Introduction
I am picking up my previous work to assess the Alzheimer’s space today, with a particular focus on INmune Bio, as the company is now heading into crucial times, with a readout of topline data of its placebo-controlled Phase 2 trial scheduled for the coming months.
Expect several updates over the course of the coming months.
I have also started a free discord chatroom for discussion purposes: https://discord.gg/JEA8r7wCGY
On myelin, white matter and oligodendrocytes
Alzheimer’s has been historically described as a dementia with the presence of amyloid pathology and neurofibrillary tau tangles. Chronic neuroinflammation is a more recent hallmark.
One aspect that appears overlooked by literature is the impact of myelin in the disease. For reference, the amount of publications on Alzheimer’s disease on PubMed related to amyloid and tau is about 50x the amount of publication on myelin.
That is limited, knowing that the half of the brain’s function consists of white matter. So what is white matter, as opposed to grey matter? White matter represents the wires in our brain, the axons, which are covered by a fatty sheath of myelin which gives them their typically white color.
About 60% of the entire brain consists of white matter, meaning it is a subject not to be ignored.
Together, they ensure macro-connectivity of the brain. Without such connectivity, there would not be normal brain function.
White matter is organized in bundles – tracts – which connect different parts of the brain. This is an example of such tracts.
The myelin sheath is understood to be primarily managed by specific cells of the immune system, namely oligodendrocytes. They interact with microglia and astrocytes, the more abundant immune cells of the CNS.
The fatty sheath which is myelin consist of lipids and proteins. The APOE gene regulates lipid metabolism. The APOE4 allele is by far the strongest genetic risk factor for sporadic Alzheimer’s disease, which accounts for 95% of all Alzheimer’s cases. APOE4 is expressed in more than half of all Alzheimer’s disease patients (more on that in my previous blog: on fast-progressors in AD, APOE4, TREM2 and EMACC), suggesting an important role for lipid metabolism in the disease. Given the vast amount of white matter in the brain, lipid metabolism dysregulation may be implicated in disease progression.
XPro matters to myelin
Multiple sclerosis is generally considered a white matter disease. In 2021, INmune Bio’s CEO RJ Tesi put out an opinion piece in which he argued that Alzheimer’s disease should be approached as a white matter disease, and not a gray matter disease.
I believe that opinion piece was based on:
- previous understandings, such as the demyelination occurring in Alzheimer’s disease;
- XPro’s promotion of remyelination, as compared to the demyelination seen with traditional TNF inhibitors;
- the concrete impact of XPro as seen in the Phase 1 study.
So what exactly did INmune see in the Phase 1 study?
First of all, rapid onset of recovery. A cognitive recovery contrary to normal progression of disease so rapid, and supported by biomarkers, that one would consider that this does not just concern repair of neurons – where memories are stored.
If a treatment would allow prevention of further decline, one could argue that future death of neurons is prevented.
If a treatment would allow restoration of memory, i.e. not just prevention of further decline, one would have to revise that thesis. Apparently, there must be situations where the memories are not gone yet, but that their connections are failing.
XPro induced a 16% reduction of radial density over the course of 12 months of treatment, which occurred mostly as of the three-month timepoint. A reduction of radial density means remyelination is occurring, contrary to further demyelination as seen in normal Alzheimer’s patients To be clear, like axonal integrity, remyelination is the result of treatment. One could consider it a biomarker as it does not test cognition, but I see it as a measure showing concrete effect of treatment. With effects showing as of the three-month timepoint, the onset is rapid.
In different webinars on the matter, INmune stated that particularly the arcuate fasciculus, a white matter brain region critical in language, saw a dramatic (40.6%) reduction of neuroinflammation following XPro treatment.
Earlier improvement, such as improvement in brainwaves following 4 weeks of XPro therapy, had been noted as well. Patients who received weekly XPro™ treatment for four weeks had a statistically significant increase in Alpha wave frequency and power (p<0.05). Reduced Alpha power is linked with cognitive decline and the progression of Alzheimer’s Disease. Alpha waves represent synchronized brain network activity that are essential for internal functions like mental arithmetic, short-term and working memory, and visual-spatial mental imagery exercises. In individuals with AD, Alpha wave power is diminished due to the breakdown of brain networks associated with degeneration.
