Applying insights from novel Alzheimer’s treatments to autism – mast cell stabilizers, brain cholesterol reduction, menthol, and vitamin D

 

Treating autism has many parallels with treating other complex neurological conditions like dementia or MS. You need to treat multiple individual features of the disease and then you will the greatest effect, this is called polytherapy.

·        Mast cell activation is a common feature in both autism and Alzheimer’s.

·        Neuroinflammation is a fundamental part of autism and Alzheimer’s. It looks like both menthol and vitamin D may have a role to play.

·        Impaired cholesterol metabolism in the brain is a key feature of Alzheimer’s and occurs in some autism. It can be either too much, or too little. 

An interesting new idea in Alzheimer’s research is to use a potent mast cell stabilizer called Masitinib. It is interesting because this drug has already been commercialized to treat pets.

 

Masivet UK (Kinavet US) Cancer Treatment Tablets for Dogs

 

There is great deal in this blog about mast cells and autism.

Many readers give their child cromolyn sodium, which is an excellent mast cell stabilizer, but it poorly crosses the blood brain barrier. While cromolyn sodium is effective for conditions where mast cell activity is predominantly peripheral, its limited CNS action makes it less suitable for addressing neuroimmune dysregulation in autism, or other brain-related conditions.

Ketotifen is another mast cell stabilizer and it does cross the blood brain barrier better. It has also been widely used in autism. It is cheap in some countries but expensive in others.

One known feature of mast cell activation is an impaired blood brain barrier (BBB), so some of these drugs may be more effective than expected.

Studies suggest that masitinib can cross the BBB, particularly in conditions where the BBB is disrupted (inflammation, neurodegenerative diseases, or neuroimmune disorders).

Masitinib works by inhibiting tyrosine kinases  involved in mast cell activation and degranulation. By reducing mast cell activity, it may help to mitigate neuroinflammatory processes implicated in conditions like autism, Alzheimer's disease, and indeed multiple sclerosis (MS).

For those that want an up to date summary of mast cell activation in autism there is an excellent new paper.

 

The role of mast cells (MCs) in Autism Spectrum Disorder

 

Highlights

·        Increased MC activity may be linked to the development of ASD.

·        MC mediators influence neuroinflammatory pathways that are altered in ASD.

·        MCs can interact with other immune and neuronal cells contributing to ASD symptoms.

·        The role of MC in gut permeability and microbiota dysbiosis may also underly gastrointestinal comorbidities in ASD.

·        Targeting MC activity offers promising therapeutic avenues in treatment of ASD.

 

ASD represents a multifaceted condition influenced by genetic, environmental, and immune-related factors. MCs have emerged as pivotal players in the immune processes associated with ASD, impacting neuroinflammation, autoimmunity and gastrointestinal health. They interact with other immune cells, release mediators that influence neurological processes, and help maintain the integrity of the blood-brain and gut barriers. Evidence of alterations in these processes in ASD patients, supported by extensive data from relevant animal models, has highlighted disruptions in these processes among individuals with ASD, underscoring the critical role of MCs in ASD pathology.

Current ASD treatments primarily aim at managing symptoms rather than addressing underlying mechanisms. However, targeting MC activity may represent a promising innovative approach for intervention. The development of novel MC inhibitors could significantly enhance our understanding of ASD pathobiology while potentially offering therapeutic benefits for a defined subset of individuals with ASD, improving their symptoms and quality of life.

 

Alzheimer’s research is very well funded and so we already have results from the use of Masitinib in humans.

 

Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial

Abstract

Background

Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer’s disease (AD).

Methods

Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12–25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.

Results

Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, −1.46 (95% CI [−2.46, −0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [−0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of −2.15 (97.5% CI [−3.48, −0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [−0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [−0.48, 2.50]) (representing an overall functional improvement) versus −0.81 (95% CI [−2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib’s known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.

Conclusions

Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.

 

Not surprisingly there is a similar study in MS.

 

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Discussion

Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.

 

Masitinib has already been patented to treat ALS the motor neuron disease.

 

Masitinib  for autism?

I think the people who respond to cromolyn sodium, but feel it lacks potency would be the ones who might benefit.

You either consult Prof Theoharides, or the local vet (It’s a doggy medication).

 

 

Low dose Efavirenz to activate CYP46A1 to reduce brain cholesterol 

Our reader Katya did raise the idea, a few months ago, of low dose Efavirenz to lower cholesterol in the brain.

Elevated cholesterol in the brain is a feature of some specific variants of autism.

