γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD).

Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment.

Design, Setting, And Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD.

Comparison of cerebrospinal fluid, plasma and neuroimaging biomarker utility in Alzheimer's disease.

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning.

Antecedents of mind wandering states in healthy aging and mild cognitive impairment.

Objective: Mind wandering refers to periods of internally directed attention and comprises up to 30% or more of our waking thoughts. Frequent mind wandering can be detrimental to ongoing task performance. We aim to determine whether rates of mind wandering change in healthy aging and mild cognitive impairment and how differences in mind wandering contribute to differences in attention and working memory.

Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study.

Background: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored.

A flexible modeling approach for biomarker-based computation of absolute risk of Alzheimer's disease dementia.

Introduction: As Alzheimer's disease (AD) biomarkers rapidly develop, tools are needed that accurately and effectively communicate risk of AD dementia.

Methods: We analyzed longitudinal data from >10,000 cognitively unimpaired older adults. Five-year risk of AD dementia was modeled using survival analysis.

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect.

Neurofilament Light Predicts Decline in Attention but Not Episodic Memory in Preclinical Alzheimer's Disease.

Background: Cerebrospinal fluid tau and neurofilament light (NfL) are two biomarkers of neurodegeneration in Alzheimer's disease. Previous reports have shown that the influence of tau on cognitive decline depends on levels of amyloid burden whereas NfL predicts decline independently of amyloid. Most studies use a global cognitive composite as the primary outcome, and it is unknown if critical cognitive domain scores are similarly sensitive to rates of decline due to neurodegeneration.

Two-period linear mixed effects models to analyze clinical trials with run-in data when the primary outcome is continuous: Applications to Alzheimer's disease.

Introduction: Study outcomes can be measured repeatedly based on the clinical trial protocol before randomization during what is known as the "run-in" period. However, it has not been established how best to incorporate run-in data into the primary analysis of the trial.

Methods: We proposed two-period (run-in period and randomization period) linear mixed effects models to simultaneously model the run-in data and the postrandomization data.

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

Introduction: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).

Methods: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations.

Results: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145).

Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease.

Objective: To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS-Aging) and age-related diseases and to evaluate its contribution to cognitive impairment in the elderly.

Methods: Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University (St. Louis, MO).

Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease.

Objective: To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.

Methods: A total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (F-AV-1451) tau PET scan, a florbetapir (F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St.

A classification algorithm for predicting progression from normal cognition to mild cognitive impairment across five cohorts: The preclinical AD consortium.

Introduction: We established a method for diagnostic harmonization across multiple studies of preclinical Alzheimer's disease and validated the method by examining its relationship with clinical status and cognition.

Methods: Cognitive and clinical data were used from five studies ( = 1746). Consensus diagnoses established in each study used criteria to identify progressors from normal cognition to mild cognitive impairment.

Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease.

Identifying which neuropsychological measures detect early cognitive changes associated with Alzheimer disease (AD), brain pathology would be helpful clinically for the diagnosis of early AD and for the design of clinical trials. We evaluated which neuropsychological measures in our cognitive battery are most strongly associated with cerebrospinal fluid (CSF) biomarkers of AD brain pathology. We studied a large cohort (n = 233) of middle-to older-aged community-dwelling individuals (mean age 61 years) who had no clinical symptoms of dementia and underwent baseline CSF collection at baseline.

Cerebrovascular perfusion among older adults is moderated by strength training and gender.

Cerebral perfusion is important in older adults as it is linked to cognitive declines. Physical activity can improve blood flow in the body but little is known about the relationship between physical activity and cerebral perfusion in older adults. In particular, no study has investigated the relation between strength training and cerebral perfusion.

Physical activity and cognitive trajectories in cognitively normal adults: the adult children study.

Increased physical activity may protect against cognitive decline, the primary symptom of Alzheimer disease. In this study, we examined the relationship between physical activity and trajectories of cognitive functioning over serial assessments. Cognitively normal (Clinical Dementia Rating 0) middle-aged and older adults (N=173; mean age, 60.

Left atrial size is independently associated with cognitive function.

Left atrial (LA) diameter is easily attainable from echocardiograph and sensitive to underlying cardiovascular disease severity, although its association with neurocognitive outcomes is not well understood. Fifty older adults (64.50 ± 9.

Cortical thickness of the cognitive control network in obesity and successful weight loss maintenance: a preliminary MRI study.

Cortical thickness of the cognitive control network was contrasted between obese (OB), successful weight loss maintainers (SWLM), and lean individuals. OB individuals had significant thinning, most notably in the anterior cingulate and posterior parietal cortices. SWLM individuals exhibited trends towards thicker cortex than OB individuals, which may be important in future studies.

Brain response to food stimulation in obese, normal weight, and successful weight loss maintainers.

As many people struggle with maintenance of weight loss, the study of successful weight loss maintainers (SWLM) can yield important insights into factors contributing to weight loss maintenance. However, little research has examined how SWLM differ from people who are obese or normal weight (NW) in brain response to orosensory stimulation. The goal of this study was to determine if SWLM exhibit different brain responses to orosensory stimulation.

Metabolic syndrome is associated with learning and recall impairment in middle age.

Aims: To determine whether middle-aged individuals with metabolic syndrome, both with and without type 2 diabetes, exhibit cognitive impairments, and to determine the role of each metabolic syndrome component in those associations.

Methods: 143 participants were drawn from ongoing studies of normal aging. Metabolic syndrome was diagnosed in 73 participants (age: 60.