Cheryl A. Luis, Ph.D.
Associate Clinic Director, the Roskamp Institute, Sarasota, Florida, recipient of a 2009 New Investigator Research Grant
The support of the Alzheimer's Association has allowed me to pursue an area of research that I refer to as the other major piece of the puzzle: cost-effective methods of earlier detection of Alzheimer's disease.
Impact of Association funding
Without funding from the Alzheimer's Association, I would not be able to move forward with this important line of investigation, which will examine how accurately the combined use of MoCA and blood tests of beta-amyloid, CD-40 and CD-40L, and APOE-e4 detect the presence or absence of Alzheimer's.
Science is moving closer to finding therapies that slow or stop the progression of Alzheimer's, but for these therapies to be truly beneficial, we must start treatment very early in the course of the disease. It makes little sense to halt the progression of the disease when an individual has already suffered considerable cognitive decline and functional impairment. My research at the Roskamp Institute has focused on developing practical methods for earlier detection of dementia.
The New Investigator Research Grant (NIRG) will allow further refinement of a screening approach that I and my colleagues have been studying for several years. This novel approach combines a cognitive test with studies of biomarkers in blood. Biomarkers are physical changes that indicate the presence of a disease or an elevated risk of developing a disease. In addition, this approach may prove useful in measuring the impact of potential new Alzheimer's drugs.
Beta-amyloid in the blood as a biomarker
Traditional cognitive tests of dementia severity such as the Mini-Mental State Exam (MMSE) are inadequate in detecting the early cognitive signs of the illness and mild cognitive impairment (MCI). MCI is a possible transitional state from normal cognition to Alzheimer's. One of the few cognitive tests that has been consistently effective in identifying those with MCI is the Montreal Cognitive Assessment (MoCA). It is more comprehensive than the MMSE in that it includes items assessing immediate and delayed memory, language fluency, visuospatial skill (the ability to understand and use symbols and maps, for example, and the brain's ability to translate visual signals into a correct impression of where objects are in space), abstract reasoning and divided attention (the ability to pay attention to more than one task at once, such as carrying on a conversation while preparing a meal).
The physical and functional changes of Alzheimer's are intimately linked to the abnormal accumulation of fragments of the amyloid precursor protein called beta-amyloid 1-40 and 1-42. Increased production and decreased removal of beta-amyloid is thought to precede the early symptoms of Alzheimer's, which typically include a decline in episodic memory, the ability to remember the people, places and events of episodes from one's past. As beta-amyloid accumulates, a cascade of inflammation, cognitive and behavioral decline and, ultimately, cell loss ensues.
We have been studying beta-amyloid in blood for its potential use as a marker of disease onset and progression because obtaining a blood sample is far more cost-effective and applicable for wide-scale use in routine healthcare settings than lumbar puncture and beta-amyloid imaging of the brain. Using a series of blood samples, we have shown that these markers in blood are less variable in people with Alzheimer's than in healthy, nondemented individuals. We and others have also shown that levels of beta-amyloid in the blood are predictive of cognitive decline in healthy at-risk seniors and in individuals with MCI. In addition, in a group of individuals at high-risk for Alzheimer's whom we have been studying for several years, we have shown that beta-amyloid levels in blood are impacted by vascular disease.
Moreover, we have shown that beta-amyloid levels in blood are associated with the cognitive changes seen in Alzheimer's. In individuals with MCI or early Alzheimer's, higher levels of beta-amyloid 1-42 in blood are associated with poorer performance on episodic memory tests while higher levels of beta-amyloid 1-40 are correlated with impaired language fluency and processing speed, as well as impaired divided attention, which are indicators of disease progression.
Furthermore, Alzheimer's is associated with increased levels of inflammation-causing proteins around beta-amyloid deposits in the brain. We have shown that a blood sample tested for the biomarkers beta-amyloid, inflammation-related proteins CD40 and CD40L, and Alzheimer's risk gene apolipoprotein E-e4 (ApoE-e4) has a high degree of accuracy in diagnosing Alzheimer's.
Moving research forward
Without funding from the Alzheimer's Association, I would not be able to move forward with this important line of investigation, which will examine how accurately the combined use of MoCA and blood tests of beta-amyloid, CD-40 and CD-40L, and APOE-e4 detect the presence or absence of Alzheimer's. We hope that further refinement of this screening method will lead to funding from the National Institutes of Health to take this approach into the primary care setting for further study.
Wide-scale, cost-effective methods for very early detection of Alzheimer's will allow us to start disease-modifying treatment early and hopefully prevent the significant loss of cognitive abilities currently experienced by people with Alzheimer's.
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