Introduction

Are you a physician or caregiver thirsting for an update on the latest research on Alzheimer disease, or are you a basic researcher curious about the latest advances in clinical diagnosis and care?
 

Tom Wisniewski and Marcin Sadowski led this live discussion on 20 May 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:
Live Discussion led by Thomas Wisniewski and Marcin Sadowski on 20 May 2005.

Participants: Thomas Wisniewski, New York University; Marcin Sadowski, New York University; Tom Fagan, Alzforum; David Corbin, New York; Jungsu Kim, Mayo Clinic College of Medicine; June Kinoshita, Alzforum.

Note: The transcript has been edited for clarity and accuracy.

Tom Fagan
Thomas, Marcin, what prompted you to write the book 100 Questions and Answers About Alzheimer's Disease?

Thomas Wisniewski
Tom, we wrote the book because of the volume of questions our patients were asking.

Tom Fagan
I'm curious about the types of questions you were getting from patients. Does it appear that they have a good grasp of the biology behind AD?

Thomas Wisniewski
Tom, for the most part, our patients initially do not have a good grasp of the biology, but we try to teach!

David Corbin
Hi, congrats to Dr. Wisniewski on his prion vaccine work.

Thomas Wisniewski
David, Thanks. We are hoping to take this work to the next step.

Tom Fagan
Thomas, I wasn't aware that you were working on prion vaccines. Can you tell us a bit more?

Thomas Wisniewski
David, we have been working on prion vaccines for a few years and have several different vaccines in development (see Sadowski and Wisniewski, 2004 for a review on the vaccine work).

David Corbin
By the way, Professor Bengt Winbald at the Karolinska Institute in Stockholm is launching a phase I trial of the CAD106 vaccine with the support of Novartis. There are going to be 60 people in the trial; he told me that he has not determined the dosage.

Thomas Wisniewski
David, I heard this also. It is a promising approach.

David Corbin
Also, at the same institute in Sweden, they have a preclinical monoclonal antibody approach, sort of like the Elan trial. Do you view the monoclonal antibody approach as less promising than a vaccine approach?

Thomas Wisniewski
David, I think the passive immunization approach is the easiest for now, but active immunization will be cheaper and better in the long run.

June Kinoshita
Do you think the initial problems with active immunization can be overcome, and how?

Thomas Wisniewski
June, I think changing the formulation of the vaccine to eliminate a cell-mediated response will work.

June Kinoshita
Is this something that is well-understood in the vaccination development field?

Thomas Wisniewski
The toxicity of the vaccine approach seems to be linked to cell-mediated immunity in the brain. Reducing this can be done in many ways (see ARF related news story on vaccination strategies and ARF news story).

Thomas Wisniewski
The immunology field has been working on these types of issues for many years. AD researchers need to catch up with this literature.

June Kinoshita
This sounds like a good topic for another live forum! One thing I'm wondering is whether you are getting more people coming in seeking an earlier diagnosis.

Thomas Wisniewski
June, absolutely. This is a positive thing, as interventions are best early.

June Kinoshita
What do these patients understand about early diagnosis? What motivates them to seek a diagnosis? What are their expectations in terms of available treatments?

Thomas Wisniewski
Patients are typically worried about getting AD themselves; then they have seen family or friends affected. They are hoping for medications to extend good function.

June Kinoshita
What do you advise patients to take in order to maintain cognitive function?

Thomas Wisniewski
Use it or lose it! Keeping the mind active is a positive thing in many ways. Our AD center (as do other centers) has several programs to help with this.

Tom Fagan
Is there any particular way of using it that you recommend?

Thomas Wisniewski
Tom, activities like crossword puzzles, other games, and computer programs are useful.

Tom Fagan
There is the theory that one should take up new mental activities, like a musical instrument that one has never played, etc. Do you think novelty is an important aspect to mental training?

Thomas Wisniewski
I think novelty is important in learning.

June Kinoshita
I think retirement from a career can be devastating. People can get quite disconnected from their social network and structured, mentally demanding daily activities. What kinds of programs can help such people?

Thomas Wisniewski
Interacting with other individuals in the same position.

June Kinoshita
What kinds of organizations exist to enable this kind of interaction?

Thomas Wisniewski
I think the local chapters of the AD association can help with this. Also, most AD research centers have programs.

June Kinoshita
What about nutritional supplements? People must ask about these frequently.

Thomas Wisniewski
For most individuals nutritional supplements are not needed, but will do no harm.

June Kinoshita
Homocysteine has been getting more attention. What do you think about screening for elevated homocysteine levels and prescribing folate to treat it?

Thomas Wisniewski
As part of the cognitive workup, vitamin B12 and folate levels are measured. If there are abnormalities, then supplementation is needed.

Jungsu Kim
Recently, Dr. Holtzman's group showed that ApoE4 contributed to delaying Aβ deposition in parenchyma (see ARF related news story). What is your thought regarding your peptide inhibitor (see Sadowski et al., 2004)? In your paper, your peptide inhibits the interaction of Aβ with ApoE.

