Hope in Alzheimer's?

 From Medscape Neurology

Martin R. Farlow, MD

Authors and Disclosures

Posted: 08/01/2012

Hello. I am Dr. Martin Farlow, Professor of Neurology and Vice Chairman for Research in the Department of Neurology and Associate Director of the Alzheimer's Center at Indiana University School of Medicine.
A number of very exciting studies and findings have been presented at the Alzheimer's Association International Conference. I have chosen to focus on 4 topics of particular importance to therapy for Alzheimer disease.
The first presentation is by Randy Bateman^[1] of the Dominantly Inherited Alzheimer's Network Consortium, which follows patients with mutations and 1 of 3 genes associated with early-onset Alzheimer disease. From family histories, Dr. Bateman and colleagues were able to estimate the mean age of onset (typically in the 40s) and then looked at younger gene carriers, and investigated the sequence of biomarker changes occurring before dementia. They found that:

• 20 years before dementia onset, beta-amyloid levels in cerebrospinal fluid began to drop;
• 15 years before dementia onset, beta-amyloid deposits can be detected by amyloid imaging scans, tau levels begin rising in cerebrospinal fluid, and atrophy of the brain begins to become detectable by MRI;
• 10 years before dementia onset, brain metabolic changes are present on FDG-PET and the first hints of episodic memory deficits begin; and
• 5 years before dementia onset, patients develop mild cognitive impairment.

Therefore, for the first time, we have a timeline of events suggesting the need for early intervention, with available biomarkers that can be measured to assess the effects of drug therapy.
A second major presentation by Kari Stefansson and colleagues^[2] reported finding a mutation in approximately 1 of 100 Icelanders that may reduce risk for Alzheimer disease by as much as 5-7 times compared with the general population. The mutation is in the amyloid precursor protein (APP) gene and appears to interfere with the ability of beta-secretase to act on APP cleavage, inhibiting creation of beta-amyloid protein. Levels of beta-amyloid protein are reduced about 40% in individuals with this mutation. This study represents a natural experiment confirming for the first time that lower beta-amyloid levels are associated with lower risk for Alzheimer disease and may further help guide drug development.
A number of presentations and posters^[3-9] at this conference suggest renewed and growing interest by pharmaceutical companies and the academic community in developing beta-secretase inhibitors as dementia-delaying or modifying therapies for Alzheimer disease. In particular, investigators associated with Merck (Whitehouse Station, New Jersey), Eli Lilly and Company (Indianapolis, Indiana), and Eisai Pharmaceuticals (Woodcliff Lake, New Jersey) presented phase 1 data on candidate drugs, suggesting (at least preliminarily) their safety and their ability to penetrate the central nervous system, and reliable dose/response characteristics in lowering beta-amyloid levels, potentially by 50%-90%. These findings raise hope that 1 or more of these oral agents may prove useful as disease-modifying therapy for Alzheimer disease.
Finally, back to symptomatic therapies for Alzheimer disease. I presented a poster describing the Novartis ACTIVE study^[10] that investigated the effects of the rivastigmine 13.3-mg patch vs the 4.6-mg patch in patients with severe Alzheimer disease. This was a 24-week, double-blind trial conducted in 98 centers across the United States, in patients with Mini-Mental State Examination scores of 3-12 at baseline.
Patients did statistically significantly better on the primary outcome measures, which were the Alzheimer Disease Cooperative Study Activities of Daily Living (ADCS ADL), a measure of function and activities of daily living; the severe impairment battery, a measure of cognition at 24 weeks; and the ADCS Clinical Global Impression of Change (CGIC), a measure of global functioning. However, no difference was seen between the groups on the neuropsychiatric inventory, an instrument measuring behavior. These results suggest that the 13.3-mg rivastigmine patch, which is not currently approved by regulatory authorities, may have a future role in the treatment of Alzheimer disease.
Thank you for your attention.