Residential Neighborhood Disadvantage and Amyloid Positivity: Findings from IDEAS.

Background: Residence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.

Dissociable spatial topography of neurodegeneration in Early‐onset and Late‐onset Alzheimer’s Disease: A head‐to‐head comparison of MRI‐derived atrophy measures between the LEADS and ADNI cohorts.

Background: Understanding how early‐onset Alzheimer’s disease (EOAD) differs from typical late‐onset AD (LOAD) is an important goal of AD research that may help increase the sensitivity of unique biomarkers for each phenotype. Building upon prior work based on small samples, here we leveraged two large, well‐characterized natural history study cohorts of AD patients (LEADS and ADNI3) to test the hypothesis that EOAD patients would show more prominent lateral and medial parietal and lateral temporal cortical atrophy sparing the medial temporal lobe (MTL), whereas LOAD patients would show prominent MTL atrophy.

Method: We investigated differences in the spatial topography of cortical atrophy between EOAD and LOAD patients by analyzing structural MRI data collected from 211 patients with sporadic EOAD and 88 cognitively unimpaired (CU) participants from the LEADS cohort as well as 144 patients with LOAD and 365 CU participants from the ADNI3 cohort.

Amyloid‐PET in patients with a clinical diagnosis of sporadic early‐ versus late‐onset AD: comparison of the LEADS and ADNI cohorts.

Background: Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age≥65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).

Method: 731 patients meeting the 2011 NIA‐AA criteria for AD dementia or MCI were included (505 early‐onset from LEADS, 226 late‐onset from ADNI3, Table 1).

CU PET Aβ and Tau Positive Individuals Show Impairment in MoCA Delayed Recall.

Background: Identification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances.

Voxel‐wise comparison of [F]MK6240 and [F]Flortaucipir for the diagnosis of individuals across the Alzheimer’s disease spectrum – the HEAD study.

Background: In vivo studies using the tau PET tracers have shown high performance for the diagnosis of Alzheimer’s disease dementia and patterns of tracer uptake that resemble those observed in post‐mortem studies. However, tau tracers present distinct patterns of binding that might influence their performance in detecting AD pathology. In a head‐to‐head study, we investigated the performance of [F]MK6240 and [F]Flortaucipir for the diagnosis of AD.

Identifying anatomical subtypes of sporadic EOAD in LEADS via unsupervised clustering of MRI‐based regional atrophy patterns.

Background: Neurodegeneration in sporadic early‐onset Alzheimer disease (EOAD) is topographically heterogeneous, as suggested by variability in syndromic presentation. We performed an unsupervised clustering analysis of structural MRI data to identify anatomical subtypes of EOAD. We hypothesized that distinct clusters will be present but will: (1) share areas of overlap focused around posterior regions of our newly developed EOAD signature of cortical atrophy (Touroutoglou et al.

Clinical Impact of Amyloid PET in Diverse Medicare Beneficiaries with Cognitive Impairment: Preliminary Results from New IDEAS.

Background: The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study demonstrated that amyloid PET changes patient management in >60% of Medicare beneficiaries with MCI/atypical dementia. IDEAS had limited racial/ethnic diversity and excluded patients with “typical” amnestic clinical presentations. Here we present preliminary results from the New IDEAS study, which evaluates the clinical impact of amyloid PET in a more racially, ethnically and clinically diverse cohort.

Vaccine hesitancy or hesitancies? A latent class analysis of pediatric patients' parents.

Vaccine hesitancy is an attitude of indecision toward vaccination that is related to but not determinative of vaccination behaviors. Although theories of vaccine hesitancy emphasize it is often vaccine-specific, we do not know the extent to which this is true across sociodemographic groups. In this study, we asked: What latent classes of vaccine hesitancy might exist when examining parents' attitudes toward vaccines in general and COVID-19 and human papillomavirus (HPV) vaccination specifically? Which sociodemographic, health access, and health-related variables are predictive of membership in those classes? To answer those questions, we analyze online survey data from parents of pediatric patients recruited through eight clinics within the University of Arkansas for Medical Sciences Rural Research Network.

Differential associations between plasma p‐tau181 and hippocampal subfield integrity across the Alzheimer’s disease diagnostic continuum.

Background: Plasma p‐tau181 is an increasingly established diagnostic marker for Alzheimer’s disease (AD); however, its precise relationship with brain tau pathology and the neural mechanisms underlying its association with cognitive impairment remain elusive. Our objective was to assess the association between plasma p‐tau181 and hippocampal (HC) subfield integrity and to investigate whether the subfields mediate the relationship between plasma p‐tau181 and cognition.

