Alzheimer's Disease | Biotech Strategy Blog

Can we use immunotherapy to treat or delay Alzheimers Disease?

Preserved section of the Berlin Wall

I have a personal interest in Alzheimers Disease, my mother Audrey died from it three years ago back in 2014.

Since then, I’ve watched with fascination and excitement the progress made in using the body’s own immune system against cancer. There’s still a long way to go, but a revolution in treating cancer is underway, as we’ve been documenting on this blog and the Novel Targets Podcast.

In recent years in the United States we’ve also seen grand initiatives targeting cancer such as Vice President Biden’s Moonshot, as well as large philanthropic support e.g. the creation of the Parker Institute for Cancer Immunotherapy.

Sadly, we’ve not seen the same level of interest in targeting dementia or funding research into new treatments for Alzheimers disease.

In the United States, the media doesn’t talk much about Alzheimers (compared to cancer), unlike for example, in the United Kingdom where any promising data is heralded with headlines that frequently deliver “hype over hope.”

Alzheimers is an insidious disease that removes the ability of the person to advocate and care for themselves, instead placing the burden on families and caregivers, often for extended periods of time. Ultimately many people end up in supported living or nursing homes.

As we debate healthcare insurance in the United States, who is going to pay for the cost of dementia care as the population grows older? Caring for dementia is arguably the greatest public health challenge that the western world faces.

Which is why I was excited to talk with a researcher who is thinking outside of the box and leading the way in how we could use our immune system against Alzheimers.

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Everton FC leads the way in community dementia support

Dementia care is a “quiet crisis” that already touches many families and will touch many more as we live longer in our old age and the huge baby boomer population reaches retirement age.

The Alzheimer’s Research Trust estimate that 1 in 3 over the age of 65 will have dementia by the time they die. Alzheimer’s disease is one type of dementia.

To cope with this explosion, more care will need to be provided in the community.

Mersey Care NHS Trust, who provide mental health care in Liverpool, Sefton and Kirby, have partnered with Everton FC, an English Premier League Club to support members of the local community with dementia.

Everton FC vs Crystal Palace at Goodison Park on April 16, 2014.

The innovative program called “Pass on the Memories” (Twitter: @efc_potm) helps more than 120 people with memory loss through activities that take place two days a week at Goodison Park. Support is offered via facilitators in the club and health professionals from Mersey Care.

The meetings help trigger sporting memories, but also engages participants in group social activities and visits, thereby keeping them mentally active and engaged.

When I visited, members of the group were about to head off for a visit to the Museum of Liverpool, which would no doubt stimulate powerful memories for many.

As some readers of the blog may know, my mother Audrey (who died recently at age 89) had Alzheimer’s disease. It’s a progressive disease with no known cure. I watched her memory slowly but surely deteriorate over several years. A keen dancer, she reached a point where she couldn’t remember how to dance anymore.

What Everton FC is doing by lending their support to the Pass on the Memories scheme, is something that sporting clubs around the world should all consider in their communities.

Sporting clubs derive considerable support from local communities and have facilities that are vastly underused outside of games. Many of their fans will sadly develop dementia. Engaging the local community in this way is a tremendous way of giving back.

As social services continue to be cut back in Liverpool due to budget cuts, I’m impressed by the way Mersey Care and Everton FC are helping those with dementia have the best quality of life they can through this type of local partnership.

If it didn’t exist, I expect many people would end up just sitting at home all day with little mental stimulation or interaction.

During my visit to Goodison Park, I spoke with Everton FC Community Engagement Manager, Henry Mooney (@HMooney23) who plays a key role in running the Pass on the Memories program at the club. He told me you don’t have to be an Everton fan to participate. 🙂

Living with Alzheimer’s disease is not easy. Unlike a physical disability, you can’t readily tell if someone has dementia, they look normal much like the rest of us.

Tommy Dunne, 61, was diagnosed with early stage Alzheimer’s disease three years ago. He told me that just because he has dementia, does not mean he is demented. Raising awareness of dementia and getting rid of the stigma associated with it is something we all can help with.

As the number of people with dementia grows, those who provide services (shops, transport etc) will need to be educated on how they can help people with dementia maintain their independence and undertake the activities of daily living that we all take for granted.

I was pleasantly surprised and pleased to see that Tommy is active on Twitter (@TommyTommytee18). It’s a great way to share his experiences.

I’ve included excerpts of the interviews I did with Tommy and Henry Mooney in the radio documentary on dementia that I produced – you can listen via the embedded SoundCloud at the end of this post or using this link.

If you are in the Liverpool area and have a family member with dementia, I encourage you to find out more about this innovative program.

Taking a more strategic view, I’m still shocked by how little progress there has been in drug development to tackle dementia, and in particular Alzheimer’s disease.

In comparison to oncology where research is focused on multiple new targets for drugs, as well as novel biomarkers that can help predict who are more likely to respond, dementia research seems like a record stuck in the groove.

Focusing on one target has failed to yield an effective Alzheimer’s drug despite spending hundreds of millions on clinical research.

More needs to be done to understand the biology of Alzheimer’s disease and generate new insights into potential new targets that at the very least delay the progression of a disease that many of us will possibly end up with in the future.

Update April 30, 2014: Everton FC write up my visit on their Community news site

I was thrilled to hear that John Howard, (@JHowEFC08) Media Officer for Everton in the Community has written about my visit to the Pass on the Memories program. He’s published a really well written post on the Everton FC community website that goes into more detail about the program.

Pieter Droppert interviewing Tommy Dunne. Picture Credit: John Howard, Everton FC

Here’s the link to John’s piece if you are interested in more information: Pieter’s views on Pass on the Memories

Update May 19, 2014: Talking about Dementia on BBC Radio Merseyside Daybreak show

At the start of Dementia Awareness Week in the UK, I was very grateful for the opportunity to go on the May 18, 2014 edition of BBC Radio Merseyside’s Daybreak show, produced by Helen Jones.

I talked about my late mother, Audrey and some of the innovations in dementia care that I’ve written about on the blog. If you have the chance do listen to an excerpt from the show:

Update June 5, 2014: listen to living well with dementia – a personal journey

My research into Everton’s Pass on the Memories program was undertaken while on a BJTC accredited diploma in radio journalism course based at Radio City in Liverpool. You can listen via SoundCloud to the documentary I produced on living well with dementia – a personal journey:

A personal perspective on Alzheimer’s: my mother doesn’t dance anymore

My mother has Alzheimer’s disease – I first suspected some form of dementia when her friends told me that she didn’t dance anymore. Of course she insisted she did, but it was clear she had “forgotten” the steps in a way that was beyond the forgetfulness of getting older.

As a European snow bird she would travel to Malta each year to escape the damp, grey English winters. One year when I visited her in Malta, I noticed when she went up to the hotel dinner buffet, she could not “remember” where to return to.

With a blank and vacant look she would gaze out hoping to find a clue that jarred her memory. Friends gently directed her to the right table and diffused the embarrassment with humor.

Sadly during my visit I saw that she could no longer remember the names of people she had holidayed with for 10 years each winter, or what clothes she had worn the day before. Her holiday companions and the hotel treated her with kindness, but it was the beginning of a decline, and her last winter in Malta.

At home, she has struggled to manage activities of daily living and the need for care has increased. As a family, we’ve endeavored to support her independence for as long as possible, but a nursing home is now in the not too distant horizon.

Which is why I have a personal interest in Alzheimer’s disease. It’s an area where innovation needs to catch up with demand for treatment and therapies, not to treat it when it’s happened – it’s too late to untangle the damage, but to delay it’s occurrence in those at risk.

This week in the New England Journal of Medicine (NEJM), research showed that continued treatment of moderate to severe Alzheimer’s disease with donepezil (Aricept) provides modest cognitive and functional benefits.

By the time moderate to severe disease has set in, the damage has already been done, and the train has left the station metaphorically speaking. Those with this status require the support of caregivers. This study was undertaken in community-dwellings i.e. some form of nursing home or care facility.

In their NEJM paper, Robert Howard of the Institute of Psychiatry & UK colleagues assessed changes in Standardized Mini-Mental State Examination (SMMSE) & Bristol Activity of Daily Living (BADLS) scores in moderate to severe Alzheimer’s patients who received donepezil or memantine in a double-blind, placebo controlled trial.

Patients continued to decline over the course of the study, so what the study showed was that by giving a cholinesterase inhibitor, the rate of decline was slowed. The functional benefit was equivalent to 32% of the total deterioration seen over 12 months.

However, dramatic as this significant benefit sounds, the author’s rightly caution that the improvements in cognition and function were small relative to the overall decline in cognitive and functional status seen in all patients.

While this paper offers evidence-based medicine for the continuation of donepezil in those with moderate to severe disease, this treatment does not lead to a cure or restoration of function.

A study sample size of 430 was estimated to give a 95% power to detect a 1.0 point difference in SMMSE scores between donepezil and placebo groups, and 90% power to detect a 2.0 point difference. In the end a total of 295 participants were enrolled.

The results showed that:

“Patients who were assigned to continue taking donepezil, as compared with those assigned to discontinue donepezil, had scores on the SMMSE that were higher (indicating better cognitive function) by an average of 1.9 points (95% CI, 1.3 to 2.5; P<0.001) and scores on the BADLS that were lower (indicating less functional impairment) by an average of 3.0 points (95% CI, 1.8 to 4.3; P<0.001).”

The researchers noted that:

“The severity of dementia at entry significantly influenced the effect of donepezil on SMMSE scores, with larger benefits observed in patients with moderate disease (SMMSE score, 10 to 13) than in those with severe disease (SMMSE score, 5 to 9).”

More information on the study design and detailed results can be found in the published NEJM paper.

My Mother takes donepezil and I’m pleased to see that there’s now some clinical data to support its continued use, as she will no doubt progress.

All those with loved ones who have Alzheimer’s will be pleased with any news that delays the progression of this debilitating disease.

Reference

Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., Burns, A., Dening, T., Findlay, D., Holmes, C., Hughes, A., Jacoby, R., Jones, R., Jones, R., McKeith, I., Macharouthu, A., O’Brien, J., Passmore, P., Sheehan, B., Juszczak, E., Katona, C., Hills, R., Knapp, M., Ballard, C., Brown, R., Banerjee, S., Onions, C., Griffin, M., Adams, J., Gray, R., Johnson, T., Bentham, P., & Phillips, P. (2012). Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease New England Journal of Medicine, 366 (10), 893-903 DOI: 10.1056/NEJMoa1106668

ARVO 2011 Using the eye as a window into the brain

By Pieter Droppert on May 4, 2011

Due to the pressure of other commitments, I only had the pleasure of attending the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) for two days, but one of my key take home messages from the meeting is how we can use the eye as a window into the brain. This is particularly relevant to Alzheimer’s research.

ARVO researchers at a lunchtime workshop that I attended asked the question of what can we learn from shared disease mechanisms in age-related macular degeneration (AMD), Alzheimer’s Disease (AD) and Glaucoma to devise therapies of the future?

What I learnt in the introduction by Nicholas Bazan from LSU Health Sciences is that both AD and AMD are both multifactorial, genetically complex, progressive, late-onset neurodegenerative conditions. Common features include:

Age-related neurodegeneration
Amyloid precursor protein mis-processing
Non-resolving inflammatory response
Selective apoptotic cell death

Researchers in the workshop presented early experimental findings.

Catherine Bowes Rickman from Duke presented data that showed anti-amyloid immunotherapy blocks retinal pigment epithelium (RPE) damage and visual function defects in an AMD-like mouse model. Interesting questions were raised as to whether mouse Aß aggregates differently to human, so is this a good model?

Adriana Di Polo from the University of Montreal discussed Glaucoma and AD: common neurodegenerative pathways and therapeutic targets. It was interesting to note that high rates of visual abnormalities, including glaucoma, have been reported in AD patients, but causality has not been established. Neuronal loss in both glaucoma and alzheimer’s disease occurs via common cell death processes including altered metabolism of Amyloid Precursor Protein (APP) and Aß.

What Di Polo highlighted in her talk was the potential to use therapies effective in one disease to treat the other e.g. galantamine is approved for treatment of mild to moderate AD symptoms. Because it crosses the retinal-brain barrier and has high bioavailability, she presented results using this in an animal model of glaucoma.

Her conclusion was that “therapeutic modalities that promote neuroprotection in AD may be useful in glaucoma and vice versa.”

The third speaker of this fascinating workshop was Ian Trounce from Melbourne, who challenged the Amyloid theory of AD. His hypothesis was that sAPPα may trigger oxidative stress in mitochondria and be the problem. He discussed the increasing acceptance/overlap in pathologies between Parkinson’s and AD. He presented data that sAPPα overexpression protects retinal ganglion cells (RGC) from rotenone via PI3K-AKT activation.

Critical feedback on the three presentations was provided by Guy Eakin of the American Health Assistance Foundation (AHAF) and Imre Lengyel from UCL.

As Dr Lengyel succinctly notes in his UCL Institute of Ophthalmology bio:

“It appears that the development of age related macular degeneration (AMD) and Alzheimer’s disease (AD) share similar histopathology, vascular risk factors and genetic predisposition. In addition, the development of AMD appears to use similar or identical steps on the cellular and molecular levels to AD: vascular damage, oxidative stress, inflammation, extracellular protein and peptide degradation or deposition, and the role for lipids and trace elements (especially zinc) in the degenerative process are amongst the many common features. Furthermore, amyloid beta peptides are an integral part of drusen (the hallmark lesion in AMD) and their formation might be similar to plaque formation in AD.”

I applaud ARVO for looking at how the eye can be used as a window into the brain. It raises the intriguing prospect that research on AMD may not only help understand the cause of AD, but that the eye may serve as an experimental model for future new treatments. Collaboration between Opthalmology and Alzheimer’s researchers is something I expect and hope we will see more of.

MRI may detect Alzheimer’s disease 10 years before symptoms show

By Pieter Droppert on April 19, 2011

Changes in brain structure, function and molecular processes occur several years before clinical symptoms of Alzheimer’s disease (AD) become apparent.

The big question then, is can you detect patients who are cognitively normal, but will go on to develop AD before they show symptoms, i.e. pre-symptomatic patients? The answer is “Yes” according to results published in the April 19, 2011 issue of Neurology by Brad Dickerson and colleagues.

In this small study, the team of researchers from two centers (Massachusetts General Hospital and Rush University in Chicago) followed a small sample of cognitively normal (CN) subjects over time with magnetic resonance imaging (MRI) and then sought to identify what structural changes had taken place in those subjects who were initially cognitively normal, but went on to develop AD, on average 11.1 years later.

The researchers found that changes in brain cortical thickness were associated with AD:

AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05)

They concluded that:

By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

Some of the limitations of this research and questions that come to mind are:

Small sample size: only 8 individuals who developed AD and 25 in the cognitively normal control group.
Reproducibility: the 0.2mm difference seen is small and the extent to which other centers may be able to reproduce this measurement is uncertain
Accuracy of detection: in any screening tool the issue of false positives and negatives arises i.e. in a larger sample size will there be a margin for error that results in some people being included in the pre-symptomatic AD group, when they may be normal? Also will the proposed measurement remain valid in a large population of patients with other disease symptoms and chronic illnesses?
Validity of biomarker: are the changes in cortical thickness causally linked to AD or just an incidental correlation i.e. is this a valid biomarker?

Brad Dickerson in the excellent Neurology podcast available with this publication clearly sees this currently as a research tool, especially given the requirement for considerable computer power to make these types of cortical measurements in the brain. The podcast interview is well worth listening to.

The MRI biomarker proposed by Dickerson is therefore not something that is really applicable to screen the general population at the moment.

However, the promise from this and other biomarker research is that at some point in the not too distant future we will be able to detect those at risk of developing AD. Those patients could then be given neuroprotective drugs that may delay the onset of the clinical symptoms of AD such as memory loss and cognitive impairment.

Biomarkers that identify those at risk of developing AD will also be useful as inclusion and screening tools for clinical trials of drugs aimed at slowing disease progression in pre-symptomatic patients.

Alzheimer’s disease has been called “The challenge of the Second Century,” we still have a long way to go before this is overcome.

Story Source: BBC Health

Dickerson, B., Stoub, T., Shah, R., Sperling, R., Killiany, R., Albert, M., Hyman, B., Blacker, D., & deToledo-Morrell, L. (2011). Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults Neurology, 76 (16), 1395-1402 DOI: 10.1212/WNL.0b013e3182166e96

10 warning signs of Alzheimer’s Disease

By Pieter Droppert on January 26, 2011

My theme for blog posts this week has been the diagnosis and detection of Alzheimer’s Disease, a therapeutic area I was first introduced to while working as a Global Project Director at the Canadian CRO, CroMedica before it was acquired by PRA. The then CEO of CroMedica, Erich Mohr Ph.D is now Chairman and CEO of MedGenesis Therapeutix Inc. in Victoria, BC.

