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Wednesday, July 25, 2012

Early Results of IV Bapineuzumab Study

Dear Readers,

The results of the first of four Phase 3 trials of intravenous bapineuzumab, a monoclonal antibody against beta-amyloid, show that it failed to meet its co-primary endpoints in some 1,100 patients with mild to moderate Alzheimer’s disease who carry at least one ApoE4 gene.

Three other trials are still underway. Pfizer is conducting a second Phase 3 trial in ApoE4 carriers in Europe. Janssen AI is leading two Phase 3 studies of patients who are ApoE4 carriers and non-carriers at sites primarily in North America. Pfizer is conducting two Phase 3 studies of patients who are ApoE4 carriers and non-carriers at sites primarily outside of North America, the first of which was presented yesterday.

The breakdown in ApoE4-carriers versus non-carriers is important because there is a feeling that the drug might work better, if at all, in patients who do not carry the ApoE4 gene. Readers of this blog will recall that ApoE4 status is associated with an increased risk of cognitive decline and elevated amyloid deposition. It is believed that the different forms of ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, and they do so with different efficiencies. It has been shown that ApoE4 seems to be the slowest in removing beta-amyloid from the brain, which may be why it confers the most genetic risk.

Why did the trial fail? A useful analogy might be to think of heart disease.
High cholesterol levels are associated with a higher incidence of heart attacks. However, a patient does not present to their doctor with any symptom associated with high cholesterol. In fact, until 25 years ago when cholesterol levels started to be routinely checked, many patients would present with a heart attack as the first symptom of their long standing high cholesterol levels. The same is thought to be true about AD.

The symptoms of dementia are to the brain much like a heart attack is to the heart. By the time the symptoms of dementia have developed, there have been years of an underlying pathological process affecting the brain, namely the accumulation of beta-amyloid and the loss of synapses and neurons. And, much the same way, if a patient presents to an emergency room with a heart attack, prescribing a cholesterol lowering medication for the first time may be too late. Specifically, 15-20 years too late. Now that we can check cholesterol levels earlier in life with a simple blood test, in the absence of any symptoms, we can start patients on cholesterol lowering medications to reduce their risk of having a heart attack in the first place.

The same is believed to be true about treatment of Alzheimer’s disease dementia. By treating Alzheimer’s disease early, by lowering beta-amyloid levels, we may be able to prevent the dementia phase from ever developing. ApoE4 carriers have more amyloid in the brain and are further along the pathological cascade that leads to dementia, and may not respond as much to amyloid-lowering drugs as non-ApoE4 carriers.

We eagerly await the results from the remaining phase 3 studies of Bapi, in particular the effects on non-ApoE4 carriers.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
Author: Michael Rafii MD,PhD at 12:05 PM 0 Comments

Wednesday, July 18, 2012

Stabilizing AD in Phase 2 of the IVIG Immunotherapy Trial

Dear Readers,

With the Alzheimer’s Association International Conference in full swing this week, I wanted to give an update on some recent findings that are being reported.
As you may recall, it has been known for some time that IVIG, which is derived from human blood, contains antibodies that bind to the beta amyloid protein. Each dose of IVIG contains pooled antibodies extracted from the plasma of more than 1,000 blood donors. IVIG is prescribed to treat immune deficient patients who have decreased or absent antibody production capabilities to prevent infections. It is mainly used in immune deficiencies, autoimmune diseases, and certain neurological disorders.

Results from previous work show that IVIG appears to promote the clearance of beta amyloid from the brain and block its toxic effects on brain cells resulting in a stabilization or improvement in cognition and functioning of patients with Alzheimer's disease.

Although IVIG is not currently approved to treat Alzheimer's disease, 35 academic institutions in conjunction with the NIH and the Alzheimer's Disease Cooperative Study Group have been conducting the 18 month long Phase 3 clinical trial to try and confirm the encouraging results using IVIG that have been reported in the Phase 1 and Phase 2 trials. In the earlier trials it was shown that patients tolerated the IVIG therapy with minimal adverse reactions and all patients had stabilization of their cognitive abilities with many of them demonstrating a significant improvement in cognitive ability over the course of the six months of IVIG treatment. Volumetric MRI also showed less brain atrophy or shrinkage in IVIG treated subjects as compared with placebo.

At his week’s conference, Dr. Norman Relkin reported results from the extension study of 16 of the original 24 subjects who were in the phase II trial. The 24 participants in that study received six months of treatment followed by a 12-month open-label extension where all subjects received IVIG. Sixteen of the originally enrolled subjects received treatment for 36 months, including five originally given placebo and 11 treated with various doses of IVIG. The main findings were:

Study participants who were treated with IVIG every two weeks for the full 36 months had the best outcome, with no decline on several standard measures of cognition, memory, daily functioning and mood at the three year endpoint. As a group, the 11 participants who received IVIG for the full 36 months had favorable outcomes in terms of their thinking abilities, behavior and daily function. The five participants who were initially treated with a placebo and then switched to IVIG declined while on placebo but experienced less rapid decline while receiving a uniform dose of IVIG.

The results of the Phase 3 trial should be reported some time next year, and it is hoped, will confirm these findings in a much larger number of subjects.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego

Author: Michael Rafii MD,PhD at 12:58 PM 0 Comments

Thursday, July 12, 2012

A Gene Mutation that Protects Against AD

Dear Readers,

Previously, I have written about the role of APP in the development of Alzheimer’s disease (AD). Just to review, all neurons secrete a protein called Amyloid Precursor Protein (APP), and APP is cleaved by two scissor-like proteins, gamma secretase and beta secretase. This results in the production of beta-amyloid, a toxic protein fragment that accumulates in the brain over time, causing brain cell damage eventually leading to dementia, and deposits into amyloid plaques. Genetic mutations in either APP or either one of the scissor-like secretases that cleave it lead to inherited forms of Early Onset Alzheimer’s disease that strike patients in their 30’s and 40’s.

