Abstract INTRODUCTION We investigated the diagnostic utility of the plasma glial fibrillary acidic protein (GFAP)/neurofilament light chain (NfL) ratio in genetic frontotemporal dementia (FTD) and compared its performance with GFAP and NfL alone. METHODS Baseline plasma samples were available from 391 pathogenic variant carriers and non‐carriers, with longitudinal samples (≥2) from 259 participants. Linear mixed‐effects models were used to assess baseline differences between clinical groups, longitudinal trajectories, and the ability of the GFAP/NfL ratio to discriminate underlying TAR DNA‐binding protein (TDP) versus tau pathology. RESULTS Baseline GFAP/NfL ratios differed across clinical groups; however, the ratio did not outperform GFAP or NfL alone in any clinically relevant comparison. No significant differences were observed between symptomatic carriers with underlying TDP versus tau pathology. DISCUSSION The GFAP/NfL ratio provides no added value over NfL alone as a diagnostic or susceptibility biomarker in genetic FTD.
Abstract BACKGROUND Black and Hispanic/Latino Americans experience higher risk of Alzheimer's disease and related dementias (ADRD). Modifiable biological and social risk factors may contribute to this risk but remain underrecognized. METHODS In this cross‐sectional study, we evaluated 105 cognitively normal Black and Hispanic/Latino‐White adults in a Northeast Florida longitudinal cohort. Assessments included clinical exams, objective cardiometabolic/laboratory testing, brain magnetic resonance imaging, and amyloid and tau positron emission tomography (PET) imaging. We compared subjective versus objective risk factors and explored potential associations with prespecified neuroimaging biomarkers. RESULTS Participant median age was 64.2 years, and 63% were female. Nearly all participants (98%) had at least one modifiable ADRD risk factor; 58% had at least three. Objective testing identified higher prevalence of abnormal hemoglobin A1C and vitamin B12 deficiency than self‐report. Black participants had greater white matter hyperintensity burden than Hispanic‐White participants, whereas PET measures were similar. Measured risk factors were not clearly associated with neuroimaging biomarkers. DISCUSSION Potentially modifiable ADRD risk factors were common and underrecognized in this modest‐sized cohort of Black and Hispanic/Latino Americans. These findings reinforce the importance of objective assessment of modifiable risk factors to inform early prevention strategies while emphasizing the need to validate these preliminary findings in larger, representative cohorts.
Abstract INTRODUCTION The amyloid/tau/neurodegeneration (ATN) framework characterizes Alzheimer's disease (AD) biomarkers but does not fully capture neuroinflammation. The choroid plexus (CP), a critical blood–cerebrospinal fluid (CSF) barrier component, has emerged as a neuroinflammatory imaging marker whose relationship to established AD biomarkers remains unclear. METHODS We analyzed multimodal data from 641 Alzheimer's Disease Neuroimaging Initiative participants using magnetic resonance imaging, amyloid/tau positron emission tomography, CSF/plasma biomarkers, and cognitive measures. Associations were examined via correlations, amyloid‐stratified analyses, and structural equation modeling (SEM). RESULTS CP volume was consistently associated with hippocampal atrophy but did not differentiate amyloid‐positive from amyloid‐negative individuals. Plasma glial fibrillary acidic protein showed the strongest association with CP volume, particularly in amyloid‐positive participants. SEM linked CP volume and entorhinal tau to hippocampal atrophy, with amyloid contributing indirectly through tau. DISCUSSION CP volume reflects neuroinflammatory processes more closely tied to neurodegeneration than to amyloid or tau pathology, supporting its role as a complementary biomarker within the ATN framework.
Abstract INTRODUCTION We analyzed baseline diffusion magnetic resonance imaging (MRI) data including diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to predict cognitive transitions over a 1‐year follow‐up in older adults without dementia. METHODS A total of 366 participants from the Wake Forest Alzheimer's Disease Research Center (ADRC) Healthy Brain Study (HBS) were included. The outcome was cognitive migration (CM) , defined based on Clinical Dementia Rating (CDR) global score transitions: CDR 0 to 0 (CDR‐0 Stable), CDR 0 to 0.5 (Migrant − ), CDR 0.5 to 0.5 (CDR‐0.5 Stable), and CDR 0.5 to 0 (Reverter + ). NODDI free water (FW) and DTI metrics (fractional anisotropy [FA] and mean diffusivity [MD]) from whole brain and white matter (WM) association tracts were examined for their association with 1‐year CM status. RESULTS CM transition rates were: 46% CDR‐0 Stable, 29% CDR‐0.5 Stable, 16% Reverter + , and 9% Migrant − . In WM association tracts, the Reverter + group had higher DTI FA and lower MD than the CDR‐0.5 Stable group. DISCUSSION FA and MD (not FW) may be sensitive markers for reversion during early transitions in WM association tracts.
Abstract INTRODUCTION Individuals with preclinical Alzheimer's disease may develop objective subtle cognitive decline (OSCD) as they transition between the cognitively unimpaired and mild cognitive impairment stages. Selection of individuals with OSCD into clinical trials may provide enrichment for participants likely to benefit from treatment. We examined how choice of operational criteria for OSCD impacted clinical staging. METHODS We analyzed data from 6154 older adults in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease clinical trial to evaluate differences in clinical categorization rates by operational approach, as well as interactions with sex, race, and ethnicity. RESULTS: Multinomial generalized estimating equation models yielded significant differences in clinical categorization rates: Interview‐based methods led to the lowest proportion of individuals categorized with OSCD, cognitive screeners yielded the highest proportion, and multi‐test neuropsychological methods provided a balance. These main effects were moderated by significant interactions with sex and race/ethnicity. DISCUSSION Choice of OSCD criteria will have significant impacts on trial sample makeup.
