Prognostic Value of Plasma Glial Fibrillary Acidic Protein in Cognitively Unimpaired Older Adults: Results from the A4 Study.

Introduction: Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been linked to Alzheimer's disease; however, its prognostic value in cognitively unimpaired (CU) individuals remains unclear.

Methods: We included 949 CU older adults from the A4 preclinical AD trial, and its companion LEARN cohort. Baseline plasma GFAP was measured, and longitudinal associations with cognitive decline, clinical dementia rating (CDR) progression, and imaging biomarkers were assessed over 240 weeks.

Estimating the preclinical Alzheimer's disease course with multimodal data.

Introduction: In observational studies of preclinical AD, an arbitrary "baseline" can obscure where an individual is located along a theoretical continuum. Optimizing longitudinal trajectories can distill multiple, non-linearly distributed observations into a single metric and inform where an individual may be along the disease course.

Methods: We developed a cognitive time (c-time) metric based on longitudinal cognitive data (mean = 7.

Concurrent Changes in Plasma Phosphorylated Tau 217, Tau PET, and Cognition in Preclinical Alzheimer Disease.

Importance: Developing disease-modifying treatments is a priority for Alzheimer disease research.

Objective: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PET) to assess disease modification in treatment trials.

Design, Setting, And Participants: This diagnostic/prognostic study used longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study collected from April 2014 to June 2023.

Racial and ethnic differences in plasma p-tau217 ratio biomarker eligibility rates in a preclinical AD trial with lecanemab.

Introduction: Consistent predictive performance across racial and ethnic groups is essential to the use of plasma biomarkers as screening tools in preclinical Alzheimer's disease trials.

Methods: Logistic regression examined racial and ethnic group differences in plasma eligibility using an algorithm that included Phosphorylated tau217 to non-phosphorylated tau217 ratio, amyloid beta 42/40, age, and apolipoprotein E to predict > 18 Centiloids on amyloid imaging in cognitively unimpaired individuals.

Results: Among 6437 participants screened, with non-Hispanic (NH) White as the reference group, odds ratios of plasma ineligibility were 2.

Assessing Stages of Objective Memory Impairment and neuroimaging as risk factors of incident cognitive impairment.

Objective: The Stages of Objective Memory Impairment (SOMI) system, based on the Free and Cued Selective Reminding Test (FCSRT), is a potential marker of subtle cognitive impairment in cognitively normal persons defined by a Clinical Dementia Rating (CDR) = 0. We investigated SOMI's ability to predict incident cognitive impairment (CDR >0) in combination with demographic features and neuroimaging biomarkers.

Methods: Cognitively unimpaired participants (CDR = 0) from the Harvard Aging Brain Study had baseline FCSRT scores, MRI, FDG-PET, and PiB-PET as well as follow-up CDRs for 5 years.

The Mobile Toolbox for remote, self-administered cognitive assessment in older adults: associations with in-clinic cognitive testing and Alzheimer's disease biomarkers.

Introduction: Remote, smartphone-based cognitive assessments such as the Mobile Toolbox (MTB) may increase the accessibility of Alzheimer's disease (AD) clinical trials. We examined the feasibility of the MTB among cognitively unimpaired (CU) older adults and investigated its associations with standardized in-clinic cognitive testing and amyloid and tau positron emission tomography imaging.

Methods: A total of 100 CU older adults self-administered the MTB remotely on their personal devices.

Modernizing diagnosis of Alzheimer's disease: A review of global trends and Asia-specific perspectives.

The landscape of Alzheimer's disease (AD) and related dementias (ADRD) diagnosis is evolving rapidly, driven by advances in disease understanding, biomarker tools, and disease-modifying therapies. Modern diagnostic approaches emphasize biological precision, early detection, and dynamic frameworks that adapt to treatment-induced changes in disease biology. These frameworks enable opportunities for personalized interventions-encompassing pharmacological and non-pharmacological strategies-and for enhanced clinical trial design.

Cognitive decline across five cognitive batteries: Sample size implications for clinical trials.

Introduction: We evaluated the statistical power for a theoretical randomized trial of anti-amyloid treatment in preclinical Alzheimer's Disease across five cognitive composites in preclinical Alzheimer's Disease across five cognitive composites: Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC); Preclinical Alzheimer's Composite with Semantic Processing (PACC5); Preclinical Alzheimer's Cognitive Composite (PACC); and global and episodic memory composites.

Methods: We utilized annual cognitive assessments from 517 decedents (78.2 ± 4.

Relationship between BrainAge Polygenetic Risk Score and plasma biomarkers in the A4/LEARN studies.

Background And Objectives: To examine the association between genetic predisposition to accelerated brain aging-measured with polygenic risk scores (PRS) derived from BrainAge models-and plasma biomarkers of Alzheimer's disease (AD), with attention to age and sex-specific effects.

