Anti-tau antibodies for the treatment of Alzheimer’s disease

One of the exciting alternatives to the amyloid immunotherapies in clinical trials for Alzheimer’s disease (AD) are anti-tau antibodies.

There are several of these drugs in earlier stages of development, although none that I know of in phase 3. To take two concrete examples, let’s focus in on BioGen’s two anti-tau immunotherapies:

• BMS-986168/BIIB092 = an humanized IgG4 monoclonal antibody targeting extracellular tau
• BIIB076 = a monoclonal antibody against both monomeric and fibrillar tau

Both of these drugs are also being tested in PSP, which is a relatively rare, classical familial tauopathy in a way that AD isn’t — because in PSP, the 1-5% of familial cases are known to be caused by certain MAPT mutations. Whereas I don’t know of well-validated genetic mutations in MAPT that are associated with increased risk of Alzheimer’s, except for some preliminary reports of small statistical associations, such as this one.

To try to force myself to be accountable and quantitative, what is my prediction for the probability that each of these two drugs will be approved by the FDA by the end of 2025? Same rules and disclosures as my previous post about this, but two years extended because these drugs are in earlier stages of development.

I’m going with 2.5% for BIIB092 (in phase II) and 1.5% for BIIB076 (still in phase I). Clearly abnormalities in tau proteins are highly associated with pathogenesis in AD, indeed more strongly associated than Aβ, and there have been a number of suggestions that the tau abnormalities are causal.

But in my opinion, we don’t know for sure yet that these tau abnormalities are truly causal, and that stopping tau aggregation will be helpful.

On one hand, if an anti-tau antibody works, why shouldn’t an anti-NFL antibody, or any of the other proteins that are markers of axonal damage in AD and are inversely associated with cognitive status? Maybe they all would, but this thought experiment is a bit troubling to me.

On the other hand, anti-tau antibodies have already been shown to be helpful in an APP-overexpressing AD mouse model, improving both cognitive function and the proportion of mushroom dendritic spines.

Castillo-Carranza et al 2015 Fig 1D; TOMA = anti-tau oligomer-specific monoclonal antibody, Tg2576 = APP-overexpressing AD mutant mouse; http://www.jneurosci.org/content/35/12/4857.long

It is asking a lot, but I would be more confident about the clinical relevance of this type of mouse study if it were shown that immunotherapies against other protein markers of axon damage, such as anti-NFL antibodies, were not successful in ameliorating cognitive decline, as a negative control.

Certainly I will be rooting for these anti-tau drugs to be successful in clinical trials and I think they make a lot of sense, but like most AD drugs in development, my prediction is that they are a long shot.

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Problems with the diagnosis of idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephaus (NPH) is a diagnosis of occult hydrocephalus with normal CSF pressure on LP that was first described in 1965 and is often considered one of the treatable causes of dementia.

The original paper used the now uncommon brain imaging technique of pneumoencephalography, which involved draining the CSF, injecting air as a contrast medium, and performing a brain xray:

Figure 2 from Adams et al 1965 showing uniformly enlarged ventricles; doi: 10.1056/NEJM196507152730301

At my med school we learned NPH by the triad of “wet, wobbly, and wacky”, referring to its classic triad of symptoms: urinary incontinence, gait disturbance, and cognitive impairment.

Like many symptom triads, these symptoms are non-sensitive, with the full triad seen in <60% of patients. It is also non-specific, as urinary incontinence is seen in ~20-40% of those over 60, gait impairment is seen in ~20% over those over 75, and mild cognitive impairment is seen in ~35% of those over 70.

Espay et al explain all of this in the introduction of their critical literature review of idiopathic NPH. One of their major points is that ventricle enlargement is also non-specific, as it is common in other neurodegenerative diseases such as AD, DLB, and PSP.

Here are some of their other points:

• There are no specific clinical, imaging, or neuropathologic findings in NPH.
• The determination of ventricle enlargement on MRI is subjective and not standardized.
• A “true” diagnosis is dependent upon a treatment response to CSF diversion via a ventriculoperitoneal shunt (VPS), which is circular and problematic.
•  There has never been a well-defined RCT to evaluate the use of VPS in NPH.
• Because many patients diagnosed with NPH may in fact have NPH that is secondary rather than a precursor to other neurodegenerative diseases, the fact that VPS may lead to short-term cognitive amelioration even in these patients suggests that VPS should still be considered as a way to improve cognition even in patients that are diagnosed with these neurodegenerative diseases.

Overall, this paper is well worth a read for people interested in treatments for dementia.