XPro has also been shown to have a dose-dependent effect on proteins that regulate synapses in Alzheimer’s Patients after a 12-week treatment.
Rethinking progression to neuron death
The traditional thinking is that amyloid plaques and neurofibrillary tangles somehow cause the death of neurons. That thinking is derived from the presence of amyloid plaques and neurofibrillary tangles in the brains of persons with Alzheimer’s disease, at the time of their death.
Perhaps in earlier stages of the disease, the damage occurs more in the myelin sheath and axons. There is recent literature supporting that idea, for example:
“Surprisingly, the levels of these genes rank highest in oligodendrocytes compared to other cell types. […] Approximately 80% of oligodendrocytes express both APP and BACE1, indicating their capability to produce Aβ.”
- Literature suggesting that oligodendrocytes are the missing link in AD (note: the last quoted piece is by Prof. Karl Herrup, author of ‘How not to study a disease’, which I will cover in an upcoming blog post).
So how would this work in practice, and how could inhibiting of soluble TNF be related? That’s where a 2024 publication on the effects of XPro on myelination comes in.
The 2024 study showing XPro promotes remyelination
A Greek study, the results of which have been published in 2024, had tested whether XPro could indeed provoke remyelination in a demyelinating disease model. Logically the impact of such an investigation could have implications beyond Alzheimer’s, if results were to be positive.
The study can be found here, and a previous webinar can be found here. The pictures below are from the webinar. The study showed that soluble TNF converts microglia – my blog post on microglia – from a reparative, remyelinating cell to a damaging, demyelinating cell.
I am repeating that: in 2024, it has been established that soluble TNF – the bad TNF – is responsible for the signaling that moves microglia from a nurturing remyelination phenotype away to a damaging demyelinating phenotype.
Hence, blocking soluble TNF is a promising strategy for treating demyelinating diseases. The slide below shows how XPro enhances remyelination in this preclinical model – further confirming what had been seen in the Phase 1 study.
The study then proceeded to investigating how this pro-myelinating effect was established, and found out that as of week three, there was a huge astrocytic activation, and enhanced microglial responses.
“Together, the results show that pharmacological inhibition of solTNF increases early microglia and astrocyte activation, microglia phagocytosis of myelin debris, and OPC differentiation in response to cortical demyelination, effects that lead to improved remyelination.”
Obviously, the immune system of the CNS as a whole is reacting positively to inhibition of soluble TNF by XPro.
Microglial responses were also seen to be preceding increased remyelination.
The study furthermore showed that, when the receptor for soluble TNF was deleted on microglia, the same effects were seen as those seen when inhibiting soluble TNF, namely promotion of remyelination associated with accelerated improvement of motor performance, contrary to reduction of remyelination and impaired functional recovery following demyelination.
Logically, INmune Bio’s Phase 2 trial will be assessing whether remyelination occurs in the Phase 2 trial, and if so, to which extent:
There is no competitor that I am aware of that is looking at white matter as such as a marker for (the progression or recovery of) Alzheimer’s disease.
Conclusion
Putting the pieces together, the drastic cognitive effects seen in the Phase 1 trial of XPro mayd be related to the rapid recovery of the myelin sheath insulating axons.
Oligodendrocytes, microglia and astrocytes all seem to be implicated in that process.
Myelin is everywhere in the brain: white matter accounts for 60% of the brain, and is organized in white matter tracts that connect different brain regions. Oligodendrocytes are primarily involved in creating myelin, but may also be implicated in production of amyloid.
XPro is the only TNF inhibitor that allows for remyelination.
The rapid-onset recovery of memory as seen in patients indicates that although their cognitive abilities had been impaired prior to treatment, their neurons were not yet gone, suggesting that remyelination may be implicated in their recovery.
Contrary to the normal course of disease, treatment on XPro led to a 16% reduction of radial diffusivity, a marker for remyelination, over the course of one year of treatment, with onset after three months.
A 2024 study has confirmed that treatment with XPro promotes remyelination and leads to fast-onset effects on microglia and astrocytes. Inhibition of the receptor for soluble TNF equally promotes remyelination.
From different angles, therefore, inhibition of soluble TNF by XPro appears to be a good therapeutic approach for the treatment of Alzheimer’s disease, with rapid-onset effects.
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