Examination of MGMT as a risk gene for dementia in the Amish.

Introduction: Recently, the O-6-methylguanine-DNA methyltransferase (MGMT) locus was proposed as influencing the risk of Alzheimer's disease (AD) in women who did not carry the apolipoprotein E ε4 allele. We examined an Amish founder population for any influence of genetic variation in and around the MGMT locus on the risk for dementia.

Methods: Genetic association was performed for single nucleotide polymorphisms (SNPs) surrounding the MGMT locus.

Measuring clinically relevant change in apathy symptoms in ADMET and ADMET 2.

Objectives: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales.

Design: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores.

Setting: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively.

Building expert consensus regarding sharing of individual research results in Alzheimer's disease research: a Delphi study protocol.

Introduction: Informed decisions to enrol in the clinical investigations of Alzheimer's disease and related dementias (ADRD) require careful consideration of complex risks and uncertain benefits. Decisions regarding whether to receive information about biomarker status are complicated by lack of scientific consensus regarding biomarkers as surrogate endpoints for Alzheimer's disease and how information about individual risk should be evaluated and shared with research participants. This study aims to establish stakeholder consensus regarding ethically optimal approaches to sharing individual results with ADRD research participants.

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

Objectives: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia.

Methods: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months.

Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.

Introduction: Alzheimer disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age.

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants.

Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.

Background: Verbal and visuospatial memory impairments are common to Alzheimer disease and Related Dementias (ADRD), but the patterns of decline in these domains may reflect genetic and lifestyle influences. The latter may be pertinent to populations such as the Amish who have unique lifestyle experiences.

Methods: Our data set included 420 Amish and 401 CERAD individuals.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

Introduction: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study.

Methods: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

Objective: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate.

Design: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori.

Computerized Block Games for Automated Cognitive Assessment: Development and Evaluation Study.

Background: Cognitive assessment using tangible objects can measure fine motor and hand-eye coordination skills along with other cognitive domains. Administering such tests is often expensive, labor-intensive, and error prone owing to manual recording and potential subjectivity. Automating the administration and scoring processes can address these difficulties while reducing time and cost.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive.

Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months.

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease.

Background: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer's disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects.

Effects of Hypertension on Alzheimer's Disease and Related Disorders.

Purpose Of Review: To review the pathophysiology of hypertension in Alzheimer's disease and related dementias and explore the current landscape of clinical trials involving treatment of hypertension to improve cognition.

Recent Findings: Hypertension is increasingly recognized as a contributor to cognitive impairment. Clinical trials that explore blood pressure reductions with cognitive outcomes have been promising.

Cognition/Psychological Burden and Resilience in Cutaneous T-Cell Lymphoma and Psoriasis Patients: Real-Life Data and Implications for the Treatment.

Background: Psoriasis and cutaneous T-cell lymphoma (CTCL) expose patients to chronic inflammation as well as physical and psychological disabilities, but the impact of such alterations on cognitive function is unknown.

Objective: This study is aimed at determining if CTCL and psoriasis impact cognitive functioning in relation to psychological and health-related quality of life (HR-QOL) status.

Methods: A cross-sectional study was performed in an outpatient dermatology clinic of a university teaching hospital.

Graph Theory Analysis of Semantic Fluency in Russian-English Bilinguals.

Background: Semantic category fluency is a widely used task involving language, memory, and executive function. Previous studies of bilingual semantic fluency have shown only small differences between languages. Graph theory analyzes complex relationships in networks, including node and edge number, clustering coefficient, average path length, average number of direct neighbors, and scale-free and small-world properties.

Biomarkers and Mindfulness: A Way Forward.

After years of anticipation, non-invasive tests for detecting cerebral amyloidosis and Alzheimer's disease (AD) are entering clinical care. The PrecivityADtrademark test from C2N is a plasma-based test yielding an Amyloid Probability score with high sensitivity and specificity for brain amyloid accumulation, but some samples may have inconclusive results. The AGREEDementia consortium raised concerns that the field needs study of how best to use and communicate results of PrecivityADtrademark.

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant.

Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets.

Introduction: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI.

Methods: A total of 1522 individuals screened for CI were genotyped.

Plasma amyloid beta, neurofilament light chain, and total tau in the Systolic Blood Pressure Intervention Trial (SPRINT).

Introduction: Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non-disease-specific neurodegeneration.

Methods: We examined the effect of intensive (< 120 mm Hg) versus standard (< 140 mm Hg) BP control on longitudinal changes in plasma amyloid beta (Aβ) and Aβ , total tau, and neurofilament light chain (NfL) in a subgroup of participants from the Systolic Blood Pressure Intervention Trial (N = 517).

Disclosing Genetic Risk of Alzheimer's Disease to Cognitively Unimpaired Older Adults: Findings from the Study of Knowledge and Reactions to APOE Testing (SOKRATES II).

Background: Current practice guidelines recommend against Apolipoprotein E (APOE) testing. However, advances in Alzheimer's disease (AD) research and care may soon change this.

Objective: To examine longitudinally the experience of learning an APOE result and, if an ɛ4 carrier, taking a disease-specific treatment to reduce one's risk of AD.

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.

Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.

Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.

Design, Setting, And Participants: This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care.

Diagnostic criteria for apathy in neurocognitive disorders.

Introduction: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed.

Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019.