The challenges of Alzheimer’s research

What makes studying cognitive decline so difficult? Why has research been so slow to identify treatments? Why haven’t we found a cure yet? These are just some of the questions families ask amid the frustration and pain of watching a loved one decline mentally and physically from a neurodegenerative disease.

The global Alzheimer’s research community is still trying to figure out how the disease works, and every answer seems to lead to more questions, explains Ara Khachaturian, PhD, Executive Editor, and Zaven Khachaturian, PhD, Editor-in-Chief of Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, in a special submission to Medpage Today. Pushing research forward, they write, means tackling three formidable challenges: 1) understanding the complexity of the disease, 2) finding a way to detect the disease earlier and 3) ramping up clinical trials efforts.

Complex expressions

When it comes to neurological conditions, dementia is not the average bear. Alzheimer’s disease is so complex that scientists haven’t isolated a root cause, if there is one. The biggest discovery about Alzheimer’s to date is there is no single expression of the disease, making it difficult to define and even harder to diagnose early on.

Until recently, researchers assumed the defining answer to Alzheimer’s disease was hidden somewhere amid too many beta-amyloids and tau tangles. But those may turn out to be more symptoms than the root causes, as was first thought. The more researchers study the disease, the more the scientific community sees a wider and wider range of risk factors—everything from various genetic factors and comorbidities to eating habits, exercise and other lifestyle choices.

“Now it appears that Alzheimer’s may not be a single disease, but rather a ‘heterogeneous’ condition with differing patterns of expression,” the Khachaturians write. “This means the disorder (or syndrome) has different forms, where individuals may differ in their age of onset, behavioral-clinical profile, neuropathology, family history, genetics, risk factors, lifestyle and other comorbid conditions.”

The “before” stage

Most of the clinical trials prior to 2016 have focused on subjects who already have clinical symptoms and on developing treatments to stave off or improve those symptoms. But that research has revealed that dementia-causing diseases can have a very long prequel stage where the disease is developing without any apparent outward symptoms. “This discovery that the disease has a long, clinically silent stage has begun to define the new frontier for the discovery of cures,” the authors write.

The other side of the array-of-factors coin is that interventions—including physical exercise, brain training, cardio-healthy diets and other wellness efforts—can play an important role in slowing the progression of the disease. Therefore, the big push is to discover tools and technologies that can help clinicians detect the disease at earlier stages. That, of course, means knowing what risk factors matter most in the early development of the disease—and filling in what the Khachaturians call “major gaps” in understanding the microbiological and chemical workings of Alzheimer’s and related dementia diseases.

Clinical trial recruitment

When it comes to deciphering dementia-causing diseases, researchers predominantly agree on two things, as of now: We need much more data, and we need to know a lot more about the earlier stages of disease. Some research even suggests that drugs designed to reduce dementia symptoms may be more effective at earlier stages than in later stages.

The need to detect the disease at far earlier stages raises the emphasis on clinical trials—including trials and research projects that include people with no diagnosis or notable symptoms. The Brain Health Registry and other national and global projects are reaching out to healthy and younger individuals in an attempt to build a massive database of “before” data and then tracking those participants over time—a database that could greatly assist tomorrow’s researchers in targeting clinical trial participants for more specific explorations.

The Imaging Dementia—Evidence for Amyloid Scanning(IDEAS) Study is developing a medical imaging database to gather brain-scan data and develop new ways to diagnose neurodegenerative diseases, especially Alzheimer’s, using PET scan technology and other types of medical imaging.

Others are creating electronic games designed to test certain brain functions and using the games in a crowdsourcing format to capture as much data as possible in a short span of time.

Regardless of the data-gathering approaches, researchers will make the fastest progress on unlocking the mysteries of Alzheimer’s disease and related dementia-causing diseases if they can learn more about how the diseases begin and how they develop in the earliest stages. Encouraging family members to become part of national knowledge initiatives, crowdsourcing efforts or clinical trials can help researchers gather crucial data and give families give them a sense of purpose at the same time.

Dementia risk and resident populations

What determines the chances of developing a dementia-causing disease? Plenty, researchers say.

There’s no single defining way a neurodegenerative disease will manifest in a diagnosed person. Recent research has discovered that even Alzheimer’s disease has several atypical forms, says Nicole Absar, MD, Medical Director at the Integrace Copper Ridge Memory Clinic, Sykesville, Maryland, who spoke on the topic at the 2017 Spring IASC Memory Care Forum in Philadelphia.

While researchers are still unsure exactly what initially triggers the onset of a neurodegenerative disease like Alzheimer’s, studies have brought certain factors to light:

Ethnicity

Current research has shown that Alzheimer’s disease seems to appear more frequently in some ethnic populations, although no one is sure why. A recent report from the Centers for Disease Control and Prevention using mortality data from 1999-2014 shows that while the death rates attributable to Alzheimer’s disease rose by about 55 percent overall during the study period, rates for Latinos were 107 percent higher and rates for African-Americans were 99 percent higher. While root-cause mortality reporting may be responsible for some of the differences—for example, pneumonia may have been documented as the cause of death even if it was brought on by end-stage Alzheimer’s aspiration—many researchers now suspect that racial and ethnic genetics may play a notable role.

Physical exercise

Being active and engaging in daily physical exercise has come to the fore as a key factor in delaying dementia symptoms, especially since it’s a primary way to combat vascular dementias. Multiple studies based on mortality statistics have shown physical activity and physical wellness to be much more important in delaying the development of neurodegenerative diseases than was previously thought. Likewise, other studies have shown negative factors such as obesity, immobility and even sleep disorders can increase risk of onset.

Gender

Based on mortality data, the research community has known for decades that women seem to develop neurodegenerative diseases more often than men and tend to decline from them faster than men. Some of the numerical data may be because women generally live longer than men, but many researchers are paying more attention to gender in research efforts and drug trials since gender can play a role in how diseases develop and how medications work.

Intervention stage

More than any other factor, researchers agree, early intervention is key to both ongoing functionality and quality of life for those with neurodegenerative diseases. In late 2016, several major drug trials were deemed “failures” under the predetermined study goals, yet in hindsight some dementia researchers are rethinking the end goals of such clinical trials and wondering if more focus should be on studying medication effectiveness across different stages of disease, especially earlier stages.

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