Alzheimer Cascade Starts Two Decades Before Symptoms

Neurology Today
20 October 2011; Volume 11(20); pp 45-46

Collins, Thomas R.

SAN DIEGO—The first interim analysis of data from a highly anticipated project focusing on dominantly inherited Alzheimer disease (AD) patients shows that the pathophysiologic cascade leading to the disease appears to begin 20 years before clinical symptoms arise.

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In their analysis of data from 157 participants — whose parents were affected by AD and who were identified as having a rare gene mutation that virtually ensures the development of AD, usually at a young age — researchers detected several changes before the expected start of clinical disease.

These changes included declining left hippocampal volume; increasing presence of tau protein in CSF; and increasing third ventricle volume seen on MRI.

The subjects are being matched with normal controls, and are undergoing diagnostic testing at regular intervals to track important biomarkers.

Researchers say the findings are all the more reason to look to the genetic form of the disease for trials to develop treatment for both the dominantly inherited and the more common, sporadic forms of AD.

The Dominantly Inherited Alzheimer's Network (DIAN) — a project funded by the NIH and involving researchers in the US, UK, and Australia — will start clinical trials to delay the start of symptoms or slow cognitive decline in 2012. Eleven compounds have been nominated for trials and discussions are continuing about how to proceed. About 200 participants have enrolledenrolled; they hope to enroll 400 participants for clinical trials in 2012.

Researchers liken the approach to the way the first successful statin treatment was shown through the study of genetic hypercholesterolemia.

Special attention will be given to the treatment of amyloid beta deposition, which is thought to trigger a series of pathophysiological events that lead to AD.

“By bringing treatment trials into this population, we may be able to treat people when they're getting amyloid deposition… five, ten, 15 years before they have any signs or symptoms,” said Randall Bateman, MD, associate professor of neurology at the Washington University School of Medicine and associate director of DIAN.

“The basic tenet here is that some of the first changes that we detect are in amyloid beta. Those amyloid-beta changes set off other events and cause disease in these patients. If we can treat participants early before they have significant brain atrophy, neural dysfunction, and metabolic dysfunction, we expect to prevent downstream Alzheimer disease changes from occurring and lead to improved cognitive outcomes.”

Dominantly inherited AD (DIAD), also known as autosomal dominant AD or “familial” AD, is thought to account for less than 1 percent of all cases of the disease. DIAD differs in some basic ways from sporadic AD — the patients have a genetic mutation tied to AD, and many AD patients have outward symptoms far earlier than sporadic AD. There are also some subtle biomarker differences, Dr. Bateman said.

“But to a large extent, all of the pathobiological measures that we detect in dominantly inherited AD in large part mirror sporadic AD,” he said. “So one interpretation is that the cause or pathogenesis of the disease may be different between sporadic and autosomal dominant, but they quickly converge on a similar pathophysiological pathway.

“The dominantly inherited and sporadic forms merge into problems of amyloid beta accumulation and deposition, building up high concentrations, and starting other processes — inflammation, tauopathy — eventually leading to atrophy, synapse (and) neuron loss. The manifestation of that is the cognitive impairment…. And all of that's similar between the two forms of the disease.”

Even if the project's trials produce potentially useful results, one of the challenges will be to use those biomarkers to identify those who are at risk of sporadic AD.

Joy Snider, MD, PhD, associate professor of neurology at Washington University School of Medicine, who is not directly involved with DIAN, said trials on this so far have tended to exclude patients with other causes of cognitive decline, which is not a real-life reflection of what she sees in the clinic.

“When I'm a doctor in the clinic I see people that have all sorts of stuff going on,” said Dr. Snider, who is studying the use of biomarkers in predicting AD. “So we're trying to extend these findings into the clinic population.”

Michael Rafii, MD, PhD, director of the Memory Disorders Clinic at the University of California, San Diego Perlman Ambulatory Care Center and assistant professor of neurosciences at the University of California, San Diego, said the trials are “a watershed event in AD research.”

“They will help us confirm the findings from MCI (mild cognitive impairment) and AD in asymptomatic individuals who are genetically destined to develop dementia —specifically, replicating the findings regarding changes in beta-amyloid, synaptic loss, cortical and hippocampal atrophy, and amyloid plaque deposition, with concomitant development of symptomatology,” he said. “Then, by introducing a therapeutic agent to alter the trajectory of these changes, at an extremely early stage, we will have the greatest chance of proving efficacy.”

He said there is enough overlap between the two forms of AD to yield worthwhile results.

“The sporadic form of AD is not an exact carbon copy of inherited AD, as there are differences at the genetic, molecular and even clinical phenotypes, but the pathological mechanisms are shared and revolve around beta-amyloid synaptotoxicity,” he said. “I think the most important findings will relate to the safety of taking such therapies for long periods of time, in otherwise asymptomatic individuals.”