Back in September 2019, I submitted my abstract to present a poster at the AAT-AD/PD™ Focus Meeting in Vienna (Austria). This was to be my first international conference and I was excited for the chance to talk to leaders in the field around the world about my research. By the time March came around, it seemed more and more likely that the conference would never happen thanks to the COVID-19 outbreak. However, the message from AAT-AD/PD™ was consistently that they would do everything they could to avoid cancelling the conference. To their word, 3 weeks before the conference was due to begin, the organizers announced that the conference would be fully virtual. As a result, 1143 participants from 56 countries were able to share their research from their own homes.
How does a virtual conference work?
- Talks were pre-recorded and you could watch them at any time
- Live discussion sessions took place on Zoom, where speakers could discuss topics amongst themselves as well as taking questions via a Q&A text box. As someone who struggles to ask a question in a room full of experts, I found this particularly beneficial and actually asked a couple of questions that were answered
- In the ‘meet the speaker’ sessions, you could ask questions to selected speakers via Zoom, compromising for the lack of Q&A after talks
- Poster presentations – to ‘present’ a poster, you could upload an ePoster along with your contact details and people who were interested could then message you with questions
Aβ immunotherapy – learning from ‘failures’
One of the highlights of the AAT-AD/PD™ conference was Randall Bateman’s (Washington University, MO, USA) talk, and subsequent discussions, digging into the results of the Dominantly Inherited Alzheimer’s Network (DIAN) trials with Aβ-targeting antibody therapeutics, solanezumab and gantenerumab.
In February of this year it was announced that both drugs had failed to meet the primary cognitive endpoints. This news pulled Aβ-targeting therapeutics into further questioning, after several BACE1 inhibitors were found to worsen cognition. However, as Dr Bateman explained, there were several trial limitations that contributed to this result, such as: the small sample size; the inclusion of both prodromal participants (primary prevention trial) and mild cognitive impairment/mild Alzheimer’s disease (AD) patients (secondary prevention trial); increase in dose at a late stage in the trial; and no cognitive deterioration in asymptomatic participants either on placebo or therapeutic.
Therefore, it is perhaps not surprising that the study failed to reach its primary cognitive endpoints. What is exciting, however, is the distinct improvement in biomarkers with gantenerumab treatment in both the primary and secondary intervention groups. Brain amyloid levels were reduced (PET) and the CSF Aβ42/40 ratio, total tau, pTau-181 and the marker of neurodegeneration NfL were all significantly improved. This infers that reducing Aβ levels in the brain has a positive effect on downstream pathological pathways.
As a result, DIAN-TU and Roche (Basel, Switzerland) announced that they will be launching an exploratory open-label trial with gantenerumab. It will be particularly interesting to see what effect this will have on disease development in the asymptomatic participants who did not experience cognitive decline in this study.
These findings were in line with those from the EMERGE and ENGAGE trials with the Aβ-targeting immunotherapy aducanumab, as reported by Samantha Budd Haeberlein (Biogen, MA, USA). Despite announcing that it had failed to meet its primary endpoints in March 2019, Biogen announced in October 2019 that upon reanalysis, the endpoints had been met. The initial failure was put down to a late increase in dose, similarly to DIAN-TU, which meant that when the futility analysis was undertaken, only a minority of participants had completed a full cycle on the highest dose. When the full dataset was analyzed, which included a higher proportion of those who had completed the full dosing at this high dose, the primary endpoints were met. It should also be noted that, like with gantenerumab in DIAN-TU, a reduction in CSF pTau and brain tau levels (PET) was observed alongside a reduction in Aβ.
Beyond Aβ-targeting therapeutics
AD is an extremely complex disease, which was highlighted by the huge range of therapeutic targets presented at the conference. Sessions included those on targeting tau, microglia, APOE and vascular-related mechanisms just to name a few.
