Project ideas needed from worldwide Alzheimer Disease research community

On the 9 June 2010, 119 participants from industry, academia, and related stakeholder communities in the U.S. and Europe joined Alzforum for a Webinar, "Treating Before Symptoms—ADCS Invites Ideas for Clinical Trials in Very Early AD," presented by Alzheimer's Disease Cooperative Study (ADCS) director Paul Aisen, MD. In the webinar, Dr. Aisen explained what kinds of project ideas the ADCS leaders welcome from the worldwide Alzheimer Disease research community as they prepare for a new round of federal ADCS funding next year. The ADCS runs trials with public-private collaborations, and has developed a clinical trial infrastructure and a tool kit well suited to push drug trials into the pre-symptomatic phase of the disease.

Joining Aisen for a panel discussion were these notable leaders: Reisa Sperling, BWH; Lon Schneider, USC; Randy Bateman, WashU; Maria Carrillo, Alzheimer's Association, Eric Siemers, Lilly; Pablo Lapuerta and Howard Feldman, BMS; and Dana Hilt, EnVivo Pharmaceuticals.

In his introductory text posted on the Alzforum webinar page, Dr. Aisen writes:
"In recent decades, dramatic strides in elucidating the biochemical and cellular mechanisms underlying Alzheimer disease (AD) have led to general optimism that effective disease-modifying interventions may be within reach. Plausible targets have yielded treatments that have advanced into efficacy trials. But the results of those trials have been painfully disappointing. One pivotal trial after another has failed to demonstrate favorable effects on cognitive and clinical measures; xaliproden, tarenflurbil, tramiprosate, rosiglitazone, and most recently, Dimebon have all failed to achieve their primary endpoints in Phase 3 trials. No new treatment has reached the clinic since approval of the last symptomatic medication, memantine, in 2003.

Undoubtedly, some or all of these candidate interventions failed because of insufficient brain penetration and/or target engagement. But non-pharmacological issues may be stacking the deck against the successful development of disease modifiers.

The diagnosis of AD is based on the presence of the clinical syndrome of dementia. But evidence suggests that the neurobiological features of the disease, including plaque deposition, tangle accumulation, and synaptic loss, begin a decade or more before the onset of dementia. Indeed, the prevalence of amyloid deposition in brain as indicated by amyloid PET scanning or low Aβ42 in the cerebral spinal fluid of non-demented older individuals is 20-40 percent (Jack et al., 2010), indicating a huge population of individuals with a cardinal feature of AD pathology but without dementia. If amyloid dysregulation and other neurobiological abnormalities accumulate many years prior to dementia, it is reasonable to assume that the optimal time to change the disease course by interrupting the driving neurodegenerative processes is long before dementia onset. At the late stage of brain failure represented by dementia, attacking these processes may be minimally effective or even futile. If we think of AD neurodegeneration as a smoldering fire destroying the structural integrity of the brain, we must quench the flame before the damage is irreparable.

Clearly, we should seek the tools necessary to test putative disease modifiers in the pre-dementia population, presumably as early as feasible. We must identify individuals on the AD trajectory prior to significant brain dysfunction. And to indicate treatment effects in these individuals we require outcome measures that are dynamic indicators of disease (and treatment response) when there are little or no cognitive and clinical manifestations. In other words, we need surrogate outcome measures that are reasonably likely to predict long-term, clinically relevant benefits. Progress in the development of biochemical and neuroimaging biomarkers of AD suggests that the necessary tools may be close at hand."

Here is the full text of Dr. Aisen's remarks and a recording of the webinar with slides and audio, including of the Q&A session:
http://www.alzforum.org/res/for/journal/detail.asp?liveID=180

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