Why Cassava’s Simufilam results are not a placebo effect

Any open label study without controls is subject to the reasonable criticism that any benefits seen are due to the placebo effect.  Neurologic and Psychiatric disease trials can have large (33%) placebo effects (e.g. migraine, depression).

This is very unlikely to be the case with the 1 year results of the open label trial of Simufilam in 200 patients with Alzheimer’s disease.  “47% of patients improved on ADAS-Cog over 1 year, and this group improved by 4.7 points”

It is based on my clinical experience with a drug for Alzheimer’s disease released 30 years ago — Tacrine (Cognex).  Initially it was touted as helping Alzheimer’s disease (e.g. improving thinking and memory) although later it was held to slow the decline.   The local medical school advertised it aggressively (primarily as a marketing device).

So I put my Alzheimer patients on Cognex.  I wanted them to get better. They wanted to get better, and their families and caregivers certainly did.  Just about all of them thought it might have helped on followup visits in the first month.  I couldn’t see much difference.  By the second month, they weren’t sure, and later in the first year they didn’t think it helped, and most weren’t using the drug after 1 year.

Not only that, but I was in a call group with 4 other neurologists, and they saw exactly the same thing.  I was practicing in an area with a catchment area of over a million people, and every local neurologist I talked to had the same experience. People thought that “Cognex helped” for a month or two and then they didn’t

This a classic example of a placebo effect.  Moreover it occurred in a therapeutic trial for Alzheimer’s disease.  Crucially, the placebo effect was quite transient and  absent at 1 year.

This is why the Simufilam results mentioned above are not a placebo effect.

Those not interested in neuropharmacology can stop at this point.  There were excellent clinical and theoretical reasons for the use of Tacrine.

Clinically it was apparent that drugs that blocked the effects of the neurotransmitter acetyl choline on one type of its receptors (muscarinic) profoundly impaired memory. Scopolamine is one such drug.  One of the earliest and most invariable symptoms of Alzheimer’s disease is deficient memory.

That’s the clinical part.  Here’s the theory.  So logically, increasing acetyl choline should help memory.  How to do this?  Well there are enzymes that break acetyl choline down (the acetyl cholinesterases).  So by inhibiting cholinesterases, acetyl choline levels in the brain should increase, and memory should be improved.

Impeccable logic and theory.  Unfortunately, like many such it didn’t work.

Synapses on Axons !

Every now and then a paper comes along which shows how little we really know about the brain and how it works.  Even better, it demands a major rethink of what we thought we knew.  Such a paper is — https://www.cell.com/neuron/fulltext/S0896-6273(22)00656-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627322006560%3Fshowall%3Dtrue

which I doubt you can get unless you are a subscriber to Neuron.    What [ Neuron vol. 110 pp. 2889 – 2890 ’22 ] does is pretty much prove that an axon from one neuron can synapse on an axon of another neuron.  When one neuron is stimulated the axon of another neuron fires an impulse (an action potential) as measured by patch clamping the second axon.  This happens way too fast after stimulation to be explained by volume neurotransmission (about which more later).  Such synapses are well known on the initial segment of the axon as it leaves the cell body (the soma) of the neuron.

But these synapses occur very near to the end of the axon in the part of the brain (the striatum) the parent neuron (a midbrain dopamine neuron) innervates (the striatum).   The neurotransmitter involved is acetylcholine and the striatum has lots of neurons using acetylcholine as a neurotransmitter.  There are two basic types of acetylcholine receptor in the brain — muscarinic and nicotinic.  Muscarinic receptors are slow acting and change the internal chemistry of the neuron.  This takes time.  Nicotinic receptors are ion channels, and when they open, an action potential is nearly immediate.  Also using a drug to block the nicotinic acetyl choline receptor, blocks action potential formation after stimulation.

Why is this work so radical? (which of course means that it must be repeated by others).  It implies that all sorts of computations in the brain can occur locally at the end of an axon, far away from the neuron cell body which is supposed to be in total control of it.  The computations could occur without any input from the cell body, and spontaneous activity of the axons they studied occur without an impulse from the cell body.   If replicated, we’re going to have to rethink our models of how the brain actually works.  The authors note that they have just studied one system, but other workers are certain to study others, to find out how general this.

Neuropil, is an old term for areas of the brain with few neuron or glial cell bodies, but lots of neural and glial processes.  It never was much studied, and our brain has lots of it.  Perhaps it is actually performing computations, in which case it must be added to the 80 billion neurons we are thought to have.

Now for a bit more detail

The cell body of the parent neuron of the axon to be synapsed on uses dopamine as a neurotransmitter.  It sits in the pars compacta of the substantia nigra a fair piece away from the target they studied. “Individual neurons of the pars compact are calculated to give rise to 4.5 meters of axons once all the branches are summed”  — [ Neuron vol. 96 p. 651 ’17 ].”  These axons release dopamine all over the brain, and not necessarily synapsing with a neuron.  So when that single neuron fires, dopamine is likely to bathe every neuron in the brain.This is called volume neurotransmission which is important because the following neurotransmitters use it — dopamine, serotonin, acetyl choline and norepinephrine. Each has only a small number of cells using them as a transmitter.  The ramification of these neurons is incredible.

So now you see why massive release of any of the 4 neurotransmitters mentioned (norepinephrine, serotonin, dopamine, acetyl choline) would have profound effects on brain states.  The four are vitally involved in emotional state and psychiatric disease. The SSRIs treat depression, they prevent reuptake of released serotonin.  Cocaine has similar effects on dopamine.  The list goes on and on and on.

Axons synapsing on other axons is yet another reason to modify our rather tattered wiring diagram of the brain — https://luysii.wordpress.com/2011/04/10/would-a-wiring-diagram-of-the-brain-help-you-understand-it/