definition of profound autism represents an important step forward.

It recognises that autism encompasses individuals with enormously different abilities and support needs, and that research should no longer treat them as one homogeneous population.

I fully support that objective.

However, I am not convinced that another behavioural label is the final answer.

Autism severity, intellectual ability, adaptive functioning, language, challenging behaviour and medical complexity are all independent dimensions.

They should be measured independently.

James Coplan recognised this more than twenty years ago when he separated autism severity from intellectual ability and developmental trajectory.

Today I would simply extend that framework by adding adaptive functioning, language, behaviour and medical complexity.

Most importantly, I believe the future lies beyond behavioural classification altogether.

The greatest advances in autism research are increasingly coming from the identification of biologically meaningful subgroups—whether defined by genetics, epilepsy, mitochondrial dysfunction, immune abnormalities, catatonia, regression or other underlying mechanisms.

These subgroups are far more likely to reveal targeted treatments than any single behavioural label.

The future of autism research is therefore unlikely to be shaped by a new definition such as profound autism.

It will be shaped by understanding why two people with the same autism diagnosis can have completely different biology, completely different outcomes and, ultimately, completely different treatments.

Labels describe people. Biology explains them.

 

The average IQ of South Koreans has risen dramatically over the past half century, largely through improvements in nutrition, healthcare and education. Whether the same can be said for autism researchers is perhaps more debatable. In our enthusiasm to develop new classifications, we should not overlook the valuable work carried out decades ago. James Coplan's multidimensional framework remains remarkably relevant today and arguably aligns more closely with the goals of precision medicine than many more recent attempts to subdivide the autism spectrum. Hans Asperger was 50 years ahead of his time.

 

 

Note on Hans Asperger

A 2023 investigation concluded that there was no evidence Hans Asperger knew that Am Spiegelgrund was operating a child euthanasia programme when he referred patients there in 1941. Around 800 children were ultimately killed at the institution during the Nazi period, including two of Asperger's former patients.

https://pubmed.ncbi.nlm.nih.gov/36239413/

Following the end of the Second World War, Ernst Illing, the director of Am Spiegelgrund, was arrested and tried by an Austrian court in 1946. He was convicted of murders committed at the institution, sentenced to death, and executed by hanging on 30 November 1946.

The historical record surrounding Hans Asperger continues to be debated. New evidence should always be considered carefully, but historical interpretations should be revised only when supported by robust evidence. Replacing one oversimplified narrative with another risks introducing new biases rather than improving our understanding of the past.

It is striking that some people are deeply concerned about the former diagnosis of Asperger syndrome because of ongoing historical debates about Hans Asperger and yet many give little thought to buying products from companies with well-documented links to the Nazi regime, such as Hugo Boss, whose founder was a Nazi Party member and whose company manufactured uniforms for Nazi organisations while using forced labour during the Second World War.  

In 1938, the Nazi government even awarded Henry Ford the Grand Cross of the German Eagle, the highest honour it could bestow on a foreign civilian.

Henry Ford was a pioneering industrialist, but he also promoted antisemitic views through his newspaper, the Dearborn Independent. These articles were later collected into the four-volume series The International Jew in the early 1920s. It was translated into at least 12 languages. The writings spread antisemitic conspiracy theories about Jewish people and influenced extremist movements internationally, including Nazi Germany. Adolf Hitler openly admired Ford and mentioned him favourably in Mein Kampf. Ford was the only American mentioned positively by Hitler in Mein Kampf, and Hitler later stated that he regarded Ford as an inspiration.

It does illustrate that society often applies historical scrutiny inconsistently.

I hope Simon Baron-Cohen never bought a Ford!

Is it relevant today? Not to most people.

Can restoring the brain's waste-clearance system improve brain function in Alzheimer’s and some autism?

 

One of the most exciting developments in modern neuroscience is the growing understanding of the glymphatic system—the brain's own waste-clearance system.

This network circulates cerebrospinal fluid (CSF) through the brain, removing metabolic waste products and helping maintain a healthy neuronal environment. Remarkably, the glymphatic system is most active during deep (slow-wave) sleep, suggesting that one of sleep's most important functions is to clean the brain.

Interest in this system has exploded over the past decade because impaired glymphatic function has now been implicated in Alzheimer's disease, Parkinson's disease, traumatic brain injury, stroke and several other neurological disorders.

Increasingly, researchers are also asking whether glymphatic dysfunction contributes to autism spectrum disorder (ASD).