Thomas Wisniewski
Jungsu, I think that the actions of ApoE are complex, and our inhibitor will likely work in other settings.

Jungsu Kim
Do you mean the peptide may directly inhibit Aβ aggregation, not through ApoE interaction?

Thomas Wisniewski
Dr. Holtzman's work has also shown that the presence of ApoE is very important for amyloid deposition. These issues are dependent on the system used.

Jungsu Kim
Yes. I agree.

June Kinoshita
Speaking of ApoE, I understand that people with E4 may be more likely to benefit from early treatment with Aricept (see Borroni et al., 2002, but see also Rigaud et al., 2002 for an alternative view). Does this mean people with an early diagnosis should consider being genotyped for ApoE?

Thomas Wisniewski
However, if a patient is not ApoE4, it is still worth treating early.

June Kinoshita
Can you discuss that more specifically? What benefits have been reported or have you observed directly?

Thomas Wisniewski
Using existing drugs, the existing literature, and my own experience, I believe that progression can be delayed.

June Kinoshita
Are you referring to cholinesterase inhibitors, or also to memantine (see ARF related news story)?

Thomas Wisniewski
Many of my patients are placed on both medications. None of the present drugs for AD are very effective; hence, it is worthwhile to combine as many synergistic approaches as possible (see ARF related news story on combination therapy).

Jungsu Kim
Regarding the clinical aspect, could you please summarize any medication directly targeting Aβ in clinical trials, instead of other receptors?

Thomas Wisniewski
There are a number of vaccine trials starting, and also some anti-fibrillogenesis drugs being tried. In addition, trials aimed at altering cholesterol levels are ongoing.

Jungsu Kim
Regarding anti-fibrillogenesis drugs, what is your future plan with your peptide?

Thomas Wisniewski
Jungsu, we are developing peptidomimetics to improve the pharmacokinetics, and also testing more extensively to look for cognitive changes in mice.

Jungsu Kim
I hope it will work!

Thomas Wisniewski
Jungsu, thanks. Time will tell.

David Corbin
I am particularly interested in asking about a provocative new theory about oxidative stress and tau (see Lee et al., 2005). Question: If this hypothesis is correct, what are the implications for an anti-amyloid approach, such as Elan's monoclonal antibody treatment, versus dissolving tau filament formation, as exemplified by the phase II methylene blue trial (see Wischik et al., 1996)? In essence, the hypothesis suggests: "The accumulation of phosphorylated tau might be a protective antioxidant mechanism."

Thomas Wisniewski
David, tau problems in AD are most likely downstream from the amyloid deposition. Hence, if amyloid can be stopped, so can the tau changes (see ARF related news story on clearance of tau tangles by Aβ antibodies). These types of medications can potentially be very useful, even in later stages of AD. However, I think it will be very difficult to get a good therapeutic response, as the tangles are intracellular.

June Kinoshita
Thomas, I've been wondering about the issue of delivering drugs to intracellular tau aggregates, but have been told that if the drug can cross the blood-brain barrier, then it can also get into cells.

Thomas Wisniewski
June, that is true. But the amounts of the drug getting to the target will be very small.

June Kinoshita
Thomas and Marcin, embryonic stem (ES) cells have been in the news. Patients must come in asking about them. What role do you think ES cells might play in therapy development for AD?

Thomas Wisniewski
June, stem cell research has a long way to go before it will be useful to AD patients.

June Kinoshita
Regarding stem cells: If we take a step back and look at cell transplantation, Marc Tuszynski recently reported some interesting results of his phase I trial of fibroblasts used to deliver NGF (ARF related news story). What do you think of this approach?

Thomas Wisniewski
June, that type of approach will be very useful potentially for Parkinson disease. But in AD, whole networks of neurons need to be replaced, rather than one system.

June Kinoshita
It's true that the disease eventually affects an extensive network, but the damage is quite focal in the early stages, and it has been suggested that the pattern of damage may propagate domino-style from these initial foci. Is this idea one that remains valid, and if so, might an early intervention using cell transplantation still be a rational strategy?

Thomas Wisniewski
June, it is possible these approaches will work, but the technical difficulties are large.

June Kinoshita
What are some of these hurdles?

Thomas Wisniewski
June, stimulation of neurogenesis or dendritic sprouting will need to be anatomically correct. It will be difficult to do this in the hippocampus.

Jungsu Kim
Some people, like Dr. Lansbury at Harvard Medical School, worry that by blocking Aβ aggregation, there could be accumulation of very small oligomers. What are your thoughts about this?

Thomas Wisniewski
Toxic oligomers have been a theoretical risk in many of the interventions tried so far. They have not been a problem yet.

Jungsu Kim
What do you think about the oligomer theory? Do you agree that oligomers are the ones leading to AD?

Thomas Wisniewski
Jungsu, I am not sure oligomers are an important factor in vivo.

Jungsu Kim
What is the biggest weakness of the oligomer hypothesis?

