Harmonized benchmark labels of the hippocampus on magnetic resonance: the EADC-ADNI project.

Background: A globally harmonized protocol (HarP) for manual hippocampal segmentation based on magnetic resonance has been recently developed by a task force from European Alzheimer's Disease Consortium (EADC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Our aim was to produce benchmark labels based on the HarP for manual segmentation.

Methods: Five experts of manual hippocampal segmentation underwent specific training on the HarP and segmented 40 right and left hippocampi from 10 ADNI subjects on both 1.

Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.

Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome.

Advances in therapeutics for neurodegenerative tauopathies: moving toward the specific targeting of the most toxic tau species.

Neurodegenerative disease is one of the greatest health concerns today and with no effective treatment in sight, it is crucial that researchers find a safe and successful therapeutic. While neurofibrillary tangles are considered the primary tauopathy hallmark, more evidence continues to come to light to suggest that soluble, intermediate tau aggregates--tau oligomers--are the most toxic species in disease. These intermediate tau species may also be responsible for the spread of pathology, suggesting that oligomeric tau may be the best therapeutic target.

Functional connectivity in autosomal dominant and late-onset Alzheimer disease.

Importance: Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile.

Objective: To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD.

Design, Setting, And Participants: We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites.

Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis.

Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.

Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset.

Why are spousal caregivers more prevalent than nonspousal caregivers as study partners in AD dementia clinical trials?

Objectives: Most Alzheimer disease (AD) caregivers are not spouses and yet most AD dementia trials enroll spousal study partners. This study examines the association between caregiver relationship to the patient and willingness to enroll in an AD clinical trial and how caregiver burden and research attitudes modify willingness.

Design: Interviews with 103 AD caregivers who met criteria for ability to serve as a study partner.

Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease.

Importance: Although cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it are limited.

Objective: To determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically confirmed Alzheimer disease (AD).

Design, Setting, And Participants: We compared demographic and clinical variables at the earliest visit during life at which participants were found to have cognitive impairment and compared pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression.

Neuropathologic correlates of trial-related instruments for Alzheimer's disease.

To advance disease-modifying therapies, it is critical to understand the relationship between the neuropathological changes of Alzheimer's Disease (AD) and the clinical measures used in therapeutic trials. We reviewed neuropathologically proven cases of AD from the National Alzheimer's Coordinating Center (NACC) and examined correlations between neuropathological changes and clinical-trial related instruments collected as part of the Uniform Dataset (UDS). We explored the relationships between neurofibrillary tangles, neuritic plaques, and total pathology burden with immediate and delayed recall, Clinical Dementia Rating-Sum of Boxes, Functional Activity Questionnaire, Neuropsychiatric Inventory Questionnaire, and Mini-Mental State Examination scores.

A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer's disease in an African-American woman.

Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1.

Facilitating Alzheimer disease research recruitment.

Alzheimer disease (AD) research faces challenges to successful enrollment, especially to clinical trials and biomarker studies. Failure to recruit the planned number of participants in a timely manner threatens the internal validity and success of clinical research, raising concerns about external validity and generalizability of results, and possibly leading to disparities in disease treatment. Methods to improve recruitment exist, but require varying levels of staff effort and financial resources, and evidence of effectiveness is often lacking or inconsistent.

Choosing Alzheimer's disease prevention clinical trial populations.

To assist investigators in making design choices, we modeled Alzheimer's disease prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of Boxes data, retention rates, and the proportions of trial-eligible cognitively normal participants age 65 and older in the National Alzheimer's Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for drop out, and the numbers needed to screen to successfully complete enrollment. We examined how enrichment strategies affected each component of the model.

Does study partner type impact the rate of Alzheimer's disease progression?

Most patients with Alzheimer's disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results.

New genes and new insights from old genes: update on Alzheimer disease.

Purpose Of Review: This article discusses the current status of knowledge regarding the genetic basis of Alzheimer disease (AD) with a focus on clinically relevant aspects.

Recent Findings: The genetic architecture of AD is complex, as it includes multiple susceptibility genes and likely nongenetic factors. Rare but highly penetrant autosomal dominant mutations explain a small minority of the cases but have allowed tremendous advances in understanding disease pathogenesis.

Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model.

Alzheimer disease (AD) is a form of neurodegeneration that develops over the course of multiple decades and as a result of the accumulation of the pathogenic amyloid-β (Aβ) peptide, also known as A4. In late-stage AD, failure of autophagic clearance results in neuronal cell bodies that are almost entirely consumed by autophagic vacuoles (AVs). Previously, we have shown that the potential AD drug latrepirdine (aka Dimebon(®)), a Russian antihistamine that has shown mixed results in phase II clinical trials in AD, regulates metabolism of the amyloid-β/A4 precursor protein (APP).

Should we disclose amyloid imaging results to cognitively normal individuals?

Demonstration of brain accumulation of fibrillar amyloid beta protein via positron emission tomography (PET) with amyloid specific ligands may support the diagnosis of Alzheimer's disease (AD). There is increasing recognition of the potential use of amyloid imaging to detect the pathology of AD in individuals with no ostensible cognitive impairment. Research use of amyloid PET in cognitively normal patients will be key to pursuit of therapies able to delay cognitive impairment and dementia due to AD.

Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers.

Background/aims: Oligomerization of amyloid beta (Aβ) is a hypothesized step in the formation of plaques in Alzheimer's disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease.

Methods: We measured levels of Aβ(42) using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations.

Effect of study partner on the conduct of Alzheimer disease clinical trials.

Objective: Alzheimer disease (AD) dementia clinical trials require 2 participants: a patient and a study partner. We assessed the prevalence of study partner types and how these types associate with patient-related outcome measures.

Methods: Retrospective analyses of 6 Alzheimer's disease cooperative study (ADCS) randomized clinical trials were conducted.

Risk disclosure and preclinical Alzheimer's disease clinical trial enrollment.

To identify the facilitators and barriers to preclinical Alzheimer's disease (AD) clinical trial recruitment, 50 cognitively normal participants were interviewed after being randomized to one of two hypothetical AD risk scenarios: (1) the general age-related risk for AD, or (2) being at 50% increased risk for AD. Participants provided uncued barriers and facilitators to the hypothetical decision of whether they would enroll. Thirteen themes of facilitators and five themes of barriers were identified.

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.

Introduction: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.

Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations.

Background: Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer's disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer's disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives.

Methods: Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment.

Memory performance and fMRI signal in presymptomatic familial Alzheimer's disease.

Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD.

Are patients whose study partners are spouses more likely to be eligible for Alzheimer's disease clinical trials?

Background/aims: Alzheimer's disease (AD) clinical trials enroll two participants: a patient and a study partner. The primary caregiver most often fills the role of study partner and most trial study partners are spousal caregivers.

Methods: AD trial inclusion criteria were applied to baseline data from 5,674 probable AD dementia research participants in the National Alzheimer's Coordinating Center Uniform Data Set.

Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype.

Objective: To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels.

Design: Cross-sectional comparison of plasma levels of 77 proteins measured using multiplex immune assays.

Setting: A tertiary referral dementia research center.

Plasma methionine sulfoxide in persons with familial Alzheimer's disease mutations.

Background: Convergent evidence suggests that oxidative stress plays a central role in the pathology of Alzheimer's disease (AD). We asked if consequently, oxidation of methionine residues to methionine sulfoxide (MetO) was increased in plasma proteins of persons carrying familial AD (FAD) mutations.

Methods: Plasma was collected from 31 persons from families harboring PSEN1 or APP mutations.

Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative.

This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses.