PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.
Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.
DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.
Dr. Randall Bateman
The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.
Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director.
"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.
The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.
Dr. Anne M. Fagan
"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.
The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.
"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.
Several factors provide the rationale for conducting such trials, he said.
For one thing, current therapeutic trials may be too late.
"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.
Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.
Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.
"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.