Thomas Wisniewski
No one has isolated toxic oligomers from human tissue and correlated the levels with pathology.

Jungsu Kim
I heard that many groups just couldn't detect oligomers.

June Kinoshita
I thought Bill Klein's group had published two studies now showing elevated ADDLs in AD brain (see ARF related news story).

Jungsu Kim
We have tried to detect oligomer, but have failed so far.

Thomas Wisniewski
June, Klein's work needs to be repeated by other groups.

David Corbin
Do you think it is likely that an anti-tau aggregation approach to dissolve neurofibrillary tangles (NFTs) might backfire? Lee et al. have argued the following: "It's argued that the presence of NFTs in AD serves to protect crucial cellular components from attack by reactive oxygen species. A protective role for tau phosphorylation is further supported by the fact that embryonic neurons that survive after treatment with oxidants have more phosphotau immunoreactivity relative to those that die. Tau phosphorylation is not even likely to be a factor in microtubule stability because there is no relationship between PHT-tau and microtubule alterations in the AD brain. It is clear that cytoskeletal phosphorylation and other inclusions could, in fact, be beneficial because similar phosphorylation occurs in cytokeratins in response to various stressors, such as heat shock and toxins…."

Thomas Wisniewski
I think tau aggregation inside the cell cannot be a good thing.

June Kinoshita
Well, as usual, we have generated more questions than answers! We're at the end of our hour, so I want to thank you all for participating in today's live forum. We will circulate an edited transcript to post on the Alzforum.

Thomas Wisniewski
Thanks, all.

Jungsu Kim
Thank you for your thoughts.

June Kinoshita
Thank you, Jungsu.

David Corbin
Thank you, too.

Background

Background Text

This book was written for several different groups of people: those in the autumn of their lives who have started experiencing subjective memory problems and wonder whether they are suffering from Alzheimer disease; patients with objective findings who were diagnosed with mild cognitive impairment; patients in early stages of Alzheimer disease; and caregivers and family members. We invite you to join us to discuss multiple issues associated with Alzheimer disease which we cover in our book, including the following:

1. Mechanisms of the disease, epidemiology, and inheritance

2. Differences between dementia and healthy aging

3. Risk factors, symptoms, and ways in which the diagnosis is made

4. Overview of available treatment

5. Issues a caregiver may encounter taking care of a patient with moderate or advanced disease, including agitation, problems with wandering, and issues with driving

6. Legal issues associated with the disease

7. How to find important information and help, and how to access resources

8. How to take part in the quest for a cure, i.e., what new promising treatment approaches are under development and what are the risks and benefits of joining clinical trials

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References

Webinar Citations

1. 100 Questions and Answers About Alzheimer's Disease 1 Jul 2005

News Citations

1. Sorrento: Immunotherapy Update Hot Off Lectern of AD/PD Conference 15 Mar 2005
2. Pilot Study Shows Promise of Passive Immunotherapy 14 Apr 2005
3. Lipoproteins and Amyloid-β—A Fat Connection 23 Jan 2004
4. Memantine Wins FDA Approval 21 Oct 2003
5. Trial of Memantine/Donepezil Paves the Way for Combination Therapy 22 Jan 2004
6. Tackling Alzheimer’s from the Outside In 5 Aug 2004
7. Special Delivery: NGF Trial Puts Growth Factor Where It’s Needed 28 Apr 2005
8. "Bio-Barcode" Amplifies Aβ Oligomer Signal, Proffers Candidate Diagnostic Test 4 Feb 2005

Paper Citations

1. Sadowski M, Wisniewski T. Vaccines for conformational disorders. Expert Rev Vaccines. 2004 Jun;3(3):279-90. PubMed.
2. Sadowski M, Pankiewicz J, Scholtzova H, Ripellino JA, Li Y, Schmidt SD, Mathews PM, Fryer JD, Holtzman DM, Sigurdsson EM, Wisniewski T. A synthetic peptide blocking the apolipoprotein E/beta-amyloid binding mitigates beta-amyloid toxicity and fibril formation in vitro and reduces beta-amyloid plaques in transgenic mice. Am J Pathol. 2004 Sep;165(3):937-48. PubMed.
3. Borroni B, Colciaghi F, Pastorino L, Archetti S, Corsini P, Cattabeni F, Di Luca M, Padovani A. ApoE genotype influences the biological effect of donepezil on APP metabolism in Alzheimer disease: evidence from a peripheral model. Eur Neuropsychopharmacol. 2002 Jun;12(3):195-200. PubMed.
4. Rigaud AS, Traykov L, Latour F, Couderc R, Moulin F, Forette F. Presence or absence of at least one epsilon 4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer's disease. Pharmacogenetics. 2002 Jul;12(5):415-20. PubMed.
5. Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA. Tau phosphorylation in Alzheimer's disease: pathogen or protector?. Trends Mol Med. 2005 Apr;11(4):164-9. PubMed.
6. Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11213-8. PubMed.

Further Reading