番茄社区

LONDON -- With several failed drug trials and without full understanding of the etiology of Alzheimer's disease for developing better therapeutics, dementia specialists have shifted their focus to prevention.

At this year's , press briefings featured epidemiologic data aimed at disentangling disease risk factors, rather than randomized controlled drug trials. (Some of the latter were presented at the meeting, but most were negative.)

Also heavily promoted here was a Lancet Commission report on dementia prevention and care -- though the group was originally focused on dementia care alone -- asserting that more than a third of dementia cases can be prevented by targeting certain risk factors.

And a report last month from the National Academies of Science, Engineering, and Medicine said that three interventions -- cognitive training, blood pressure management in those with hypertension, and increased physical activity -- have "inconclusive but encouraging" evidence that they can help stave off dementia.

All of this is a big change from past meetings; only two years ago, a new interpretation of solanezumab data had researchers mildly optimistic that a drug would finally halt Alzheimer's progression.

"Some may say, well, we always knew [about prevention]," Lon Schneider, MD, of the University of Southern California and a co-author of the Lancet Commission report, told 番茄社区. "But in 2010, an NIH committee said there was no prevention."

"I think the field is changing," he said.

Lancet Report

When the Lancet Commission came together two years ago, it was called the Dementia Care Commission -- but it shifted to the Dementia Prevention, Intervention, and Care Commission.

Its main finding is that 35% of all dementia -- not just dementia due to Alzheimer's disease -- is "potentially modifiable." The 24 international researchers on the committee drew that conclusion through a review of mostly epidemiologic data.

It separates those modifiable risk factors into early, mid-, and late-life prevention, with varying attributable risk:

• Early life: poor education (8%)
• Mid-life: hearing loss (9%), hypertension (2%), obesity (1%)
• Late-life: smoking (5%), depression (4%), physical inactivity (3%), social isolation (2%), and diabetes (1%)

"You can do a lot with respect to risk reduction early on," Schneider said. "It does decrease the incidence of Alzheimer's disease considerably, delaying the onset."

David Knopman, MD, of the Mayo Clinic, who was not involved in the report, agreed that there was much that could be done to reduce dementia risk, and it's mainly through preventing cerebrovascular risk -- "which people should be doing anyway," he said.

"Cerebrovascular disease on a population basis has a major contribution to dementia, and if you can reduce that burden, you can effectively delay the appearance of dementia," Knopman said. "If you can strip away that cerebrovascular burden, the Alzheimer's is going to take longer to become symptomatic."

He noted that "you're not touching the Alzheimer's pathology by itself, but by removing its sidekick, you're increasing the age at which Alzheimer's itself would lead to symptomatic manifestations."

Schneider acknowledged that the "knock on [these findings] is that these aren't experiments, this is epidemiology." It's understood that randomized controlled trials for some of these interventions -- cigarette smoking, for instance -- would be unethical, so "at a certain point you have to accept and deal with the risk factors that you do see," he said.

The second half of the report focuses on dementia care, and Schneider emphasized that the group doesn't recommend use of psychotropic drugs to treat agitation, depression, or anxiety in Alzheimer's disease.

It does recommend an individualized treatment approach to the disease, as its impacts on cognition, neuropsychiatry, activities of daily living, and other comorbid conditions vary from patient to patient.

And the commission fully supports use of psychosocial interventions for many aspect of Alzheimer's disease, particularly cognitive stimulation therapy, a group therapy that increases social interaction.

"Psychosocial interventions will improve dementia in multiple unappreciated ways," Schneider said.

The Drug Pipeline

There are still plenty of drugs for Alzheimer's disease in development, but in many cases, results aren't expected for a while.

Several of the amyloid-targeting monoclonal antibodies that met with failures are being pushed ahead in late-stage studies, including solanezumab, gantenerumab, and crenezumab. And aducanumab, which had positive results in a phase I study and jumped to late-stage trials, may offer the most promising prospects yet for an amyloid-targeting strategy. But these trials aren't expected to report out for a few years.

Drugs targeting tau, which plays a later-stage role in Alzheimer's disease, are also in development, but are still in early trials.

Drugmaker Axovant has been building support for its selective 5HT6 receptor antagonist intepirdine, which may act synergistically with donepezil (Aricept) to boost acetylcholine neurotransmission. Top-line results are expected in September, but researchers aren't holding their breath, given that a similar drug candidate from Lundbeck, idalopirdine, didn't pass its phase III tests, according to top-line results.

Knopman described that therapeutic landscape as "very cautiously optimistic." Schneider said that rather than seeing the lack of a new drug candidate as hopeless, it's a challenge to developers. The future of Alzheimer's drug development -- as is often heard in sessions here at AAIC -- will be finding the right drug for the right patient at the right time.

"It's unlikely that you'll find the one hole you can plug with one drug," Schneider said. "We're going to have to develop different targets simultaneously and put them together and figure out the right timing."

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