Elevated brain cholesterol is a contributing factor in many cases of Alzheimer's, but it is not a universal feature. It depends which version of the APOE gene the person carries.

The brain has a lot of cholesterol in it and all of it was produced there.

The brain cannot rely on peripheral cholesterol transport due to the blood-brain barrier. The enzyme CYP46A1 ensures local cholesterol balance in the brain, by facilitating clearance of excess cholesterol to maintain healthy neuronal and synaptic functions.

Proper cholesterol metabolism, facilitated by CYP46A1, supports synaptic remodeling, plasticity, and repair, which are critical for cognitive function.

Dysregulated cholesterol levels in the brain can impair synapse function, and CYP46A1 helps prevent these disruptions.

Efavirenz is a drug used in the treatment of HIV. Interestingly, at subtherapeutic doses, it has been shown to activate CYP46A1 and so increase cholesterol clearance from the brain.

 

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease

Background

Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. 

Methods

This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.

Results

In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects.

Conclusions

Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology.

 

It looks like 50mg a day of efavirenz is an effective option to reduce levels of cholesterol in the brain. Interestingly it is not effective in people already taking a high dose of atorvastatin. This should not be a surprise since atorvastatin will have already lowered cholesterol in the brain.

So to lower cholesterol in the brain you could use the 50mg of efavirenz, or if that was not possible then 40mg of atorvastatin  would be an option. The trial showed using both drugs together was pointless.

  

First patient completes new trial to test Alzheimer’s medication

13 March 2025

The existing HIV medication Efavirenz may potentially also be effective for Alzheimer’s patients, Vrije Universiteit Amsterdam neuroscientist Rik van der Kant and Amsterdam UMC neurologist Jort Vijverberg discovered. This fall, a clinical trial has begun at Amsterdam UMC, and the first patient has just completed the trial.

Participants are still being recruited. The research is led by Rik van der Kant and Jort Vijverberg (Amsterdam UMC - Alzheimer Center Amsterdam). Van der Kant has been researching new drugs for Alzheimer’s disease for years, using groundbreaking technology that allows him to test hundreds of potential medications simultaneously. 

Promising step  
“I discovered that cholesterol buildup in brain cells of Alzheimer’s patients directly leads to an accumulation of the toxic proteins Tau and Amyloid,” Van der Kant explains. “Efavirenz turned out to be suitable for reversing this buildup. It's very special and unique to be able to do all of this ourselves, within the walls of Amsterdam UMC." Vijverberg is also hopeful. “We are very curious to see how this medication will work in Alzheimer's patients. Of course, we still have to see the results, but I consider it a promising step in the right direction.” 

 

The Alzheimer’s APOE story

Apolipoprotein E (APOE) plays a critical role in lipid transport and cholesterol homeostasis in the brain. It facilitates the redistribution of cholesterol and other lipids between cells for membrane repair, synaptogenesis, and other neuronal functions.

In the brain, APOE interacts with specific receptors, such as the low-density lipoprotein receptor (LDLR), to regulate cholesterol and amyloid-beta (Aβ) clearance.

APOE Variants:

There are three major alleles of the APOE gene: ε2, ε3, and ε4, which encode the respective protein isoforms.

APOE ε2: Rare and protective against AD.

APOE ε3: The most common variant with neutral risk for AD.

APOE ε4: A strong genetic risk factor for AD.

 

APOE ε4's Impact on Cholesterol and Aβ

Reduced Cholesterol Transport: APOE ε4 is less efficient in binding and redistributing cholesterol compared to APOE ε3 or ε2. This inefficiency can lead to local cholesterol dysregulation in the brain, particularly in neurons and astrocytes.

APOE ε4 is less effective in promoting Aβ clearance via receptor-mediated pathways (e.g., LDLR, LRP1).

The isoform is associated with an increased tendency of Aβ peptides to aggregate, contributing to plaque formation. 

Cholesterol Accumulation and AD Pathogenesis:

Elevated cholesterol levels in neuronal membranes can favour the activity of β- and γ-secretases, enzymes involved in Aβ production.

The inefficient lipid transport by APOE ε4 exacerbates cholesterol accumulation in affected brain regions, creating a feedback loop that promotes amyloidogenic processing.

 

 

Vitamin D in Alzheimer’s and Maternal Immune Activation Autism

Vitamin D’s role in Alzheimer’s disease has been widely studied, with growing evidence suggesting it may influence risk and progression, but it is not a cure or primary treatment.

