The role of the Alzheimer's Disease Neuroimaging Initiative in establishing the Dominantly Inherited Alzheimer Network.

The Dominantly Inherited Alzheimer Network (DIAN) initially was funded by the National Institute on Aging (NIA) in 2008 and thus was able to adopt and incorporate the protocols developed by the Alzheimer's Disease Neuroimaging Initiative (ADNI) that had been established by the NIA in 2004. The use of ADNI protocols for DIAN neuroimaging studies and assays of biological fluids for Alzheimer disease (AD) biomarkers permitted examination of the hypothesis that autosomal dominant AD (ADAD), studied by DIAN, and "sporadic" late-onset AD (LOAD), studied by ADNI, shared the same pathobiological construct. In a collaborative effort, the longitudinal DIAN and ADNI databases were compared and the findings supported the conclusion that ADAD and LOAD share a similar pathophysiology.

Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology.

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays.

Different rates of cognitive decline in autosomal dominant and late-onset Alzheimer disease.

As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and "sporadic" late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed).

Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET.

Background And Objectives: To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).

Methods: Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale with the use of longitudinal data.

Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

Background: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD.

Methods: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014.

Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease.

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period.

Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics.

Dominantly Inherited Alzheimer Network: facilitating research and clinical trials.

The Dominantly Inherited Alzheimer Network (DIAN) is an international registry of individuals at risk for developing autosomal dominant Alzheimer's disease (AD). Its primary aims are to investigate the temporal ordering of AD pathophysiological changes that occur in asymptomatic mutation carriers and to identify those markers that herald the transition from cognitive normality to symptomatic AD. DIAN participants undergo longitudinal evaluations, including clinical and cognitive assessments and measurements of molecular and imaging AD biomarkers.

Impaired default network functional connectivity in autosomal dominant Alzheimer disease.

Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.

Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).

Preclinical Alzheimer disease and risk of falls.

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau.

Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture.

"Will I get Alzheimer disease?" when cognitively normal patients ask to be tested for Alzheimer disease.

This article presents the case of a cognitively normal patient who is requesting a procedure (amyloid imaging) recently approved for the diagnosis of Alzheimer disease (AD) in patients with cognitive impairment. The predictive value of this test in unaffected people is not clearly established. Knowing the results of the test will have no effect on therapeutic options, although the patient may make lifestyle decisions based on the results.

Clinicopathologic study of Alzheimer's disease: Alzheimer mimics.

A definite diagnosis of Alzheimer's disease (AD) can only be made at autopsy. Even at expert research centers, diagnostic accuracy is relatively low. We conducted this study to examine the accuracy of clinical diagnosis of AD and present a list of clinical and neuropsychological findings that could render the clinical diagnosis difficult.

Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network.

The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.

Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease.

Objective: To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.

Design: Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria.

Driving and dementia of the Alzheimer type: beliefs and cessation strategies among stakeholders.

Purpose: Although driving by persons with Alzheimer's disease (AD) is an important public health concern, we know little about the attitudes and perceptions of key stakeholders regarding driving safety in these individuals or the factors that precipitate and influence driving assessment and cessation decisions.

Design And Methods: We convened 10 focus groups composed of persons intimately involved in driving decisions for older adults to identify and compare beliefs and perceptions concerning AD and driving and to identify effective strategies to limit or cease unsafe driving. The 68 focus-group participants included health professionals, transportation and law-enforcement professionals, current and former drivers with AD, and family caregivers of current and former drivers with the disease.

Accuracy of collateral source reports in very mild to mild dementia of the Alzheimer type.

Objectives: To examine the reporting accuracy of collateral sources (knowledgeable informants) regarding very mild and mild dementia of the Alzheimer type (DAT) and to identify characteristics associated with collateral source accuracy.

Design: Secondary data analysis of initial visits of individuals enrolled in a longitudinal study of healthy aging and Alzheimer disease.

Setting: Urban Alzheimer disease research center.