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Alzheimer’s: the search for a cure

By Peter Schueler

This year’s 14th annual Clinical Trials on Alzheimer’s Disease (CTAD) conference — entitled: ‘A New Hope for 2022?’ — will be held in Boston in November.

And the timing couldn’t be more auspicious because, after more than two decades of clinical trial failures, there’s good reason to believe we’ll finally see a light at the end of the tunnel in research for Alzheimer’s therapies.

Recently published study results for aducanumab and donanemab, both antibodies against amyloid, showed effects that indicated some improvement in cognition and daily function in patients with early Alzheimer’s.

The aducanumab data is still under review by the US Food and Drug Administration (FDA), and a decision about granting marketing authorisation is expected in June. If approved, it would be the first drug authorised in this indication since the 2003 approval of memantine by the FDA.

Future Alzheimer’s research

Three points of interest critical to future Alzheimer’s research became more crystalised as a result of these studies:

  1. Despite their limitations, available outcome scales, such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), are sufficiently sensitive to capture clinically meaningful changes.
  2. Initiating preventive therapies at the early stages of the disease is essential. In the aforementioned aducanumab and donanemab trials, intervention started at the Mild Cognitive Impairment, or MCI, level. What’s more, the initiation of preventive therapies at earlier and pre-symptomatic stages to determine more positive outcomes is currently being investigated. Regardless, the question we need to ask is, who would want to be treated for years with drugs, which could cause adverse reactions, for the sake of a slightly improved efficacy over time
  3. Amyloids actually have some role in the pathogenesis of Alzheimer’s disease. Yet, they cannot be the only relevant factors, since reduction of amyloid plaques from patients’ brains did not completely stop disease progression and this calls into focus the need to seriously investigate other contributors to Alzheimer’s.

With regard to the last two points of interest, we need further treatment alternatives with different mechanisms, such as drugs that support the proper folding of brain proteins – specifically chaperone proteins – which are currently in clinical development.

Further, other forms of abnormal structures aside from amyloid plaques – such as soluble beta amyloid oligomers and tau proteins – are also found to be closely correlated with the patient’s cognitive status and, therefore, can be potential therapeutic targets. However, we need to question whether these proteins are a cause or a consequence of the underlying pathology.

For amyloid plaques, it seems that these are more a consequence than a cause, which explains why no close correlation exists between amyloid load and cognitive function. Tau levels may also be more of a consequence than a cause, since they increase quite late in the progression of the disease. Whether the reduction of tau
load in patient brains will create a similar or even larger treatment effect than anti-amyloid drugs will become clearer with ongoing trials.

Preventing cognitive decline

As alluded to earlier, myloid oligomers are hot candidates for being true causal contributors to cognitive decline. Clinical trials with drugs inhibiting the formation of these oligomers are ongoing and show promising initial results. Exactly how these oligomers damage brain neurons is an area of active investigation. Inflammation is a likely contributing factor, which opens the door for further treatment mechanisms using anti-inflammatory drugs.

As early as the 1990s, data from several large epidemiological studies was published indicating that chronic anti-inflammatory treatments for patients with arthritis showed protective qualities against developing Alzheimer’s.

However, because of the less advanced trial methodologies used at that point, no prospectively designed study could confirm these findings. Similar retrospective positive findings were recently published for the anti-diabetic, glucagon-like peptide-1 receptor agonist (GLP1-RA), which was also found to reduce neuroinflammation. A new prospective study with that molecule is currently ongoing.

Personalised medicine

Another area of interest in the search for a cure is in personalised medicine. Based on major progress in the development of biomarkers for Alzheimer’s disease – including the visualisation of the proteins tau and amyloid in the patient brain with newly developed tracers for Positron Emission Imaging (PET) – we can better select patients for either anti-amyloid or anti-tau treatments.

An important prognostic marker is Apolipoprotein E4 (ApoE4). It seems that patients being tested positive for that marker have a faster disease progression, but also respond better to certain therapies.

In closing, a 2020 report by the Lancet Commission identified 12 lifestyle-related risk factors for dementia. They include: smoking, excessive alcohol consumption, diabetes, depression, hypertension, hearing impairment and mid-life obesity, in addition to a lack of social contact and physical exercise.

By seeking help and making simple lifestyle changes, we can delay the onset of dementia by 40%, according to the Lancet Commission report. And that’s definitely good news for all of us.

Peter Schueler is a Neurologist and Sr VP Drug Development Neurosciences at ICON plc

In association with

20th May 2021

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