Michigan Center, MI, United States
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Wang L.-S.,University of Pennsylvania | Naj A.C.,University of Pennsylvania | Graham R.R.,Genentech | Crane P.K.,University of Washington | And 184 more authors.
JAMA Neurology | Year: 2015

IMPORTANCE Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.OBJECTIVE To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden.DESIGN, SETTING, AND PARTICIPANTS Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific samplingmethods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources.MAIN OUTCOMES AND MEASURES Genotypes for the APP A673T variantwere determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies).RESULTS The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls.We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673.CONCLUSIONS AND RELEVANCE The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations. Copyright © 2015 American Medical Association. All rights reserved.

Albin R.L.,Neurology Service and GRECC | Albin R.L.,University of Michigan | Albin R.L.,Michigan Alzheimers Disease Center | Fisher-Hubbard A.,University of Michigan | And 9 more authors.
Annals of Neurology | Year: 2015

Clinical classification of early dementia and mild cognitive impairment (MCI) is imprecise. We reported previously that molecular imaging classification of early dementia and MCI with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathological diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathological diagnosis were concordant in 33 cases (κ = 0.85). This approach enhanced specificity of Alzheimer's disease diagnosis. The strong concordance of imaging-based classifications and pathological diagnoses suggests that this imaging approach will be useful in establishing more accurate and convenient classification biomarkers for dementia research. © 2015 American Neurological Association.

Albin R.L.,Neurology Service and GRECC | Albin R.L.,University of Michigan | Albin R.L.,Michigan Morris all Center For Parkinsons Disease | Albin R.L.,Michigan Alzheimers Disease Center | And 2 more authors.
Movement Disorders | Year: 2015

The potential long-term consequences of treatments delaying manifestations of neurodegenerative diseases have not been explored. Using Huntington disease (HD) data and Markov chain Monte Carlo methods, we simulated the effects of therapies with equivalent effects on time to onset of HD and survival with HD. Our results suggest substantial potential trade-offs in effects of these therapies; significant delays in time to onset of HD were accompanied by significant prolongations of survival after onset of HD. Under a variety of assumptions, treatments delaying onset of HD result in some patients likely to have a greater increase in survival with manifest HD compared to delays in time to onset of HD. Our results suggest that future work in HD should be sensitive to the potential existence of such trade-offs and that understanding the preferences of HD patients and the broader HD community will be increasingly important. Future research, trial design, and treatment strategies in HD and other mid-life-onset neurodegenerative disorders should consider the possibility of trade-offs in long-term consequences of disease-modifying treatments. © 2015 International Parkinson and Movement Disorder Society.

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