How close are we to preventing or curing Alzheimer’s disease? Here’s where the research stands in 2021

Dr. Paul Aisen and Dr. Mindy Aisen
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The harsh reality is that Alzheimer’s disease progresses slowly and steadily over time. Historically, we thought of the progression as occurring over a span of seven to 10 years, evolving from mild to moderate to severe dementia.

Today, we talk about the Alzheimer's disease continuum where plaque slowly builds in the brain, then tangles form, progressing for up to 25 years or more. Ultimately, this is a fatal illness.

A Brief History of Alzheimer’s Disease

In the last 20 years, the rate of progress towards prevention or a cure for Alzheimer’s disease has accelerated.

To understand where we stand now in the development of new therapies for aging, it’s helpful to consider the history of Alzheimer’s disease (AD).

2000+ Years

Almost 2500 years ago, humans knew about age-related severe cognitive decline: Plato and Aristotle spoke of mental and cognitive decline as typical and possibly unavoidable symptoms and complications of aging. 20th Century In 1906, a doctor named Alois Alzheimer presented his clinical and brain findings to the medical community in Tubingen, Germany.  

Alzheimer talked about a dementing illness, characterized by memory impairment and behavioral symptoms interfering with daily life. He examined the brain of a German woman named Auguste Deter who had this syndrome and found microscopic abnormalities that we now call plaques and tangles. Deter is considered the first person to have been diagnosed with Alzheimer’s disease.

Since then, the medical community gradually came to recognize AD as a disease rather than destiny. Since the symptoms overlap with other diseases (vascular dementia, Lewy body disease and others), we could only make a diagnosis of “probable AD” in people with dementia without other identifiable cause. Not all age-related decline in function was AD. However, AD could only be definitively diagnosed at autopsy by seeing plaques and tangles in the brain.

In the 1980s, researchers showed that brain plaques were principally composed of sticky protein pieces called beta-amyloids that gradually cluster together over time.

The treatments available were focused only on managing the side effects of Alzheimer’s disease, such as stimulants to enhance alertness and memory, and psychosocial measures to help the patient and their family cope.

We had and have medications that help the memory impairment symptoms that are characteristic of AD, but no treatment to this date has been available for treating the cause and reversing the effects of the disease itself.

21st Century

The last two decades have seen important breakthroughs in how we diagnose AD and, therefore, how we can test new treatments.  This is primarily due to the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of AD. Since its launch in 2004, the landmark public-private partnership has made major contributions to AD research, enabling the sharing of data between researchers around the world. Three overarching goals of the ADNI study are:

1.  To detect AD at the earliest possible stage (pre-dementia) and identify ways to track the disease's progression with biomarkers.

2.  To support advances in AD intervention, prevention, and treatment through the application of new diagnostic methods at the earliest possible stages (when intervention may be most effective).

3.  To continually administer ADNIs innovative data-access policy, which provides all data without embargo to all scientists in the world.

It is the sharing of results by ADNI through the USC Laboratory of Neuro Imagings Image and Data Archive (IDA) that the field has expanded dramatically with the use of the latest technological advances of this century.

The Possibility of Early Diagnosis

In 2004, researchers found that amyloid was safely visualized in the brain of a living person with AD using PET neuro-molecular brain imaging. Now the possibility emerged that diagnosis did not require autopsy: a “biomarker” such as a brain scan could allow a much earlier and accurate diagnosis.

Over the past five years researchers have established molecular neuroimaging and new blood tests to diagnose AD without autopsy, possibly even years before symptoms appeared.

Today, neurologists throughout the world have increasing confidence that PET neuroimaging tests can be valid and valuable for early detection and definitive diagnosis of AD.

An important challenge for today’s researchers studying diagnostic methods is to develop widely accessible neuro-molecular imaging, and even better, more accurate blood tests that can be used to help screen people of all ages for pre-symptomatic AD. This way, treatment can begin before memory fades.

Researchers, clinicians, and ethicists are now asking themselves:

•   How will society react to the opportunity for early AD diagnosis?

•   Will people want to know years before symptoms occur?

•   Should our federal government cover the expense of this testing as routine medical care?

Developing Treatments For Those With And Without Symptoms

As of January 2021, there are no FDA-approved treatments to stop the disease from progressively damaging the brain. Treatments today focus only on managing symptoms.

We need treatments that can stop the progression of Alzheimer’s disease for those already showing symptoms, and those without symptoms but who have these abnormal biomarkers This is what’s called primary prevention. Here’s the good news about these emerging biomarkers.

We can now:

•   Safely identify plaques and tangles in a person’s brain. We can make a definite diagnosis using biomarkers or tests of the pathology, such as an amyloid PET scan.

•   Monitor disease progression. We can track the progress of the disease by following the accumulation of tau pathology tangles with tau PET.

Now we can make a diagnosis of definite AD even in people who do not have any symptoms, and we have dropped the term probable AD.

This allows us to identify the right people at any stage of disease for our therapeutic trials and it substantially increases the likelihood of success. As we have moved our attempts at therapy into these earlier, pre-dementia stages, we have evidence of early success.

We at the Alzheimer’s Therapeutic Research Institute (ATRI) are actively testing numerous experimental treatments for treating the active disease.

Looking Forward: What We Can Expect in 2021

The biggest topic of discussion in the field right now is a drug called Aducanumab, developed by Biogen and collaborating companies. This is an antibody that targets the amyloid plaque and can remove amyloid plaques from the brain. A Phase 3 clinical trial of Aducanumab in mild dementia and pre-dementia individuals showed benefit.

Aducanumab is now under review at the FDA. If Aducanumab is approved, we will have the first disease modifying treatment for Alzheimer's disease available for doctors to prescribe in 2021.

Still, the evidence that Aducanumab works shows that the benefit is modest and challenges continue. We need to continue our efforts to achieve greater disease-slowing benefits. Earlier intervention may be key.

ATRI now has two international trials of anti-amyloid treatments targeting this asymptomatic stage of Alzheimer's disease along with our participating colleagues. The first, called the A4 trial, is fully enrolled and expected to complete sometime in 2023. Just launched in July 2020 is the AHEAD 3-45 trial. These are both huge multi-center randomized controlled trials, conducted as public-private partnerships (with support from the

National Institutes of Health (NIH) as well as pharmaceutical company partners).

These trials were designed and are led by ATRI at USC with the Alzheimer’s Clinical Trials Consortium (including many collaborators around the country). We think the bright path forward is bringing the best treatments to the stage of disease at which the benefits are likely to be dramatic.

A Focus on Primary Prevention

ATRI research is now using less expensive and highly accurate methods to identify Alzheimer’s disease in middle-aged people.

We are working to find ways to prevent Alzheimer’s disease using sensitive blood tests to identify people at risk just as we now use cholesterol tests to identify people at risk for vascular disease. This takes intensive laboratory work and participation of tens of thousands of volunteers to participate in these trials.

The future is exciting. We are studying therapies that could be used in midlife to prevent Alzheimer's disease.

We have been working at this for a long, long time. But, we are making progress and the rate of progress is accelerating.