Feb. 25, 2016 -- Of the 244 potential Alzheimer's drugs tested in people over 10 years, only one of them earned FDA approval.
Since the paper was published, the agency greenlit a second drug, Namzaric. It’s a combination of two other Alzheimer's meds already on the market, donepezil and memantine. Namzaric’s arrival means there are only five approved medications for the disease.
But Cummings, director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, and others in the field remain optimistic. Researchers are testing 107 potential Alzheimer’s drugs in people, he says.
They include a number of “repurposed” drugs already on the market to treat conditions such as high blood pressure and ADHD. Most of the meds being studied aim to lessen Alzheimer's symptoms rather than attack the underlying disease process, which is an even greater challenge, Cummings says.
Among new drugs in development, researchers are testing treatments that work on pieces of two proteins -- beta-amyloid and tau -- found in the brains of people with the disease. They are also trying drugs to treat inflammation. The goal for some of these treatments is to slow the disease from getting worse.
The last 35 years of research have taught doctors that a number of things play roles in causing Alzheimer's, says Howard Fillit, MD, chief science officer and founding executive director of the Alzheimer’s Drug Discovery Foundation. “There are many ways that (brain) cells die.”
It’s unlikely that any single drug will be able to slow or reverse a disease as complex as this type of dementia, which affects more than 5 million Americans, Fillit and other experts say. They look to what's been accomplished with HIV -- no longer a death sentence, thanks to a cocktail of medications -- as a model for how to approach treating Alzheimer's disease.
“We’re going to need combinations,” says James Hendrix, PhD, director of global science initiatives at the Alzheimer's Association.
Looking for Amyloid
For decades, researchers had focused on one target: amyloid plaque, one of the two hallmark brain abnormalities in Alzheimer's, Hendrix says. Amyloid plaque is made up of clumps of brain cells and proteins called beta-amyloid. Researchers thought this plaque caused damage to brain cells in Alzheimer’s disease. Today, many think the plaques are a last-ditch defense by the brain against beta-amyloid.
Until recently, the presence of amyloid plaque could be confirmed only with a brain biopsy or by doing a brain autopsy. Autopsy studies suggest that as many as 20% of people thought to have Alzheimer’s disease don’t actually have these plaques. That could help explain why tests of anti-amyloid compounds have failed, Hendrix says.
In 2012, though, the FDA approved Amyvid, the first drug that enabled doctors and researchers to use PET (positron emission tomography) scans to see amyloid plaques in people being checked for Alzheimer's disease.
Researchers are also testing another radioactive drug that enables PET scans to pick up the “tangles” of tau protein that represent the other hallmark of the disease. These twisted strands cause brain cells to starve to death. Perhaps 20% of people with dementia in old age have tangles but no amyloid plaque, Fillit says.
Although the drug being tested hasn't yet been approved by the FDA, researchers are using it to help determine whether patients they want to enroll in studies are likely to have Alzheimer's and not some other condition that causes dementia.
Treat High Blood Pressure, Help the Brain?
Researchers say a promising area for Alzheimer's treatment is to use meds that are already on the market for other conditions or diseases. Ihab Hajjar, MD, from Emory University School of Medicine, says this can save time because the drugs are already considered safe. Doctors can begin prescribing them as soon as researchers show they’re effective for Alzheimer's.
Hajjar has received nearly $1 million from Fillit’s foundation to do two studies of a high blood pressure medication, candesartan (Atacand), in people with mild cognitive impairment, or MCI, memory loss that raises their chances of getting dementia.
Decades ago, scientists first noticed that high blood pressure might be linked to a higher risk of dementia. Hajjar says he noticed that patients whose high blood pressure was controlled with medication tended to stay sharper than those with untreated high blood pressure.
If people who take candesartan have better memory and thinking skills, Hajjar hopes to learn whether that's due to the drug’s ability to lower blood pressure or to the drug itself.
Other medications being tested include:
- Benfotiamine, a form of vitamin B1. Researchers think it may help the brain use blood sugar better and slow a decline in mental function. One theory of Alzheimer’s is that the brain loses its ability to use blood sugar effectively. Intranasal insulin, already approved to treat diabetes, is also being tested.
- Levetiracetam. This epilepsy drug may reduce seizures and other types of overactive electrical activity in the brain, which have been shown to contribute to the loss of memory and thinking ability.
- A combination of ibuprofen and a drug used in some allergy and asthma medications, called cromoglicic acid, that targets brain inflammation
Fillit says he's excited about treatments that help promote the growth and survival of nerve cells. Last year, his foundation awarded its inaugural prize for drug discovery to Frank Longo, MD, PhD, for the development of drugs that can mimic normal brain proteins, called neurotrophins, that help neurons grow and survive.
Longo, the chair of neurology and neurological sciences at Stanford University, has been able to reverse declines in mice with an Alzheimer’s-like condition. Testing in people with mild to moderate Alzheimer's disease is expected to begin later this year.
Another experimental drug, solanezumab, carries beta-amyloid out of the brain. One study has found that it appears to slow the disease from getting worse for people who are in its early stages. Other experimental treatments try to keep beta-amyloid from being created or attack tau protein.
Trying to Prevent Alzheimer’s
While some studies seek treatments to improve the health of people who’ve already been diagnosed with the disease, others are testing compounds that might prevent at-risk people from getting it in the first place.
Cummings is involved in two prevention trials. The international TOMMORROW study enrolled more than 5,000 people 65 to 83 years old who had no symptoms of memory impairment but were predisposed to getting Alzheimer’s. Potential participants all got a blood test for two genetic signs: apolipoprotein E (APOE) and TOMM40.
Scientists already know that one version of APOE, called APOE4, is a risk factor for Alzheimer’s disease in older people. TOMM40’s role as a risk factor is less clear and is one of the questions TOMMORROW hopes to answer. The study is also looking at whether the diabetes drug pioglitazone (Actos) might protect against Alzheimer’s in high-risk people.
Cummings’ other prevention trial is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease study (A4 for short). The study is enrolling people 65 to 85 years old who have no symptoms of memory impairment but do have levels of amyloid plaque in the brain, as shown on a PET scan. They're receiving either an experimental anti-amyloid antibody or a placebo at random.
“I can imagine that preventing the damage that occurs when plaques and tangles form in the brain would be easier than repairing the damage,” Hendrix says.