Highlights: 

  • Recent and past pharmaceutical interventions have failed to stop the progression of Alzheimer’s disease. 
  • Drug failures could partially be due to scientists focusing too much on one idea. 
  • For those not yet afflicted, reducing the risk of Alzheimer’s disease is possible. 

Certainly not due to a lack of trial and error, Alzheimer’s disease (AD) remains without a cure. Two drugs that target the proteins supposedly responsible for AD have recently failed human trials. In a phase 2 clinical trial (NCT03289143), published in JAMA Neurology, a drug that targets tau proteins, called Semorinemab failed to slow the progression of AD. In another clinical trial (NCT01998841), a drug called Crenezumab, which targets amyloid proteins, also failed to slow AD progression.  Genentech Inc. and Roche are among the pharmaceutical companies financing both Semorinemab and Crenezumab. 

These recent clinical trial failures only add to what has been called the Alzheimer’s drug fiasco, whereby the drug Aduhelm was granted accelerated approval by the Federal Drug Administration (FDA) despite a unanimous vote against it by an expert panel. A third of patients who take Aduhelm experience side effects such as brain swelling and bleeding, which can lead to death. Once the drug was approved, three of the panel members quit in protest. The approval stems from what could be called inappropriate interactions between the FDA, Alzheimer’s Association, and Biogen, the pharmaceutical company financing Aduhelm. 

Alzheimer’s Research Shrouded in Dogma 

One possible reason for so many failing AD drug trials is that too many scientists have chased the same ideas for too long. In a comprehensive analysis, published in the Journal of Alzheimer’s Disease, Kim and colleagues found that 23% of failed AD drugs targeted amyloid and 7% targeted tau. Amyloid plaques and tau tangles are protein aggregates that can accumulate in the brain with age, intricately linked to AD pathology. However, whether they play a causative role remains unclear. Despite this uncertainty, many scientists have held onto the idea that targeting amyloid and tau will stop the progression of AD. 

There are several reasons why reducing amyloid and tau with drugs may not be the best approach for treating AD. Among these is the fact that amyloid proteins can be found in the brains of elderly individuals without AD. That is, older adults can have amyloid plaques in their brain and be cognitively normal, suggesting that amyloid does not cause AD. Conversely, AD patients may have very few of these amyloid plaques. Furthermore, there have been drugs, including Aduhelm, that have successfully reduced amyloid and tau proteins in AD patients but still do not improve cognitive function in these patients, thus failing to halt AD progression. 

Both Aduhelm and Crenezumab target amyloid while Semorinemab targets tau. These drugs were tested under the hypothesis that getting rid of these proteins will stop the progression of AD. This remains the dominant hypothesis in the AD field and has made it difficult for young scientists to make progress with new ideas. While it is becoming more accepted that other factors such as cholesterol dysregulation, changes in energy metabolism, and neuroinflammation could lead to AD, a bulk of AD research has been focused on amyloid and tau.

Active Non-Amyloid Trials

Of the currently active phase 3 and 4 clinical trials for the treatment of cognitive impairments in AD, about half target amyloid or tau proteins. Among the rest of the active trials, drugs that enhance the neurotransmitter acetylcholine (Alfoatirin and Aripezil), target misfolded proteins and oxidative stress (ANAVEX2-73), and regulate lipid metabolism (icosapen ethyl) are included. Thus, all the money seems to be on drugs that target amyloid and tau.

Preventing Alzheimer’s Disease?

Millions of older adults across the world have AD, a number that is expected to grow with the aging population. For these individuals who have been deprived of precious memories and the freedoms of daily living, there is still hope for finding a treatment that stops or reverses AD progression. For this to happen, it will perhaps take leaps in scientific progress, or it could be that the answers are already there, but hidden behind scientific dogma. 

While scientists and pharmaceutical companies continue to search for AD drug interventions, there are those of us who can take immediate steps to potentially prevent cognitive decline and eventual AD or dementia diagnoses. In The Journal of Prevention of Alzheimer’s Disease, Zhang and colleagues discuss AD risk factors and how AD can be prevented. Indeed, one-third of AD cases worldwide are attributed to underlying modifiable risk factors. These modifications are listed below: 

  • Active engagement in cognitive activity reduces AD risk by 46%. These cognitive activities include: 
    • Analog games, such as board and card games. 
    • Bilingualism; learning a new language can boost brain connectivity. 
    • Higher educational attainment; could increase brain volume. 
  • Social engagement, such as frequent social contact with friends and family.
  • Reducing depression and stress. 

There are also diseases associated with a higher risk of AD. Many of these diseases are preventable, usually through diet, exercise, and good hygiene. These diseases and conditions include:

  • Diabetes, obesity, and cardiovascular disease, which can often be prevented by eating healthy foods and getting regular exercise. 
  • Hearing loss, which in some cases can be prevented with the use of hearing aids or cochlear implants. 
  • Oral disease, particularly tooth loss and gum disease, which can possibly be prevented by regular visits to the dentist.

Lifestyle factors, such as exercise, already mentioned above can also reduce the risk of AD. Other lifestyle factors for preventing AD and dementia include sleeping for an adequate duration every night, not smoking, and not drinking excessive levels of alcohol. When it comes to diet, there are several key nutrients that seem to have beneficial effects against cognitive decline, dementia, and AD. These include omega-3s and B vitamins. 

While there are genetic predispositions, over 90% of AD cases are sporadic, meaning that it could happen to any of us. The fact that AD is one of the top ten leading causes of death in wealthy countries like the United States makes prevention that much more important. Simple lifestyle changes, like the ones stated above, seem like a promising strategy for preventing this devastating disease.