A Cure for Alzheimer's: Why it's taking so long
Bill Holt
Bill Holt
Executive Director, Neurosciences, Scientific Affairs

Alzheimer's disease (AD) is the sixth-leading cause of death in the United States. But it’s the only cause of death among the top 10 in the United States that cannot be prevented, cured or even slowed. It kills more people than breast cancer and prostate cancer combined. One in three elderly people die with Alzheimer’s disease or related dementia. Drugs that ameliorate the symptoms of AD or treat the underlying cause are urgently needed for this condition that by some estimates will cost more than $1.1 trillion in healthcare costs by 2050 – an amount that is almost half of the US total Medicare budget for 2016.

Bill Holt, DO, Executive Director, Neurosciences, Scientific Affairs, of PRA Health Sciences discusses Alzheimer's research, both past and present, and the direction research is heading.

What is it?

Alzheimer’s is not a normal part of aging. It’s the most common form of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life. Alzheimer's disease accounts for 60 to 80 percent of dementia cases. The greatest known risk factor is increasing age; the majority of people with Alzheimer's are 65 and older.

But, surprisingly, Alzheimer's is not just a disease of old age. Approximately 200,000 Americans under the age of 65 have younger-onset Alzheimer’s disease (also known as early-onset Alzheimer’s). Unfortunately, AD is a progressive disease, where dementia symptoms gradually worsen over a number of years. In its early stages, memory loss is mild, but with late-stage Alzheimer's, individuals lose the ability to carry on a conversation and respond to their environment.

Those with Alzheimer's live an average of eight years after their symptoms become noticeable to others, but survival can range from four to 20 years, depending on age and other health conditions. Although AD has no current cure, treatments for symptoms are available and research continues.

While current Alzheimer's treatments cannot stop Alzheimer's from progressing, they can temporarily slow the worsening of dementia symptoms and improve quality of life for those with Alzheimer's and their caregivers. Today, there is a worldwide effort under way to find better options to treat the disease, delay its onset, and prevent it from developing.

Alzheimer's Research Over the Years

German physician Alois Alzheimer first identified a disease that dramatically shrank the brain and left abnormal deposits in and around brain nerve cells.

Researchers identified tau protein as a key component in Alzheimer’s.

The abnormal accumulation of tau protein is another hallmark of AD pathology. Tau protein helps maintain the structure of a neuron, including tiny tube-like structures called microtubules that deliver nutrients throughout the neuron. AADvac1 is a vaccine that stimulates the body’s immune system to attack an abnormal form of Tau protein that destabilizes the structure of neurons. If successful, it has the potential to help stop the progression of Alzheimer’s disease. A Phase 2 clinical trial enrolling 185 volunteers with mild Alzheimer’s disease began in March 2015 and is expected to be completed in February 2019.

The FDA approved the first drug specifically treating the symptoms of Alzheimer’s.

The first approved drugs for the treatment of AD were designed to increase acetylcholine, a brain neurotransmitter found to be deficient in patients with this neurodegenerative disease. Although modestly effective in improving signs and symptoms of the disease, these drugs do not alter what is felt to be the underlying pathology and ultimately disease progression ensues.

Promising developments in potential disease modification via a vaccine first reported.

This monoclonal antibody vaccine was shown to reduce the abnormal accumulation of Beta-amyloid, a putative causative agent in AD pathology. Early clinical trials were discontinued in 2002 when 6 percent of the recipients developed encephalitis due in part to the nature of the active vaccine. Despite the results of the first vaccine trial, the concept of using the immune system as a therapeutic for AD has continued to gain traction during the past 16 years.

The predominant hypothesis 15 years ago was that the removal of Beta-amyloid plaque would result in patients improving and possibly arresting the disease progression. Multiple reformulations of Beta-amyloid passive vaccines have been shown to reduce plaque burden in mild-to moderate AD patients, but none have demonstrated consistent efficacy with regards to either improving cognition or activities of daily living in AD patients in large scale trials. Current thinking is that once the amyloid cascade from plaque deposition has begun, there is an inexorable loss of neuronal function. Recent trials have focused on enrolling subjects in these types of trials that are either asymptomatic but at risk to develop AD or those in the earliest stages of the disease.

In a Phase II proof-of-concept trial, Biogen’s aducanumab showed a dose-dependent reduction in brain amyloid after twelve months as well as a dose-dependent slowing of cognitive decline compared to placebo. These encouraging results have led to the commencement of a large-scale Phase III trial, which is enrolling now.

Alzheimer’s advances to the sixth-leading cause of death in the United States.

Researchers identify new genetic risk factors for Alzheimer’s.

20 genetic variations were associated with increased risk, including almost a dozen that were not previously linked to Alzheimer’s. PRA is currently conducting a trial by the Dominantly Inherited Alzheimer’s Network (DIAN), which is testing the ability to slow amyloid accumulation and cognitive decline in individuals at high risk for processing an autosomal dominant AD gene.

Studies are launched to investigate increasing acetylcholine.

People with Alzheimer’s disease have low levels of acetylcholine, a neurotransmitter. The 5HT6 receptor found on some brain cells can lock in neurotransmitters, decreasing communication between nerve cells (neurons). Only through neuron-to-neuron communication can an individual think and function normally. Blocking the 5HT6 receptor may increase the amount of acetylcholine and help nerve cells to maintain normal communication.

Intepirdine is a 5HT6 receptor antagonist that blocks the receptor’s ability to decrease acetylcholine levels. A Phase 3 clinical trial of Intepirdine began in October 2015 with a goal of recruiting 1,150 people with mild-to-moderate Alzheimer’s disease. The trial is expected to be completed in October 2017, at which time researchers compare the thinking and functioning abilities of study participants who received Intepirdine with those who received an identical but inactive pill.

Clinical trials in AD are complex, lengthy and expensive compared to other therapeutic indications. PRA's internal team of medical, scientific and operational experts are exploring novel AD trial designs, leveraging vast pools of data available from our medical informatics group, and networking with industry sponsors and patient advocacy groups to foster innovative approaches for the advancement of future AD therapies.