Vitamin D appears to have a supportive role in brain health, potentially lowering the risk or slowing progression of Alzheimer’s disease by reducing inflammation, aiding amyloid clearance, and protecting neurons. However, vitamin D alone is not a standalone treatment for AD. Ensuring adequate vitamin D status is a simple, low-risk strategy that could contribute positively as part of a broader approach to brain health and dementia prevention.

In Japan researchers have recently found that they can prevent autism caused by maternal immune activation simply by giving a vitamin D supplement during pregnancy. This was in a mouse model, but what about its use as yet another method to prevent/reduce some human autism?

 

Supplementing with Vitamin D during Pregnancy Reduces Inflammation and Prevents Autism-Related Behaviors in Offspring Caused by Maternal Immune Activation 

Autism spectrum disorder (ASD), a neurodevelopmental disorder of unknown etiology with limited treatment options, has emerged as a significant public health concern. Studies have demonstrated that prenatal vitamin D deficiency is a risk factor for ASD development in offspring; however, the underlying mechanism remains unclear. In this project, vitamin D was administered orally to pregnant mice with/without the subsequent administration of polyriboinosinic polyribocytidylic acid (Poly(I:C)), which induced the maternal immune activation (MIA). Our results showed that vitamin D supplementation during pregnancy alleviated MIA-induced ASD-like behaviors in offspring. Moreover, vitamin D supplementation reduced the MIA-induced elevation of interleukin-6 (IL-6) and IL-17a levels in both the maternal ileum and fetal brains. It also suppressed signal transducer and activator of transcription 3 (Stat3) activation and the elevated expression of serum amyloid A1 and A2 (SAA1/2) in the ileum of MIA-affected pregnant mice. This study revealed that vitamin D may reduce the expression of IL-17a by inhibiting the IL-6/Stat3/SAA signaling pathway, thereby improving ASD-like behavior in offspring mice, and provide a new theoretical support for the prevention and treatment of ASD by scientific dietary interventions and nutritional supplement during pregnancy.

 

 

 

Menthol for Alzheimer’s and some Autism? 

I recall one reader, I think is was Natasa in London, mentioned that menthol should be a helpful autism therapy for some people. I see today that Nestle even holds an old patent on its use for autism.

The surprise is that just inhaling the smell of menthol has an anti-inflammatory effect in the mouse model of Alzheimer’s. 

 

Surprise Link Between Menthol And Alzheimer's Found in Mice

In recent years, scientists discovered something strange: When mice with Alzheimer's disease inhale menthol, their cognitive abilities improve.

It seems the chemical compound can stop some of the damage done to the brain that's usually associated with the disease.

In particular, researchers noticed a reduction in the interleukin-1-beta (IL-1β) protein, which helps to regulate the body's inflammatory response – a response that can offer natural protection but one that leads to harm when it's not controlled properly.

The team behind the study, published in April 2023, says it shows the potential for particular smells to be used as therapies for Alzheimer's. If we can figure out which odors cause which brain and immune system responses, we can harness them to improve health.

"The results suggest that odors and immune modulators may play an important role in the prevention and treatment of Alzheimer's and other diseases related to the central nervous system." 

 

Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells

 

 

 

 

Patent - Treatment or prevention of autism disorders using menthol, linalool and/or icilin

Current Assignee: Societe des Produits Nestle SA

 

Compositions for treatment or prevention of autism disorders are provided, and the compositions contain a therapeutically effective amount of a compound selected from the group consisting of Menthol, Linalool, Icilin and combinations thereof. Methods for treatment or prevention of autism disorders are also provided, and the methods include administering such compositions.

 

Menthol has shown promising effects in modulating inflammatory pathways, including those involving IL-1β and the NLRP3 inflammasome.

Menthol and IL-1β

• Menthol inhibits the production and release of pro-inflammatory cytokines, including IL-1β, which is a key mediator in various inflammatory conditions.
• Menthol primarily acts through transient receptor potential melastatin 8 (TRPM8) channels. Activation of TRPM8 can indirectly reduce inflammation by modulating neural and immune pathways.

Menthol and the NLRP3 Inflammasome

• Studies indicate that menthol may inhibit the activation of the NLRP3 inflammasome, a multiprotein complex responsible for IL-1β maturation and release.
• Menthol's ability to suppress oxidative stress and calcium influx, both of which are critical for NLRP3 activation, contributes to its anti-inflammatory effects.
• These properties make menthol a potential therapeutic candidate for diseases where the NLRP3 inflammasome plays a role, such as neurodegenerative diseases, autoimmune conditions, and metabolic disorders.

 

Conclusion

It looks like keeping an eye on research across a broad range of neurological conditions is a wise idea, if you want to treat autism.