Method: A total of 213 participants (57 cognitively normal, 109 mild cognitive impairment, and 47 AD) with plasma p‐tau181 measurements and high‐resolution T2‐weighted scans were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Investigating retrotransposon‐derived eccDNA as a source of innate immune activation in tauopathy.

Background: Retrotransposon‐derived extrachromosomal circular DNA (eccDNA) was extracted and sequenced from brains with Alzheimer’s disease, progressive supranuclear palsy, or healthy controls. Retrotransposon‐derived DNA was visualized outside of the nucleus in these phenotypes with phospho‐STING. were used as a model to study extranuclear retrotransposon DNA.

Integration of GWAS and cerebrospinal fluid proteogenomics identifies proteins for AD and shared dysregulated mechanisms in other neurological traits.

Background: Cerebrospinal fluid (CSF) is a valuable resource for the study and diagnosis of neurological diseases, but few studies have comprehensively characterized the genetic determinants of CSF protein levels that may contribute to the development of disease. These quantitative trait loci (QTL) have proven vital to identifying candidate genes for disease treatment and monitoring. Here, we utilize our largest‐to‐date CSF protein QTL atlas to prioritize potentially causal proteins for 14 neurological traits and examine the unique and overlapping disease mechanisms observed using CSF proteins.

Effort‐based decision making and white matter tracts associated with dimensions of apathy in Alzheimer’s and Parkinson’s disease.

Background: Apathy is marked by diminished motivation and goal‐directed behavior, prevalent in neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Effort‐based decision‐making paradigms (EBDM), which require choices between tasks of varying effort levels for varying rewards, are effective assessments of goal‐directed behavior. Using a transdiagnostic approach, we are examining the neurodegeneration of networks on apathy and EBDM.

Examining domain‐specific cognitive associations with p‐tau217 in a cognitively normal sample: results from the BioFINDER‐Brown Study.

Background: Emerging research on plasma Alzheimer’s disease (AD) biomarkers represents a new path towards earlier detection of AD pathology and potentially earlier intervention in cognitively normal individuals. Existing cognitive screening tools lack the sensitivity to distinguish between cognitively normal individuals with and without AD pathology. The present analysis investigated associations between performance on TabCAT digital assessment subtests and levels of plasma phosphorylated tau 217 (p‐tau217) in a cognitively healthy sample.

COVID‐19 Mortality Rates and Changes in Antidementia and Psychotropic Medication Use Among Nursing Home Residents.

Background: We examined the relationship between nursing home (NH) COVID‐19 mortality rates and changes in antidementia and psychotropic medication initiation before and during the pandemic and explored the influence of staffing and resident factors.

Method: Changes in medication initiation were collected through a nationally representative cross‐sectional Dementia Treatment Survey (2022) of NH Directors of Nursing. Outcome measures were created by collapsing a 5‐point Likert scale contrasting less/about the same vs.

Modeling the influence of presenilin‐1 mutation position on primary outcomes of a gantenerumab trial: findings from the DIAN‐TU‐001 study.

Background: In autosomal dominant Alzheimer disease (ADAD), the position of a pathogenic genetic variant within the presenilin‐1 () coding sequence influences how amyloid‐beta accumulates and how dementia progresses (Joseph‐Mathurin et al, 2024). In the first trial of anti‐amyloid monoclonal antibodies in individuals at risk for ADAD (Dominantly Inherited Alzheimer Network Trials Unit study 1 [DIAN‐TU‐001]), gantenerumab demonstrated target engagement but did not meet its primary clinical endpoint (Salloway et al, 2021). Whether the distribution of pathogenic genetic variants within the cohort may have influenced the trial results remains unclear.

Resting state EEG theta/beta power ratio and cognitive reserve in cognitively unimpaired older adults.

Background: Patients with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease show a pattern of “slowing” on resting state electroencephalography (EEG), often indexed by ratio of theta to beta power. The objective of this study was to investigate associations between theta/beta power ratio, subjective cognitive decline, and cognitive reserve in cognitively unimpaired older adults at high versus low risk for AD.

Method: Cognitively unimpaired older adults at high risk (4 carrier and positive family history; N = 25) or low risk ( non‐4 carrier and negative family history; N = 25) for AD completed questionnaires about subjective cognitive decline (SCD; Everyday Cognition Scale) and cognitive reserve (Cognitive Reserve Index Questionnaire).

Digital Assessment Approaches to Overcome Barriers to Cognitive Screening and Monitoring for Older Adults in Primary Care Settings.

