MedicalResearch.com Interview with:
Dr. Eric Reiman MD
Executive Director, Banner Alzheimer’s Institute (BAI)
Chief Executive Officer, Banner Research
Clinical Director of the Neurogenomics
Division at the Translational Genomics Research Institute (TGen)
Professor of Psychiatry, University of Arizona
Director, Arizona Alzheimer’s Consortium Phoenix Arizona
Medical Research: What is the background for this study? What are the main findings?
Dr. Reiman: Beta-amyloid plaque deposition is a cardinal feature of Alzheimer’s disease. Recent positron emission tomography (PET) have suggested that about one-fourth of patients with the clinical diagnosis of mild-to-moderate Alzheimer’s dementia—and more than a third of those who had no copies of the APOE4 gene, the major genetic risk factor for Alzheimer’s—do not have appreciable amyloid plaque deposition. We wondered whether this finding reflected an absence of appreciable brain amyloid, particularly in APOE4 non-carriers, or instead an underestimation of amyloid plaques using PET. In those patients with minimal plaque deposition, we also wondered what percentages had neuropathological evidence of another dementia-causing disease, neurofibrillary tangle pathology (the other cardinal feature of Alzheimer’s, or no known pathological contribution.
We surveyed data from the 100 APOE4 non-carriers and 100 APOE4 carriers who had the clinical diagnosis of mild-to-moderate Alzheimer’s dementia during their last visit at any of the nation’s Alzheimer’s Disease Centers and had an autopsy performed within the next 2 years.
As we reported in JAMA Neurology, 37 percent of APOE4 non-carriers and 13 percent of APOE4 carriers with a clinical diagnosis of mild-to-moderate Alzheimer’s had minimal evidence of neuritic or diffuse amyloid plaques—and those for whom we had brain samples had no evidence of increased soluble amyloid. A proportion of individuals had a different neuropathological diagnosis. While nearly half of those patients with minimal amyloid or any other pathology had extensive tangle formation, a similar percentage was found in cognitively unimpaired persons in the same age range.
Our findings suggest the PET findings are correct – that a quarter of all patients (and more than a third of APOE4 non-carriers) with the clinical diagnosis of Alzheimer’s dementia do not have appreciable amyloid pathology, and that about 10 to 15 percent of patients do not have a clear explanation for their dementia.
Medical Research: What should clinicians and patients take away from your report?
Dr. Reiman: Current investigational therapies for the treatment and possible prevention of Alzheimer’s disease are targeting beta-amyloid buildup in the brain. The findings of this study suggest that a small but significant subset of patients with mild-to-moderate Alzheimer’s may not benefit from these anti-amyloid treatments because they do not have the cardinal beta-amyloid buildup in their brains.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Reiman: Additional studies are needed to determine whether patients with the clinical diagnosis of Alzheimer’s dementia without appreciable amyloid pathology differ in their clinical features and rate of cognitive decline and to clarify the molecular mechanisms and risk factors for this form of dementia. Our findings suggest that trials evaluating anti-amyloid treatments in clinically affected patients should use PET or CSF measurements to verify the presence of amyloid pathology, and that more than a third of APOE4 non-carriers are unlikely to benefit from treatment or prevention therapies that target amyloid, even if they are able to help those with amyloid pathology.
Monsell SE, Kukull WA, Roher AE, et al. Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques . JAMA Neurol. Published online August 24, 2015. doi:10.1001/jamaneurol.2015.1721.
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Dr. Eric Reiman MD (2015). Many Patients with Clinical Alzheimer’s Do Not Have Significant Amyloid Pathology