Apolipoprotein E, Neurodegeneration, and Alzheimer Disease

Article · March 2013with15 Reads
DOI: 10.1001/jamaneurol.2013.726 · Source: PubMed
Abstract
Because of a widespread belief that effective therapies for Alzheimer disease (AD) will require intervention prior to the onset of dementia, intense effort has been devoted to identifying asymptomatic individuals who are likely to develop the disease. Major strategies include biomarker measurement to detect subtle signs of AD in asymptomatic individuals and investigation of people with genetic mutations or polymorphisms indicative of high risk. The biomarkers of greatest interest have been separated into 2 categories, one of which is the measurement of the AD hallmark protein β-amyloid (Aβ), apparent as reduced concentration in cerebrospinal fluid or increased retention of positron emission tomography (PET) tracers that bind to fibrillar Aβ. The second category includes biomarkers that are presumptive measures of neurodegeneration, such as atrophy of the hippocampus and cerebral glucose hypometabolism in the temporoparietal cortex. Genetic and biomarker approaches may be combined, as in the Dominantly Inherited Alzheimer Network, a study of people with mendelian mutations that cause AD. In the Dominantly Inherited Alzheimer Network study, evidence of brain Aβ deposition, glucose hypometabolism, and hippocampal atrophy were seen in asymptomatic mutation carriers 10 to 15 years prior to the expected age at disease onset.1 Charting the temporal course of these biomarker changes provides a basis for defining at-risk populations for treatment selection and informs us about basic mechanisms of disease.
    • "CVD, cerebrovascular disease, moderate-tosevere traumatic brain injury (TBI), and race may also be risk factors for AD [25,73]. An increasing number of investigations have focused on the identification of risk factors for AD that are " modifiable, " that is, conditions or behaviors that can be effectively treated/altered to reduce their prevalence during the asymptomatic preclinical stage [74] , which will promote a significant decrease in the prevalence of AD [70]. However, there is considerable debate on the strength of the association between AD and potentially modifiable risk factors [67,70]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Cigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. Methods: A systematic review of published studies on the association between smoking and increased risk for AD and preclinical and human literature on the relationships between smoking, nicotine exposure, and AD-related neuropathology was conducted. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. Results: Overall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD. Conclusions: A reduction in the incidence of smoking will likely reduce the future prevalence of AD.
    Full-text · Article · Jun 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers. Methods: A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume. Results: Significant differences in gray matter (p < 0.05, family-wise error-corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers. Conclusions: Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.
    Full-text · Article · Oct 2013
  • [Show abstract] [Hide abstract] ABSTRACT: In recent years, numerous laboratories and consortia have used neuroimaging to evaluate the risk for and progression of Alzheimer's disease (AD). The Alzheimer's Disease Neuroimaging Initiative is a longitudinal, multicenter study that is evaluating a range of biomarkers for use in diagnosis of AD, prediction of patient outcomes, and clinical trials. These biomarkers include brain metrics derived from magnetic resonance imaging (MRI) and positron emission tomography scans as well as metrics derived from blood and cerebrospinal fluid. We focus on Alzheimer's Disease Neuroimaging Initiative studies published between 2011 and March 2013 for which structural MRI was a major outcome measure. Our main goal was to review key articles offering insights into progression of AD and the relationships of structural MRI measures to cognition and to other biomarkers in AD. In Supplement 1, we also discuss genetic and environmental risk factors for AD and exciting new analysis tools for the efficient evaluation of large-scale structural MRI data sets such as the Alzheimer's Disease Neuroimaging Initiative data.
    Full-text · Article · Nov 2013
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