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Adapted from a PhRMA analysis of the Adis R&D Insight database on investigational drugs in various stages of clinical development; Chart: Axios Visuals

Gradually losing memories in a tangle of errant proteins and dying brain neurons from Alzheimer's disease strikes fear into many. Time after time, drug companies have struck out in trials looking to prevent or even slow the debilitating disease and are turning to fundamentally different approaches, or altogether abandoning their efforts.

Why it matters: There are currently 5.7 million Americans living with the disease — and 14 million more are expected to develop it by 2050 — all of whom are desperately seeking answers.

The big picture: There are roughly 326 active, recruiting or enrolling by invitation clinical trials on the elusive disease, per clinicaltrial.gov. The U.S. last year dramatically stepped up funding for Alzheimer's disease research, from $400 million a year to over $2 billion annually, although the Alzheimer's Association says more is needed.

The biggest problem: Scientists still don't know the cause of Alzheimer's.

  • There's a strong genetic link in the rare early-onset type (in those under 65 years) but the cause is less clear for the majority of those with Alzheimer's who are older than 65.
  • What is known: More women (2/3) than men get the disease, there are genetic risk factors, and there are 3 hallmarks — brains show increased beta-amyloid proteins leading to "plaques," there are large numbers of tau protein creating "tangles," and neurons are lost accompanied by brain-size shrinkage.

For decades, the buzz centered on those proteins, with the hope that at least one is a cause of the disease and not just caused by it — but so far none have panned out, resulting in an expensive array of halted experiments with a recent shift toward other research areas.

  • According to PhRMA (and indicated in the chart above based on an Adis database), 146 investigational drugs were halted in development and 4 were approved from 1998–2017.
  • For the discontinued trials, 40% were in early trial phases 0, 1, or 1/2; 39% in phases 2 or 2/3; and 18% had made it to phase 3 or regulatory review before being dropped, PhRMA reported.
  • The 4 that were successfully approved (Aricept, Exelon, Razadyne and Namenda) during that period all aim to lessen symptoms, like memory loss and confusion, but do not halt or slow the progress of the disease.

The latest: Here are some of the approaches now, some of which target more than one goal...

  • Staying the amyloid course: Some companies continue looking at anti-amyloid drugs, such as this phase 3 trial of BAN2401 that focuses on people with mild Alzheimer's disease or this phase 3 trial of AMG 520/CNP520 that inhibits the BACE1 enzyme that helps form plaque.
  • Examining other possible causes: Derek Lowe, a chemist who works on drug discovery and writes the blog "In the Pipeline," tells Axios he's intrigued by recent trials looking at the possible role of viruses or bacteria in setting off the disease, though he calls it "a long shot."
  • Slowing its progression: Some trials are looking to help save people's memories and slow the degeneration caused by the disease, including this phase 2 trial of PDE4D.
  • Treating its conditions: Therapies to treat some of the conditions of Alzheimer's, such as these two trials (for AXS-05 and AVP-786) try to help with agitation.
  • Finding it earlier: Diagnostics, including imaging and blood tests, are a growing field. "Let's see if we can predict the onset of Alzheimer's," NIH director Francis Collins told a press briefing last week, saying he hoped the long-term study of 1 million people in the All of Us program could assist.

New avenues aren't just in medicine and genetics but on the impact from lifestyle changes including reproductive health with its changes in the vascular and immune systems, and modifiable risk factors like sleep, cardiovascular disease and blood pressure.

  • "We're still learning more and more about what the biological changes mean and how they relate to changes in cognitive [behavior] over time," Rebecca Edelmayer, director of scientific engagement of the Alzheimer's Association, tells Axios.
  • Earlier this week, the World Health Organization issued guidelines for every day life to reduce the risk of dementia.

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