Tau accumulation and its spatial progression across the Alzheimer's disease spectrum.

The spread of tau abnormality in sporadic Alzheimer's disease is believed typically to follow neuropathologically defined Braak staging. Recent positron emission tomography (PET) evidence challenges this belief, however, as spreading patterns for tau appear heterogenous among individuals with varying clinical expression of Alzheimer's disease. We therefore sought better understanding of the spatial distribution of tau in the preclinical and clinical phases of sporadic Alzheimer's disease and its association with cognitive decline.

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer's disease.

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer's disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD.

Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer's disease model.

Deficits in synaptic structure and function are likely to underlie cognitive impairments in Alzheimer's disease. While synaptic deficits are commonly found in animal models of amyloidosis, it is unclear how amyloid pathology may impair synaptic functions. In some amyloid mouse models of Alzheimer's disease, however, synaptic deficits are preceded by hyperexcitability of glutamate synapses.

Test-retest resting-state fMRI in healthy elderly persons with a family history of Alzheimer's disease.

We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled in the "Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease" (PREVENT-AD) Cohort. Subjects with a family history of Alzheimer's disease in first-degree relatives were recruited as part of an on-going double blind randomized clinical trial of Naproxen or placebo. Two pairs of scans were acquired ~3 months apart, allowing the assessment of both intra- and inter-session reliability, with the possible caveat of treatment effects as a source of inter-session variation.

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured.

Neuroinflammation in Alzheimer's disease.

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.

Alzheimer amyloid peptide aβ42 regulates gene expression of transcription and growth factors.

The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor.

An open science resource for establishing reliability and reproducibility in functional connectomics.

Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics.

Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: the Cache County Dementia Progression Study.

Background: Single-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1, rs1868402) and the microtubule-associated protein tau (MAPT, rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR-sb). We attempted to validate the latter association in an independent, population-based sample of incident AD cases from the Cache County Dementia Progression Study (DPS).

Screening by telephone in the Alzheimer's disease anti-inflammatory prevention trial.

Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery. Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation that was completed within six months of screening.

Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study.

Objectives: Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use.

Methods: Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT.

Prevalence of neuropsychiatric symptoms in CIND and its subtypes: the Cache County Study.

Objectives: 1) To report rates of neuropsychiatric symptoms (NPS) in cognitive impairment, no dementia (CIND). 2) To compare the 30-day prevalence of NPS in CIND with that in dementia and cognitively normal individuals. 3) To compare the prevalence of NPS in amnestic MCI (aMCI) with other predementia syndromes.

Lifestyle behavior pattern is associated with different levels of risk for incident dementia and Alzheimer's disease: the Cache County study.

Objectives: To identify distinct behavioral patterns of diet, exercise, social interaction, church attendance, alcohol consumption, and smoking and to examine their association with subsequent dementia risk.

Design: Longitudinal, population-based dementia study.

Setting: Rural county in northern Utah, at-home evaluations.

Latent class-derived subgroups of depressive symptoms in a community sample of older adults: the Cache County Study.

Objective: We sought to identify possible subgroups of elders that varied in depressive symptomatology and to examine symptom patterns and health status differences between subgroups.

Methods: The Cache County memory study is a population-based epidemiological study of dementia with 5092 participants. Depressive symptoms were measured with a modified version of the diagnostic interview schedule-depression.

Early parental death and remarriage of widowed parents as risk factors for Alzheimer disease: the Cache County study.

Objectives: Early parental death is associated with lifelong tendencies toward depression and chronic stress. We tested the hypothesis that early parental death is associated with higher risk for Alzheimer disease (AD) in offspring.

Design: A population-based epidemiological study of dementia with detailed clinical evaluations, linked to one of the world's richest sources of objective genealogical and vital statistics data.

Atrial fibrillation and risk of dementia: a prospective cohort study.

Objectives: To determine whether atrial fibrillation (AF) is associated with risk of incident dementia or Alzheimer's disease (AD), beyond its effect on stroke.

Design: Prospective cohort study.

Setting: An integrated healthcare delivery system.

Extended results of the Alzheimer's disease anti-inflammatory prevention trial.

Background: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups.

Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study.

Objectives: Progression of Alzheimer dementia (AD) is highly variable. Most estimates derive from convenience samples from dementia clinics or research centers where there is substantial potential for survival bias and other distortions. In a population-based sample of incident AD cases, we examined progression of impairment in cognition, function, and neuropsychiatric symptoms, and the influence of selected variables on these domains.

Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial.

Objective: We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease.

Methods: Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of Modified Mini-Mental State (3MS) Examination trajectories with data from 2388 participants in the Alzheimer's Disease Anti-inflammatory Prevention Trial and included class-specific effects of naproxen and celecoxib.

Cognitive stimulation and cognitive and functional decline in Alzheimer's disease: the cache county dementia progression study.

Objectives: To examine the association of engagement in cognitively stimulating activities with cognitive and functional decline in a population-based sample of incident Alzheimer's disease (AD).

Method: After diagnosis, 187 participants (65% females) were followed semiannually for a mean 2.7 (SD = 0.

Histamine-2 receptor antagonist use and incident dementia in an older cohort.

Objectives: To examine whether histamine-2 receptor antagonist medications (H2RAs) are associated with a lower incidence of all-cause dementia or Alzheimer's disease (AD), as some studies have suggested.

Design: Prospective population-based cohort

Setting: Group Health, an integrated health maintenance organization, Seattle, Washington.

Participants: Two thousand nine hundred twenty-three participants aged 65 and older without dementia at baseline, with initial recruitment between 1994 and 1996.