Alzheimer's & dementia: the journal of the Alzheimer's Association

Publisher: Alzheimer's Association, Elsevier


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    Alzheimer's & dementia (Online), Alzheimer's & dementia, Alzheimer's and dementia
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Publications in this journal

  • Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2014;
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    ABSTRACT: We hypothesized that chronic brain changes are important substrates for incident dementia after stroke and transient ischemic attack (TIA). We compared clinical and imaging features between patients with consecutive stroke/TIA with (n = 88) and without (n = 925) incident dementia at 3 to 6 months after a stroke/TIA. Pittsburg compound B (PiB) positron emission tomography was performed in 50 patients, including those with (n = 37) and without (n = 13) incident dementia. Age, history of diabetes mellitus, severity of white matter changes (WMCs), and medial temporal lobe atrophy (MTLA) were associated with incident dementia. Alzheimer's disease (AD)-like PiB retention was found in 29.7% and 7.7% (P = .032) of patients with and without incident dementia, respectively. Chronic brain changes including WMCs, MTLA, and AD pathology are associated with incident dementia after stroke/TIA. Interventions targeting these chronic brain changes may reduce burden of vascular cognitive impairment.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2014;
  • Article: Editorial.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 02/2014; 10(1S):S1-S2.
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    ABSTRACT: We investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) to determine whether a highly polymorphic, intronic poly-T within this region (rs10524523; hereafter, 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified as S, short; L, long; and VL, very long based on the number of T residues. We evaluated differences in APOE messenger RNA (mRNA) and TOMM40 mRNA levels as a function of the 523 genotype in two brain regions from APOE ε3/ε3 white autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system. The expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40 mRNA levels were higher in VL homozygotes compared with S homozygotes in the temporal and occipital cortexes from normal and LOAD cases. Results of a luciferase reporter system were consistent with the human brain mRNA analysis; the 523 VL poly-T resulted in significantly higher expression than the S poly-T. Although the effect of poly-T length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the neuroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523 poly-T. These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: Although cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. Because the retina provides a noninvasive window to assess the microcirculation, we determined whether quantitatively measured retinal microvascular parameters are associated with AD. We conducted a case-control study (case:control matching ≈ 1:2). Retinal photographs were analyzed using a computer program, and a spectrum of quantitative retinal microvascular parameters (caliber, fractal dimension, tortuosity, and bifurcation) were measured. Logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval for AD adjusting for age, gender, ethnicity, smoking, hypertension, diabetes, hypercholesterolemia, and history of myocardial infarction. We included 136 demented patients with AD and 290 age-gender-race-matched controls. Persons with narrower venular caliber (OR per standard deviation [SD] decrease, 2.01 [1.27-3.19]), decreased arteriolar and venular fractal dimension (OR per SD decrease 1.35 [1.08-1.68], 1.47 [1.17-1.84], respectively) and increased arteriolar and venular tortuosity (OR per SD increase, 1.84 [1.40-2.31], 1.94 [1.48-2.53], respectively) were more likely to have AD. These associations still persisted when only AD cases without a history of cerebrovascular disease were included. Patients with AD have altered microvascular network in the retina (narrower retinal venules and a sparser and more tortuous retinal vessels) compared with matched nondemented controls. These changes in retinal microvasculature may reflect similar pathophysiological processes in cerebral microvasculature in the brains of patients with AD.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: Structural alterations of a large network characterize Alzheimer's disease (AD), but the time course of these changes remains unclear. The dynamic of these alterations was examined in the AD preclinical phase using data from the 10-year follow-up of a population-based cohort (Bordeaux-3City). Participants received neuropsychological assessments every 2 years and two identical magnetic resonance imaging (MRI) exams at baseline and 4 years later. Twenty-five incident AD cases were compared with 319 subjects who remained free of dementia. Subjects were free of dementia at baseline and at follow-up MRI. Incident AD occurred after these time points. At baseline, incident AD already presented smaller volumes only in the left amygdalo-hippocampal complex. Moreover, a higher annual rate of atrophy of the temporoparietal cortices was observed in future AD subjects during the following 4 years. Incident AD cases present mediotemporal lesions up to 5 years before diagnosis. This neurodegenerative process seems to progressively reach the temporoparietal cortices in the AD preclinical phase.