Generating a tau vaccine is an attractive AD intervention, as tau deposition correlates with dysfunctional areas of the brain. Michal Fresser (Axon Neuroscience, Larnaca, Cyprus) showed that the tau vaccine AADvac1 met its primary endpoint as it was safe and well tolerated in the Phase II ADAMANT trial. The vaccine successfully demonstrated an antibody response to tau as well as a significant reduction in plasma NfL, white matter degeneration and cortical volume loss. With ACI-35.03, a second generation anti-ptau vaccine, now in a Phase IB/IIA study following success in pre-clinical studies (presented by Marija Vukicevic, AC Immune, Lausanne, Switzerland), there is a promising foundation forming for the development of anti-tau vaccines.
Julie Schneider (Rush University Medical Center, IL, USA) gave a great plenary talk on the contribution of TDP-43 to dementia, making an important point that only a small proportion of patients who died with probable AD presented with only AD pathology. Most cases exhibited mixed pathology with Lewy bodies, TDP-43 and/or vascular diseases, and the presence of TDP-43 or vascular diseases was thought to greatly increase the risk of dementia.
As one of the known genetic risk factors for AD, several groups are working to target APOE4 gene variant-induced toxicity. A particularly intriguing drug-discovery method was put forward by Yadong Huang (University of California San Francisco, CA, USA) who, instead of targeting a specific protein or pathway, utilized the Connectivity Map (CMAP) expression profile database to screen US FDA-approved drugs for transcriptional changes that oppose those found with APOE4 genotypes. From this, he identified a drug hit that could rescue synaptic function and spatial learning in an APOE4 knock-in mouse.
Non-pharmacological-based interventions for AD
Some of the most promising findings, however, came from non-pharmacological strategies. Miia Kivipelto (Karolinska Institutet, Solna, Sweden) highlighted previously reported findings from the FINGER trial, which showed how educating participants on nutrition, monitoring and counteracting vascular risk, and providing exercise classes and cognitive training, successfully reduced cognitive decline in those at risk for AD. This has incited a worldwide expansion of the FINGER network (WW-FINGER), involving around 30 countries so far and the development of FINGER 2.0, a combination of both lifestyle and pharmacological interventions.
Similarly, positive results were shown from the LipiDiDiet study, where prodromal patients were administered with Fortasyn Connect, a nutrient-rich drink. Tobias Hartmann (Universitӓt des Saarlandes, Saarbrücken, Germany) presented the findings from the 36-month timepoint, which showed significant improvement in the hippocampal volume as well as the clinical dementia rating. While these results are promising, it is unclear what the effect was on the primary endpoint, which failed at the 24-month time point.
Sex and gender differences in AD
It was great to see an entire session dedicated to sex and gender differences in AD, with Maria Teresa Ferretti (University of Zurich, Switzerland) kicking it off with a great talk highlighting why these differences need to be studied in order for effective diagnosis and therapeutic development. Julie Martinkov (Charles University, Prague, Czeck Republic) undertook a systematic review of clinical trials for AD, which revealed that less than 20% of published studies reported sex-stratified analysis. Another interesting talk was given by Alessandra Dodich (Geneva University Hospitals, Switzerland) who explained how, by looking at 18F-flortaucipir PET in patients with MCI, she identified that females appear to show a higher brain resilience to tau deposition. It was great to see these important discussions happening on such a large platform.
How did the virtual conference compare to a regular conference?
- Freedom to watch talks irrespective of sessions
- Increased accessibility – those who are usually unable to physically attend conferences due to caring responsibilities etc. could participate
- By being able to pause and rewind talks, you could take in more detailed information
- Pets could participate
- Reduced social aspect – no mingling or networking
- No Q&A after talks
- Less interaction with ePosters – can’t trap people into asking questions with eye contact
Moving forward, it would be amazing to see aspects of this virtual setting incorporated into future conferences, for example, having on-demand talks online for those who are unable to physically attend. It is incredible what the organizers managed to do in such a short time span, providing a platform for sharing progress in therapeutic development for AD and Parkinson’s disease so that this vital research can move forward despite the circumstances.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.
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- DIAN-TU: solanezumab and gantenerumab yield disappointing results for rare form of Alzheimer’s