 

A remarkably recent discovery

One of the most surprising aspects of this story is just how new it is.

The glymphatic system was only discovered in 2012 by Professor Maiken Nedergaard and colleagues. Until then, neuroscientists knew that the brain produced metabolic waste, but nobody really understood how it was removed. Unlike the rest of the body, the brain appeared to have no conventional lymphatic system.

The discovery of the glymphatic system transformed our understanding of brain biology. Researchers showed that cerebrospinal fluid flows alongside arteries into the brain, exchanges with the fluid surrounding brain cells, and then carries away waste products before leaving alongside veins.

Only three years later, in 2015, another major breakthrough followed when researchers discovered meningeal lymphatic vessels surrounding the brain. These vessels drain fluid from the glymphatic system into the body's lymphatic system.

Together, these discoveries revealed that the brain possesses its own sophisticated waste-disposal network.

Considering that this entire field is little more than a decade old, it is remarkable how quickly it has expanded. Today, impaired glymphatic function has been linked to Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, stroke, depression, schizophrenia and, increasingly, autism.

 

Autism and the glymphatic system

Until recently, the idea that glymphatic dysfunction might contribute to autism was based largely on indirect observations.

Researchers had reported:

• enlarged extra-axial cerebrospinal fluid in some infants who later develop autism,
• enlarged perivascular spaces,
• chronic neuroinflammation,
• and the very high prevalence of sleep disorders in autism.

Now, neuroimaging studies are beginning to provide more direct evidence.

A newly published MRI study examined 78 children with autism and 48 typically developing controls using the DTI-ALPS technique, a non-invasive MRI method that estimates glymphatic activity. The investigators found significantly reduced glymphatic function in the autism group. Even more interestingly, poorer glymphatic function correlated with more severe communication difficulties and poorer visual-motor integration. Statistical modelling suggested that impaired visual-motor integration partly explained the relationship between glymphatic dysfunction and communication deficits.

Glymphatic system dysfunction in children with autism spectrum disorder as evidenced by the diffusion tensor imaging along perivascular spaces index

The authors concluded that impaired glymphatic clearance may contribute to the pathophysiology of autism and represents a promising area for future mechanistic and interventional research.

These studies do not prove that impaired glymphatic clearance causes autism. However, they do suggest that it may contribute to the biology of at least a subgroup of autistic individuals.

 

Why deep sleep matters

Perhaps the most important aspect of the glymphatic system is that it works best during deep slow-wave sleep.

During deep sleep:

• cerebrospinal fluid flows more efficiently through the brain,
• the space between brain cells expands,
• metabolic waste products are removed,
• inflammatory molecules are cleared,
• and the brain performs what is essentially its nightly housekeeping.

Sleep disturbances affect around 50–80% of autistic children, often continuing into adulthood. If glymphatic clearance depends on deep sleep, this raises the possibility that chronic sleep disruption contributes to impaired waste clearance, neuroinflammation and altered brain function, creating a vicious cycle.

This may be one reason why improving sleep often has benefits that extend well beyond simply reducing daytime fatigue.

 

Aquaporin-4: the brain's plumbing protein

The glymphatic system depends on a protein called aquaporin-4 (AQP4), which forms tiny water channels in the end-feet of astrocytes—support cells that surround the brain's blood vessels.

These channels allow cerebrospinal fluid to move efficiently between blood vessels and brain tissue, helping wash away metabolic waste products. In animal experiments, deleting AQP4 dramatically reduces glymphatic clearance, highlighting its central role in the brain's waste-disposal system.

Interestingly, several studies have reported altered AQP4 expression or localisation in autism. Although it is still unclear whether these changes are a cause or a consequence of autism, they provide another possible explanation for why glymphatic function may be impaired in at least some autistic individuals.

 

Exercise may also support the brain's cleaning system

Exercise is another intervention that may enhance glymphatic function.

Experimental studies suggest that regular physical activity can:

• improve vascular health,
• improve sleep quality,
• enhance cerebrospinal fluid dynamics,
• reduce neuroinflammation,
• and potentially improve glymphatic clearance.

Even if future studies show only modest effects on glymphatic function, exercise already has well-established benefits for cardiovascular health, cognition, mood and healthy ageing.

 

 

 A fascinating new therapeutic idea

This brings us to one of the most intriguing studies published in the last 12 months.