This privately held biopharmaceutical company is working on developing new products for neurological diseases and the treatment of Parkinson’s Disease, Glioblastoma Multiforme (GBM) and Intractable Epilepsy. I have added MedGenesis to my list of emerging biotechnology companies to watch, and look forward to writing further as their pipeline develops.

Which brings me back to Alzheimer’s disease (AD), an area which I think will touch many of us as we and our parents become older. Last week, I was visiting my elderly mother in England who struggles to remember when I am visiting, and has little or no short term memory. It’s sad to see her in a restaurant have a completely blank face when she goes up to a buffet, then cannot remember where she was sitting.

While we all have age-related decline in our memory as we get older, how do you know if it may be something more such as AD? The Alzheimer’s Association have published a useful list of 10 warning signs, that may suggest seeing a doctor:

Memory loss that disrupts daily life
Challenges in planning or solving problems
Difficulty completing familiar task at home, at work or at leisure
Confusion with time or space
Trouble understanding visual images and spatial relationships
New problems with words in speaking or writing
Misplacing things and losing the ability to retrace steps
Decreased or poor judgment
Withdrawal from work or social activities
Changes in mood or personality

While there is no cure for AD, early diagnosis using biomarkers (see my blog post on Lilly’s florbetapir and blog post on Novartis’ Aß40 oligomers), could lead to slowing disease progression as new therapeutic agents come through development to market.

Dementia, AD and other cognitive disorders are challenging for caregivers and family’s to deal with. In many ways a tangible, physical illness is easier. Not knowing the rate of progression and the future, it is difficult to plan ahead. Helping my elderly mother maintain her independence in the face of the mental challenges she faces is something that we as a family have to face up to, as I am sure many others will too.

Aß40 Oligomers are a potential biomarker for diagnosis of Alzheimer’s before amyloid plaque develops

By Pieter Droppert on January 25, 2011

Following on from yesterday’s blog post about Lilly’s florebetapir, a recent paper published in PLoS One (open access) describes how Aß40 Oligomers have potential as a biomarker for Alzheimer’s disease (AD), prior to the development of amyloid plaque.

Thanks to BayBio for giving me the idea for this post when they mentioned it in their news about member & partner, Novartis Vaccines and Diagnostics in Emeryville, CA.

Alzheimer’s disease is an important target therapeutic area for the biotechnology industry. According to the Alzheimer’s Association, one in eight people aged 65 and older in the United States have Alzheimer’s disease (5.1 million). By 2030, the prevalence will have increased by approximately 50%, when an estimated 7.7 million will have the disease.

Neurodegenerative diseases place a large burden on the healthcare system and caregivers. There is a major unmet need for effective treatments that will either delay the onset of Alzheimer’s or slow down the rate of disease progression.

In their paper, Gao et al describe how using the knowledge that soluble Aß oligomers play an important role in the pathogenesis of AD, they were able to use a Misfolded Protein Assay (MPA) to capture Aß in the cerebrospinal fluid (CSF) of AD patients. Their results suggest that Aß40 oligomers are a novel biomarker for the early diagnosis of AD.

What I found interesting is that Aß40 oligomers were found in late-stage AD patients with low clinical Mini-Mental State Examination (MMSE) scores as well as those with early stage AD and higher MMSE scores. (p<0.01 between normal and all AD groups).

These results based on data from 26 patients clinically diagnosed with AD need to be viewed with caution since they are very early stage, but there is sufficient promise for future clinical trials. A CSF test based on Aß40 oligomers could potentially pick up early-stage AD disease before it has progressed to the point where a clinically significant level of amyloid beta plaque (evidencing neuronal loss) appears in the brain.

Novel biomarkers could play an important role in drug development by biotechnology companies, allowing disease progression to be monitored. It will be interesting to see whether this research on Aß40 oligomers from Novartis Vaccines and Diagnostics, ends up being confirmed as a valid biomarker.

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Posts tagged ‘Alzheimer’s Disease’