Background: Routine cognitive screening for older adults in primary care could improve AD early detection and streamline referrals for treatment or clinical trials. Digital assessments, especially when self‐administered online, can overcome time barriers to cognitive screening in primary care settings and are conducive to repeat testing for disease monitoring and the evaluation of treatment outcomes. We report preliminary data on the feasibility and acceptability of three digital screening approaches for older adults completing annual follow‐up visits with a primary care provider (PCP)

Methods: Cognitive screening approaches included: 1) remote online screening with the Boston Online Cognitive Assessment (BOCA) 1‐4 weeks prior to the PCP appointment, 2) self‐administered BOCA in the waiting room before or after the appointment, and 3) provider‐administered screening during the appointment using the Digital Clock and Recall (Linus Health DCR).

Cognitive clusters in sporadic early‐onset Alzheimer’s disease patients from the LEADS study.

Background: Early‐onset Alzheimer’s disease (EOAD) occurs before age 65 and has more diverse disease presentations than late‐onset AD. To improve our understanding of phenotypic heterogeneity among EOAD individuals, we analyzed cognitive scores using data‐driven statistical analysis.

Method: Baseline cognitive data from 286 sporadic EOAD individuals from the Longitudinal EOAD study (LEADS) were transformed to z‐scores using data from 95 cognitively normal (CN) individuals.

Strategy Use on Digital Cognitive Assessment Differs Between Individuals with and without Elevated Phosphorylated Tau 217 in Cognitively Normal Older Adults: Results from the BioFINDER‐Brown Study.

Background: New immunotherapies for Alzheimer’s Disease (AD) have shown promise in slowing disease progression and are most effective in the early stages of the disease. New, low‐cost methodologies are needed to detect early AD pathological change. Digital cognitive tools may represent a cost effective, efficient, and sensitive method to detect early AD‐related pathological change.

The added value of metadata on test completion time for the quantification of cognitive functioning in survey research.

Objective: Information on the time spent completing cognitive testing is often collected, but such data are not typically considered when quantifying cognition in large-scale community-based surveys. We sought to evaluate the added value of timing data over and above traditional cognitive scores for the measurement of cognition in older adults.

Method: We used data from the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD) study ( = 4,091), to assess the added value of timing data over and above traditional cognitive scores, using item-specific regression models for 36 cognitive test items.

Data‐driven analysis of 10,361 amyloid‐PET scans from the IDEAS study reveals two primary axes of variation.

Background: The variability in the regional distribution of Aß‐PET signal and its relation to clinical features is debated. We used data‐driven approaches to uncover heterogeneity in cortical Aß‐PET signal from a large representative sample collected through the IDEAS study.

Methods: We analysed cross‐sectional Aß‐PET collected from 10,361 patients with MCI or mild dementia scanned in 295 PET facilities using one of the 3 FDA‐approved tracers.

Comparison of [F]MK6240 and [F]Flortaucipir standardized uptake values (SUVs): the HEAD study.

Background: Differences between on‐ and off‐target retention characteristics between [18F]MK6240 and [18F]Flortaucipir (FTP) complicate the harmonization across tracers. Our objective here was to separate the impact of the reference region by evaluating correlations between [18F]MK6240 (MK) and [18F]FTP standard uptake values (SUVs).

Method: Participants (Figure 1, n=90) received an amyloid‐β (Aβ) PET scan ([11C]PIB or [18F]NAV4694) and two tau‐PET scans: [18F]MK (90‐110 minutes post‐injection) and [18F]FTP (80‐100 minutes post‐injection).

Comparison of tau‐PET tracers for in vivo Braak staging: the HEAD Study.

Background: Tau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.

Amyloid‐PET in patients with a clinical diagnosis of sporadic early‐ versus late‐onset AD: comparison of the LEADS and ADNI cohorts.

Background: Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age = 65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).

Method: 731 patients meeting the 2011 NIA‐AA criteria for AD dementia or MCI were included (505 early‐onset from LEADS, 226 late‐onset from ADNI3, Table 1).

Association between Default Mode Network Connectivity Compared Between Two Tau Tracers (Flortaucipir vs. MK6240) – HEAD Study.

Background: Default mode network (DMN) resting state connectivity has been correlated with heightened amyloid and tau – hallmarks of Alzheimer’s Disease (AD). Tau is postulated to impact a meta‐temporal area including DMN‐associated regions like amygdala, entorhinal cortex, fusiform gyrus, parahippocampus, inferior temporal, and middle temporal gyrus. We recruited individuals with varying cognitive status to undergo resting state connectivity and imaging with two tau tracers (Flortaucipir and MK6240).