The gene for APP resides on the 21st chromosome, and in people with Down Syndrome, who are born with an extra copy of the 21st chromosome, each of their brain cells produce 50% more APP and subsequently 50% more beta-amyloid and therefore have a much greater incidence of AD. Intriguingly, individuals with Down syndrome who have an extra-copy of the 21st chromosome, but lacking the segment that includes the APP gene, do not seem to get AD.

Now, researchers in Iceland led by Dr. Kari Stefansson at DeCode Genetics, have found a mutation in APP that significantly decreases its cleavage by beta-secretase, leading to much less production of beta-amyloid, about 40%. This mutation also appears to confer resistance to the development of Alzheimer’s disease in patients. That is, people with the mutation make substantially less beta-amyloid and do not get AD.

Moreover, patients who have two copies of the gene ApoE4 are known to have a reduced ability to remove beta-amyloid produced in their brain, and have an increased risk of developing AD. In fact, 90% of people with two ApoE4 genes develop Alzheimer’s by age 80. But of the 25 subjects in this study who had two copies of ApoE4, none have Alzheimer’s disease.

Currently, most clinical drug trials for AD are targeting beta-amyloid, either by directly removing it with intravenously administered antibodies, or decreasing its production by blocking cleavage of APP by gamma-secretase or beta-secretase. The results of this paper further confirm the central role of beta-amyloid in the development of AD, and give us hope that these strategies will help prevent AD in the near future.

Jonsson et at, A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline, Nature 2012.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
Author: Michael Rafii MD,PhD at 1:38 PM 0 Comments

Monday, July 09, 2012

Strain and Correlation Among Dementia Caregivers

Dear Readers,

I recently quoted the following statistics from the Alzheimer's Association at a multi-ethnic, caregiver-focused Alzheimer's Awareness community event:

(1) Approximately 11 million Americans provide unpaid care for a person with Alzheimer's disease (AD) or another dementia.

(2) Almost one half of unpaid caregivers of people with AD said that the person's AD or other dementia was his/her main health problem

(3) Caregivers of AD and other dementias provide more hours of help than caregivers of other older people.

(4) Sixty percent of family and other unpaid caregivers of people with AD and other dementias are women.

(5) More than 40% of family and other unpaid caregivers of persons with AD and other dementias state that their emotional stress of caregiving was as high or very high, and about 1/3 of family caregivers of people with AD and other dementias have symptoms of depression. Thus the article from the 10/66 Dementia Research Group, was timely to review, as it sought to examine the association of known factors related to caregiver stress/burden in Western cultures to a multi-ethnic population sample.

The 10/66 study consists of a series of cross sectional geographic cachement areas surveyed between January 2003- 2007. The target sample size was 2000 persons from each country, and all community residents aged 65+ were eligible for participation. A total of 677 participants who were diagnosed with dementia and needing care were eligible for this survey. Dementia severity was rated with the Clinical Dementia Rating scale and the Community Screening Instrument for Dementia COGSCORE. Severity of behavioral and psychiatric symptoms was assessed with the NPI. Neuropsychiatric symptoms were assessed by the Neuropsychiatric Index (NPI) and categories were grouped by: depression, anxiety, apathy and irritability. Other interview questions assessed the extent of care provided, time over the last 24 hours spent in specific caregiving activities, data on the occupation of the carer, and the extent to which the carer had cut back on or stopped work. Carer perceived strain was assessed using the Zarit Burden Interview.

The proportion of those with dementia rated as needing care varied widely between sites and was higher in urban than in rural sites. Across all sites neither carer age, nor occupation was associated with strain. Married carers reported less strain than non-married carers. Other findings with respect to relationships revealed that those persons who provided care and were not related reported lower levels of strain compared with spousal carers. Neither age nor gender was associated with carer strain, however co-morbid depression, psychosis and anxiety were associated with carer strain. Clinical severity of dementia was also linearly positively associated with carer strain, a finding noted in Cuba, Venezuela and rural India.

Time spent assisting with activities of daily living (ADL) care was also associated with care strain and there was minimum variation in the size of the this association across sites. Mean scores were higher for carers who had cut back or stopped work in all sites with the exception of urban India. Paid carers were common in Cuba, Dominican Republic, urban Peru, Venezuela and urban China. In the final set of analyses, incorporating all variables associated with carer characteristics, carer strain was highest in urban China, Cuba and Venezuela and lowest in rural Mexico, rural China and urban India.

This study underscores important findings in the care receiver and caregiving relationship, in diverse population samples. Specifically, this study was able to investigate whether these relationships were similar or dissimilar across multiple countries. The article not only highlights the contribution of carer and care recipient characteristics to caregiver strain, but also highlights the global need for caregiver support, education and training.

Here are three articles you can review to learn about this study, and other studies examining the oldest old.

Prince M, Brodaty H, Uwakwe R, et al. Strain and its correlates among carers of people with dementia in low income and middle income countries. A 10/66 Dementia Research group population based survey. Int J Geriatr Psychiatry

Prince MJ, Acosta D, Castro-Costa E, et al. (2009) Packages of care for dementia in low and milddle income countries. PLoS Med 6(11)

Alzheimer’s Disease Facts and Figures 2010, Alzheimer's Association

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL

Author: Neelum Aggarwal MD at 8:44 AM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.