CHICAGO—A three-year pilot study of people with DownSyndrome (DS) could identify early signs of Alzheimer's disease (AD) because ofsimilar neuropathology in the two conditions. Researchers are aiming forpreventive therapy or early intervention for the dementia associated with bothdiseases through a longer-term collaborative program.
At a workshop at the Alzheimer's Association headquarters inSeptember, Janssen Research & Development LLC, a Titusville, N.J. -basedunit of Johnson & Johnson, reported on its participation in and seedfunding of the study, which would culminate in a public-private partnershipinvolving academia, government and industry. At the core of the study is anattempt to identify high levels of amyloid precursor protein (APP), whichcauses plaques and tangles in the brain in both conditions.
Most people with DS have three copies of chromosome 21, knownas trisomy 21. The gene that codes for APP resides on chromosome 21. Mostearly-onset AD results from mutations in the APP gene or in one of two genesknown as presenilin 1 or presenilin 2. Positron emission tomography (PET) imaging scans and autopsy resultsfrom individuals with DS show the same kind of plaque development as those fromnon-DS individuals with AD.
Most studies of treatments for AD have focused on people whoalready exhibited symptoms. The researchers hope that studying a population likelyto develop the symptoms and then developing proof of principle will provideefficient drug development, early intervention and "a roadmap to benefiteveryone involved, with as little risk as possible to patients," says Dr.Michael Krams, head of neurology at Janssen.
"Adults with Down Syndrome develop the plaques and tanglesby their mid 30s and dementia in their 40s," explains Dr. Seth Ness, medicalleader, pediatrics and neuroscience at Janssen. "It's an enriched populationfor developing dementia, unlike the general population, so the sample size canbe smaller and the length of the study shorter."
"We can achieve more efficient drug development when weobserve patients before they are given a drug and start intervention sooner. Ifa base inhibitor for APP is administered early enough, it can delay dementia bysome timeframe. We're looking for common denominators," adds Krams.
The Down Syndrome Biomarker Initiative (DSBI) is scheduledto begin in late 2012 by studying 12 adults with DS in collaboration with theAlzheimer's Disease Cooperative Study and the University of California SanDiego Down Syndrome Research and Treatment Center. Researchers hope the pilotstudy of amyloid and other biomarkers will establish the infrastructure andprove the feasibility of the approach and serve as the impetus for a larger,multinational DSBI study that will run for five years and include more than1,000 subjects.
DSBI will include "neuropsychological testing (focused onlearning, memory, executive function and processing speed), retinal amyloidimaging and delayed eye-blink classical conditioning, brain PET amyloid imagingand volumetric magnetic resonance imaging, as well as the use of establishedand promising blood biomarkers and clinical endpoints," according to an articlein Nature Reviews Drug Discovery("Down's syndrome and Alzheimer's disease: towards secondary prevention,"September 2012), which claims that "this study would be the first of this scaleto integrate all of these classic and novel endpoints together with the goal ofproviding sentinel cohorts for future trials." It would determine how thebiomarkers affect cognition.
Ultimately, researchers in the study want to establish aplatform for clinical trials to test drug interventions that could slow theprogression of the clinical signs of AD. The study would administer "a safe andwell-tolerated pharmacological treatment" to "a homogeneous sample that islarge enough to allow for robust inferences, in which treatment for allparticipants is started at the same stage of the underlying disease," accordingto the Nature article. Then theeffects of the treatment would be analyzed over time.
The standardized approach for assessment in DSBI is similarto that of the Alzheimer's Disease Neuroimaging Initiative, a public-privatepartnership that helped identify biomarkers linked with Alzheimer's. However,DSBI would also offer a platform for clinical trials to test pharmacologicalinterventions aimed at delaying the onset of clinical decline and slowing theprogression of amyloid deposition and other AD neuropathology.