December 23rd, 2014

Advances in the Primary Prevention of Alzheimer’s Disease

Advantages in the Primary Prevention of Alzheimer's Disease

Although the focus of Alzheimer's disease (AD) research efforts remains on finding a treatment that slows disease progression and recovers cognitive decline, interest in primary prevention of the disease is growing, especially because there are several confounding, modifiable factors believed to be associated with elevated risk of AD.^1,2

“It is important to recognize that AD begins in the brain prior to clinically apparent symptoms. This preclinical phase may be our best opportunity for successful treatment in AD,” said Reisa Sperling, MD, of Harvard Medical School, Brigham and Women's Hospital, and Massachusetts General Hospital in Boston.

Identifying Diagnostic Measures Sensitive to Earliest AD Signs

However, diagnostic approaches aimed at the primary prevention of AD have not yet penetrated the clinical practice setting.²

“Preclinical AD is still ‘strictly a research initiative,' so this is not a diagnosis one should expect to find outside the setting of a clinical trial or other study,” said Michael Donohue, MD, of the University of California, San Diego. “In short, preclinical AD is defined by evidence of elevated accumulation of amyloid plaque in the brain in absence of mild cognitive impairment (MCI).”

As AD research moves into presymptomatic disease phases, researchers need to develop outcome measures sensitive to the earliest signs of the disease. In this effort, Donohue and colleagues used the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) to evaluate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology.³

“The study demonstrated that groups identified as preclinical AD tended to decline more, compared to those without evidence of elevated amyloid, over the next three years,” said Donohue.

The ADCS-PACC is primarily intended as a tool to track cognitive decline during preclinical AD and is heavily weighted towards episodic memory – the type of short-term memory that is affected very early in AD.

“The important point for clinicians and patients is that AD begins years, probably more than a decade, prior to the stage of dementia, and probably more than five years before the stage of MCI,” said Sperling. “For me, this is ‘a glass half full,' as this provides an excellent opportunity to intervene and try to prevent progression at a stage we hope we can still rescue the brain.”

Individuals at Increased AD Risk

In order to uncover preclinical markers, researchers are attempting to identify subgroups of individuals thought to be at increased risk for AD.

In one study, Deborah E. Barnes, PhD, MPH, of the University of California School of Medicine in San Francisco, and colleagues evaluated specific estimates for seven modifiable risk factors including diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment.⁴

“The interesting thing is that all seven of the risk factors we looked at are really very weak risk factors. For each of them, the risk of AD is increased by only 50% to 80%, so they really just shift a person's risk slightly. The key factor that is driving these estimates is how common the risk factors are in society,” said Barnes.

Making small changes at a societal level could potentially have a huge impact. If 10% fewer people had these seven risk factors, Barnes and colleagues estimated that about 8,800 fewer people would develop AD by the year 2050. A 20% reduction in these risk factors would result in an estimated 16,000 fewer cases by 2050.

Drugs Targeting Early Prevention of AD

Because AD has been characterized by the presence of amyloid-beta plaques, anti-amyloid treatments are a main focus of research targets for the primary prevention of disease.

In two phase 3 studies, Rachelle Doody, MD, PhD, of Baylor College of Medicine in Houston, Texas, and colleagues evaluated the efficacy of solanezumab, a humanized monoclonal antibody that binds amyloid. Solanezumab did not improve cognition and functional ability for this group of patients, overall, they found.⁵

“As part of the analysis of the first study, the data were also examined for the mild and moderate AD patients separately. Although dividing the data this way was not the primary endpoint, we did see a trend toward benefit in patients with mild AD. Therefore, the analysis plan for the second study was amended to make analysis of the mild patients the primary aim,” said Doody. “Again, the primary aim was not met because the measure that the company designated as the primary measure did not reach statistical significance.”

However, the data raised the hypothesis that solanezumab could work for patients with mild AD or patients at an earlier stage in their disease process. There are additional ongoing studies evaluating this drug in mild patients and as a preventive strategy.

Specifically, there are three ongoing studies, including the A4 study, to evaluate the drug as a preventive strategy in healthy individuals who have high amounts of amyloid in their brains but do not have symptoms of dementia or AD.⁶

Solanezumab is just one of several monoclonal antibodies being studied to prevent or treat AD.

“Any intervention that could prevent cases, or even delay the onset for as little as ten years, would greatly reduce the prevalence of this disease. We are hopeful that this sort of anti-amyloid approach will begin a new era in the treatment of Alzheimer's-related brain disease,” Doody said.

Beth Gilbert is a freelance health and science writer. She has an undergraduate degree in chemical engineering from Lehigh University and a Master's in biomedical engineering from Columbia University.

References

1. Alzheimer's facts & figures. Alzheimer's Association. Available here: http://www.alz.org/alzheimers_disease_facts_and_figures.asp#prevalence
2. Preclinical alzheimer's disease. Mayo Clinic. Available here: http://www.mayoclinic.org/medical-professionals/clinical-updates/neurosciences/preclinical-alzheimers-disease
3. Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 2014;71(8):961-70.
4. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-94.
5. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):311-21.
6. Clinical trial of solanezumab for older individuals who may be at risk for memory loss. Clinicaltrials.gov. Available here: https://clinicaltrials.gov/ct2/show/NCT02008357.

All electronic documents accessed Dec. 15, 2015.