Methods: We analyzed 1994 cognitively unimpaired participants from the A4/LEARN studies (71.5±4.

BrainAge moderates associations between Alzheimer's disease biomarkers and cognitive decline: a meta-analysis across A4/LEARN, HABS and ADNI cohorts.

BrainAge delta, the difference between a person's predicted brain age and their chronological age, is a promising marker of the accumulation of neurodegeneration that may increase vulnerability to Alzheimer's disease (AD). We examined whether BrainAge delta moderates the relationship between AD biomarkers and longitudinal cognitive decline performing a meta-analysis across three cohorts (2,279 cognitively unimpaired [CU]; 416 with mild cognitive impairment [MCI]). Higher BrainAge delta was linked to faster decline in CU (β = -0.

Revisiting Centiloids using AI.

The Centiloid scale is the standard for Amyloid PET quantification, widely used in research, clinical settings, and trial stratification. However, variability between tracers and scanners remains a challenge. This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalising implausible longitudinal trajectories during training.

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex.

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia.

Five years of the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT-AD).

Background: First held in 2020, the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT-AD) is a program to train the next generation of Alzheimer's disease (AD) and related dementias (AD/ADRD) clinical trialists.

Methods: IMPACT-AD includes didactic, workshop, and small group components.

Results: IMPACT-AD has trained 18 alumni-scholars (accepted from 424 applicants), of whom 67% were female.

Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity.

Importance: Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD).

Objective: To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes.

Design, Setting, And Participants: Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024.

Midlife Steroid-Binding Globulin Levels and In Vivo Neuroimaging Measures of Tau in Older Men and Women.

Objective: In men and women, sex steroid hormones have been associated with increased risk of Alzheimer's disease (AD) dementia. We aimed to investigate the influence of midlife testosterone and sex hormone binding globulin (SHBG) levels on later-life in vivo markers of β-amyloid (Aβ) and tau deposition in clinically healthy older men.

Methods: This time-lagged study includes participants enrolled in the Framingham Heart Study (FHS) Third Generation cohort.

Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults.

We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer's disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes.

Association of Alzheimer's disease concerns with amyloid burden and lifestyle behaviors in cognitively unimpaired older adults.

Introduction: The extent to which Alzheimer's disease (AD) concerns relate to pathological changes in cognitively unimpaired populations is unclear.

Methods: We analyzed screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to determine if AD concerns are associated with amyloid burden in cognitively unimpaired older adults, and how they relate to lifestyle. AD concerns were measured using the six-item Concerns about Alzheimer's Disease Questionnaire.

Changes in Daily Functioning in Association With Tau and Amyloid Among Unimpaired Older Adults With and Without Elevated Amyloid.

Background And Objectives: Everyday functioning declines gradually over time in Alzheimer disease (AD), with the earliest changes potentially occurring at the preclinical stage. We investigated how changes in everyday functioning relate to (changes in) amyloid and tau in a large sample of cognitively unimpaired older adults, most of whom had elevated amyloid levels at the start of the study.

Methods: This prospective study included participants from a 240-week randomized controlled trial of an anti-amyloid drug, solanezumab, and individuals who screen-failed because of a negative amyloid PET scan.

Localization of Network-Level Atrophy in Preclinical Alzheimer's Disease.

Brain atrophy may precede symptoms in Alzheimer's disease (AD), but it remains unclear whether atrophy in this preclinical stage falls within a distinct brain network or is associated with transitional cognitive changes. We investigated cortical thickness in cognitively unimpaired older adults with varying amyloid-β accumulation and estimated the connectivity of each individual's atrophy pattern using a large normative connectome (n = 1000). A distinct network was connected to atrophy patterns in amyloid-β-positive (n = 1242) versus negative (n = 536) participants.

Relationship between use of anti-platelet agents, oral anti-coagulants, and Aβ burden with cerebral microhemorrhages in cognitively asymptomatic adults.

Introduction: Cerebral microhemorrhages (CMHs) are detectable by magnetic resonance imaging (MRI). CMHs in deep brain regions are linked to hypertensive vasculopathy, while those in lobar regions with amyloid beta (Aβ) deposition in blood vessels. This study aims to determine the association between anti-thrombotic treatment and CMH prevalence among cognitively asymptomatic adults, and to assess the role of Aβ markers, apolipoprotein E (APOE) ε4 carrier status, and cardiovascular risk factors in CMH development.

Lower locus coeruleus integrity is associated with diminished practice effects in clinically unimpaired older individuals.

The locus coeruleus (LC), one of the earliest structures affected by tau pathology in Alzheimer's disease (AD), plays an important role in modulating arousal and learning. In asymptomatic early stages of AD, more sensitive measures to identify subtle cognitive changes are needed. Previous studies indicate that practice effects can signal initial AD-related learning deficits.

Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease.

Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis.