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Alzheimer's research is moving toward early diagnoses and biomarkers

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By Nuala Moran
Staff Writer

SAN JOSE, Calif. – The industry's expensive attempts to develop treatments for Alzheimer's disease have been confounded by the difficulties of diagnosis, and multiple drugs targeting amyloid plaques, administered once overt symptoms are well established, have failed in development.

With the medical and social need ever more urgent, scientists are regrouping, focusing efforts on ways to make earlier diagnoses, finding biomarkers for disease initiation and progression, shifting discovery and development away from amyloid plaques and onto preventing the formation and spread of tau tangles, and looking to well-defined, rare, neurodegenerative diseases as proxies for Alzheimer's.

Those and other developments in the field were discussed at two sessions looking at the latest advances in Alzheimer's disease research at the AAAS meeting on Friday and Saturday.

That dementia is now recognized as a major public health crisis is underscored by the response of the G7 nations, which over 2014-15 organized a series of events examining different aspects of the disease and took stock of emerging research, with the aim of creating a concerted global push to develop new treatments.

One result has been to highlight under-investment in Alzheimer's research compared to cancer and other serious, common diseases, as noted by Simon Lovestone, of Oxford University, who told attendees of a major UK initiative announced on Monday. Alzheimer's Research UK, the largest dementia research charity in the world will invest £30 million (US$46 million) in three drug discovery institutes at Cambridge and Oxford universities and University College London.

The institutes will employ 90 scientists with a brief to fast-track the discovery of new therapies. Basic research from the three universities and elsewhere will be handed straight over to the institutes to drive development of a pipeline of drug leads.

Lovestone, who is to co-lead the institute at Oxford University, said dementia is playing catch-up with other areas of disease research and needs a step change. The new institutes "represent the best coordinated and strategic effort to make progress in dementia research and will build on successes in tackling other diseases to give us the best chance of making a difference," he said.

THE EXOSOME TEST

By the time the symptoms of Alzheimer's disease are on display, the affected neurons have been damaged beyond repair. Most products tested after the onset of symptoms have failed and the only registered treatments have a modest effect over a short period of time.

The key target in drug development to date has been amyloid beta, which forms plaques on the outside of neurons. While it is possible to detect amyloid buildup as long as 20 years before symptoms are manifest, using magnetic resonance imaging and analysis of cerebrospinal fluid, those are expensive tests.

Yet it is really important to know who has preclinical disease, said Erin Abner, of the University of Kentucky Alzheimer's Disease Center. "The last Alzheimer's disease drug was approved in 2002; it's now 2015. But it's not for lack of trying; there have been many, many clinical trials."

"We really need to do better and we think we can do better if we can intervene earlier in the disease process – we think we failed from treating too late," Abner said. What is needed is a good blood test. However, Abner noted, there has not been much success in trying to measure amyloid in the blood, because there is high degree of variability.

Dimitrios Kapogiannis, of the National Institute of Aging in Baltimore, described an emerging class of diagnostics based on exosomes or membrane vesicles, that are shed by all the cells in the body and can be isolated from blood. Exosomes from Alzheimer's disease patients contain amyloid beta, tau and other pathogenic proteins.

Since exosomes express cell-specific markers, it is possible to single out vesicles shed from neurons in blood samples. "We can capture exosomes from neurons and measure the proteins inside; we think we have a window into the brain," Kapogiannis told delegates.

The researchers at the National Institute of Aging have found significant differences between Alzheimer's disease and controls for levels of tau and amyloid in neuronal exosomes. "There is literally no overlap for the values for controls and Alzheimer's," Kapogiannis said. "The test looks to distinguish Alzheimer's disease patients from the cognitively intact elderly."

Indeed, the exosome test is better than magnetic resonance imaging and cerebrospinal fluid analysis combined, in diagnosing Alzheimer's disease. There also is preliminary evidence that exosomes can be used to detect Alzheimer's disease in advance of symptoms developing, with the researchers finding abnormal proteins in biobanked samples up to 10 years before a formal diagnosis was made.

Those diagnostics could be used to distinguish mild cognitive impairment from the cognitive deficits of normal aging. Exosome diagnostics may also advance the understanding of what is going wrong in Alzheimer's disease.

In addition, biomarkers from exosomes could be used to assess whether drugs are engaging with their targets, and if so, whether that leads to clinical improvements, Kapogiannis suggested.

FROM ANYLOID BETA TO TAU

Adam Boxer, director of the Neurosciences Clinical Research Unit at the Memory and Aging Center, University of California, San Francisco, described how the clinical development of Alzheimer's disease therapies is being refined in the light of the multiple failures of trials targeting amyloid beta.

One of the first responses was to assess whether failed amyloid-targeting drugs might be effective if used before symptoms occur, and a number of such trials are running currently. "Treating patients early and trying to remove amyloid seems promising," Boxer said.

The work is being assisted by the arrival over the past two years of fluorescent markers for amyloid beta and tau, making it possible to visualize the proteins in living people. "We can use this to see if drugs are effective," said Boxer.

With attention turning to targeting tau, those fluorescent markers are extremely important tools for drug development.

While tau is now thought to be responsible for causing the damage that is the hallmark of Alzheimer's disease, tau tangles occur in a number of other neurodegenerative diseases, which are better defined.

"This allows us to be cleverer about trials, by selecting patients," Boxer said.

Boxer has singled out progressive supranuclar palsy (PSP), a rare tauopathy.

"We think there are a number of advantages of focusing in on rarer neurodegenerative diseases," he said. Those include better targeting, more rapid progression of disease, allowing for faster trials, and regulatory incentives for orphan drug development.

"If [a drug] worked in PSP, we would also believe it would work in other tauopathies," Boxer said.