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin (GRN) mutation carriers. Ten cognitively normal subjects (five mutation carriers, GRN+; years to estimated disease onset: 12 ± 7; five mutation noncarriers, GRN-) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. GRN+ showed smaller cortical thickness than GRN- in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: In this study we assessed increased cortisol in Alzheimer's disease (AD) patients. The selective 11-β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor ABT-384 blocked regeneration of active cortisol and this tests the hypothesis that intracellular hypercortisolism contributes to cognitive impairment. In this double-blind, placebo- and active-controlled phase II study we examine the efficacy and safety of ABT-384 given 10 mg or 50 mg once daily, donepezil 10 mg once daily, or placebo for 12 weeks in subjects with mild-to-moderate AD. The primary efficacy end point was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. The study was terminated for futility after randomization of 267 subjects. ABT-384 did not improve ADAS-Cog scores or any secondary end point; however, donepezil significantly improved both cognition and functional end points. Overall incidence of adverse events was similar among treatment groups. ABT-384, when tested at doses associated with complete brain HSD-1 inhibition, did not produce symptomatic improvement in AD.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: Gender-specific risks for dementia and Alzheimer's disease (AD) starting in midlife remain largely unknown. Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD on the basis of the Kaplan-Meier method (cumulative incidence) or accounting for competing risk of death (lifetime risk [LTR]). Overall, 777 cases of incident dementia (601 AD) occurred in 7901 participants (4333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women older than 85 years of age. LTR of dementia/AD at age 45 was 1 in 5 in women and 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from approximately 6 at 45 to 54 years of age to less than 2 after age 65. Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: It is unclear whether the predictive strength of established cognitive variables for progression to Alzheimer's disease (AD) dementia from mild cognitive impairment (MCI) varies depending on time to conversion. We investigated which cognitive variables were best predictors, and which of these variables remained predictive for patients with longer times to conversion. Seventy-five participants with MCI were assessed on measures of learning, memory, language, and executive function. Relative predictive strengths of these measures were analyzed using Cox regression models. Measures of word-list position-namely, serial position scores-together with Short Delay Free Recall of word-list learning best predicted conversion to AD dementia. However, only serial position scores predicted those participants with longer time to conversion. Results emphasize that the predictive strength of cognitive variables varies depending on time to conversion to dementia. Moreover, finer measures of learning captured by serial position scores were the most sensitive predictors of AD dementia.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: Spanish is the second-most common language spoken in the United States, and Spanish speakers represent one third of the aging population. The National Alzheimer's Coordinating Center's Uniform Data Set implemented a Spanish neuropsychological battery. Previous work described the neuropsychological performance for English speakers. Here we describe performance on the Spanish version. Data from 276 Spanish speakers with normal cognition were summarized, with descriptive tables of performance on individual cognitive tests. Regression techniques were used to evaluate the effect of demographics on cognitive performance. Spanish speakers were younger (70.0 vs 74.0 years) and less educated (10.7 vs 15.7 years) with more females (76% vs 63% female) than the previously described English speakers. Higher education and lower age were associated with better performance. This national cohort of well-characterized Spanish-speaking elders provides descriptive data on cognitive performance, an important tool for clinical and research efforts.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;
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    ABSTRACT: Alzheimer's disease (AD) is an age-related neurodegenerative disease leading over the course of decades to the most common form of dementia. Many of its pathologic features and cognitive deficits may be due in part to brain insulin resistance recently demonstrated in the insulin receptor→insulin receptor substrate-1 (IRS-1) signaling pathway. The proximal cause of such resistance in AD dementia and amnestic mild cognitive impairment (aMCI) appears to be serine inhibition of IRS-1, a phenomenon likely due to microglial release of inflammatory cytokines triggered by oligomeric Aβ. Studies on animal models of AD and on human brain tissue from MCI cases at high risk of AD dementia have shown that brain insulin resistance and many other pathologic features and symptoms of AD may be greatly reduced or even reversed by treatment with FDA-approved glucagon-like peptide-1 (GLP-1) analogs such as liraglutide (Victoza). These findings call attention to the need for further basic, translational, and clinical studies on GLP-1 analogs as promising AD therapeutics.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014; 10(1):S12–S25.
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    ABSTRACT: Background Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD. Methods The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia. Results There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function. Conclusions The data suggest a neural mechanism for APOE–PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014;

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