The influence of intermittent hypercapnia on cerebrospinal fluid flow and clearance in Parkinson’s disease and healthy older adults

Researchers investigated whether they could artificially stimulate the glymphatic system by having volunteers breathe alternating short periods of air containing 5% carbon dioxide, followed by normal air.

Rather than continuously increasing carbon dioxide, the intermittent exposure generated rhythmic expansion and contraction of cerebral blood vessels.

Brain imaging demonstrated increased cerebrospinal fluid movement, while blood tests suggested increased movement of brain-derived proteins into the circulation, consistent with enhanced glymphatic clearance.

Importantly, this was not an autism or Alzheimer's treatment study. It was a proof-of-concept experiment involving healthy older adults and people with Parkinson's disease.

Nevertheless, it demonstrated something remarkable:

The human glymphatic system appears to be modifiable.

Mimicking what happens during deep sleep

Perhaps the most fascinating aspect of the study is the proposed mechanism.

The intermittent carbon dioxide exposure generated slow vascular oscillations remarkably similar to those naturally seen during deep sleep, when glymphatic clearance reaches its maximum.

In effect, the researchers may have temporarily reproduced one of the physiological mechanisms by which deep sleep naturally cleans the brain.

That opens an entirely new therapeutic concept.

Rather than trying to remove individual proteins such as amyloid with drugs, perhaps we can improve the brain's own housekeeping system.

 

How the intermittent CO₂ therapy was performed

The researchers did not expose participants to continuous carbon dioxide. Instead, they used a carefully controlled pattern of intermittent increase in the level of carbon dioxide (CO₂) in the blood (hypercapnia). The hypercapnia was designed to create rhythmic changes in cerebral blood flow.

Interestingly, several studies have reported abnormalities in cerebral blood flow regulation in autism, including reduced blood flow in specific brain regions and altered responses of cerebral blood vessels to changing carbon dioxide levels. Since the glymphatic system depends on rhythmic vascular pulsations to drive cerebrospinal fluid through the brain, impaired vascular regulation could potentially contribute to reduced glymphatic clearance.

Participants underwent three treatment sessions, each lasting approximately 10 minutes, for a total treatment time of about 30 minutes.

During each session they repeatedly alternated between:

• 35 seconds breathing a gas mixture containing 5% carbon dioxide
• 35 seconds breathing normal air

This cycle was repeated 24 times across the three sessions. The sessions were performed during a single visit, with short breaks between them.

The rationale was that the repeated dilation and relaxation of cerebral blood vessels would generate slow vascular oscillations similar to those that naturally occur during deep slow-wave sleep, when the brain's glymphatic system is most active.

MRI scans demonstrated increased cerebrospinal fluid movement through the brain, while blood tests showed increased concentrations of several brain-derived proteins—including amyloid-β, tau, GFAP and neurofilament light—in the circulation. The researchers interpreted these findings as evidence of enhanced glymphatic clearance rather than brain injury.

 

A new way of thinking

Much autism research has focused on inflammation, oxidative stress, mitochondrial dysfunction and altered neurotransmission.

But perhaps, in some autistic individuals, these abnormalities are partly downstream consequences of impaired brain waste clearance.

Instead of asking:

Which drug treats autism?

perhaps we should also ask:

Can we restore the brain's own housekeeping system?

That strategy might include:

• protecting deep sleep
• treating sleep disorders
• exercising regularly
• maintaining good cardiovascular health
• and perhaps one day therapies that directly stimulate glymphatic flow

 

Looking ahead

This remains a hypothesis.

Neither the imaging studies nor the intermittent hypercapnia study prove that improving glymphatic function will improve autism symptoms.

However, taken together they suggest something genuinely exciting.

For the first time we now have:

• evidence that glymphatic dysfunction is present in autism,
• evidence that poorer glymphatic function is associated with more severe communication difficulties,
• and evidence that the human glymphatic system may be therapeutically stimulated.

That does not yet constitute a treatment.

But it does provide the foundations for an entirely new direction of autism research—one aimed not at treating individual downstream abnormalities, but at restoring one of the brain's most fundamental maintenance systems.

If this hypothesis proves correct, the simplest interventions may remain among the most important: protect deep sleep, exercise regularly, maintain good cardiovascular health, and treat sleep disorders whenever possible. Future research will determine whether directly stimulating glymphatic flow can add to these fundamental approaches.

While a variety of therapies are marketed as improving lymphatic drainage, there is currently no convincing evidence that they enhance glymphatic clearance in humans.