Dr Kelsey Sewell

INTRODUCTION
Subjective cognitive concerns frequently diverge from objective cognitive performance in cognitively unimpaired (CU) older adults, yet the neurobiological basis of this mismatch remains unclear.

METHODS
In 648 participants from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), we defined four profiles by integrating subjective and objective cognitive status. We examined associations with plasma neurofilament light chain (NfL), phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), a magnetic resonance imaging–based volumetric Alzheimer's disease (AD) signature reflecting atrophy, and brain-predicted age difference (brain-PAD).

RESULTS
Joint profiles were differentially associated with NfL (P = 0.0427) and brain-PAD (P = 0.0296). Follow-up contrasts further indicated higher NfL and lower volumetric AD signature in the concordant lower functioning profile, and higher brain-PAD in discordant profiles. p-tau217 and GFAP did not differ across profiles.

DISCUSSION
Joint subjective–objective cognitive profiles may capture biologically meaningful heterogeneity relevant to neurodegeneration and brain aging in older adults.

TRIAL REGISTRATION
ClinicalTrials.gov: NCT02875301

Introduction
Poor sleep is associated with neurodegenerative disease, but mechanisms are unclear. Greater volume of the choroid plexus (ChP), a brain structure supporting neurotoxic waste clearance, is linked to neurodegeneration and cognitive decline. We tested whether poor sleep promotes neurodegeneration and cognitive deficits via ChP dysfunction.

Methods
Baseline magnetic resonance imaging (MRI) -derived ChP, hippocampal, ventricular, and gray matter volumes from 635 cognitively unimpaired older adults were analyzed. Sleep was measured with the Pittsburgh Sleep Quality Index and accelerometry. Confirmatory factor analysis generated cognitive domain scores.

Results
Poorer self-reported sleep quality was associated with greater ChP volume, while accelerometry measures were not. Greater ChP volume was associated with smaller hippocampi and gray matter, and larger ventricles. ChP mediated relationships between sleep quality and hippocampal and ventricular volumes. Gray matter mediated associations between ChP and cognitive domains.

Discussion
Altered ChP morphology may link poor sleep to neurodegeneration and cognitive decline in older adults.

Objectives: This study examined whether peripheral biological pathways including inflammation, insulin resistance, and arterial stiffness, partially explain the link between cardiorespiratory fitness (CRF) and cognitive function in older adults.

Methods: In a cross-sectional sample of cognitively unimpaired older adults (N = 648, 71% female, M age = 69.88 ± 3.75 years), participants completed a comprehensive cognitive battery assessing executive function (EF)/Attentional control, episodic memory, processing speed, working memory, and visuospatial abilities. CRF was measured using a maximal graded exercise test performed on a motorized treadmill. Peripheral biomarkers included low-grade systemic inflammation (Interleukin-6; IL-6), insulin resistance (Homeostatic Model Assessment for Insulin Resistance; HOMA-IR) and arterial stiffness (carotid-femoral pulse wave velocity; cfPWV). Parallel mediation models, adjusted for age, sex, APOE4 carriage, body fat percentage, study site and years of education, tested whether these biomarkers statistically mediated associations between CRF and cognitive performance.

Results: IL-6 emerged as a consistent significant mediator of the relationship between CRF and EF, episodic memory, visuospatial processing and working memory. HOMA-IR statistically mediated the association between CRF and both EF and processing speed. In contrast, cfPWV did not statistically mediate an association between CRF and performance in any cognitive domain.

Conclusion: These findings suggest that low-grade systemic inflammation broadly mediates the relationship between CRF and cognitive function, while metabolic pathways show more domain-specific associations. Together, these results highlight the need for understanding the plural, yet distinct, biological mechanisms by which higher CRF relates to better cognitive performance, with the goal of identifying potential targets for interventions aimed at preserving cognitive health in older adulthood.

Introduction
Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with reduced risk of cognitive decline and dementia, yet their relationships with dementia-related pathophysiology remain unclear. In a community-dwelling older adult cohort, we examined associations between objectively measured PA, CRF, biomarkers of Alzheimer's disease (AD)-related pathology, and cognition.

Methods
Participants (n = 648, 71% female, age 69.88 ± 3.75) completed a comprehensive cognitive evaluation, objective assessments of moderate-to-vigorous PA (MVPA) and CRF (VO2peak), and AD-related brain (positron emission tomography [PET] amyloid beta [Aβ]) and blood biomarkers (Aβ1–42/1–40, phosphorylated tau [p-tau]217, p-tau181, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]).

Results
Greater MVPA (β = −0.107; p = 0.013) and CRF (β = −0.114; p = 0.027) were associated with lower NfL, but not Aβ PET, p-tau217, Aβ1–42/1–40, or GFAP. Aβ positivity moderated the CRF–NfL relationship, with higher CRF linked to lower NfL specifically among Aβ-positive individuals. NfL mediated relationships between MVPA, CRF, and cognitive performance in select domains.

Discussion
Neuroprotective benefits of PA may be conferred through mechanisms influencing neurodegeneration, particularly among those with emerging AD pathology.

Highlights
∙ Greater objectively measured physical activity was associated with lower neurofila-ment light chain (NfL) levels.
∙ Physical activity was unrelated to biomarkers of core Alzheimer’s disease pathology(amyloid beta [Aβ] positron emission tomography, phosphorylated tau 217).
∙ NfL mediated associations between physical activity and cognition in select domains.
∙ Similar patterns were found for cardiorespiratory fitness (CRF), a physiologicalmeasure of aerobic fitness.
∙ Higher CRF was related to lower NfL specifically among Aβ–positive individuals.

Plasma amyloid-β (Aβ) peptides, alone or in ratio with p-tau217, show strong potential as Alzheimer's disease biomarkers. While immunoprecipitation-mass spectrometry (IP-MS) is the preferred method for plasma Aβ quantification, current assays are resource- and time-intensive. Here, we developed a streamlined IP-MS method using a cost-effective instrument that significantly improved the efficiency of an original assay by incorporating a single immunoprecipitation step, an optimized buffer system, and approximately 75% reductions in antibody and sample volume requirements. Technical validation revealed excellent dilution linearity (r²>0.99), high precision (< 10% variation), enhanced sensitivity, improved Aβ recovery, and markedly increased signal-to-noise ratios. In a large cohort of cognitively normal older adults (n = 317), the plasma Aβ1-42/Aβ1-40 ratio achieved stronger concordance with Aβ-PET and superior accuracies to identify abnormal scans (AUC 0.81 vs. 0.65 for the original assay). Notably, accuracies remained high even with plasma volumes as low as 100 μL. The improved IP-MS method enables robust and simplified plasma Aβ assessment in Alzheimer's disease, with implications for prognosis, diagnosis and intervention trials.

Background and Objectives
Maintaining cognitive function despite the presence of Alzheimer disease (AD) pathology is the foundation of cognitive reserve. Although the theory of cognitive reserve is strongly supported by empirical research, the field lacks standardized, validated methods for quantifying cognitive and brain reserve. We tested whether associations between AD pathology and cognitive function were modified by proxy measures of cognitive reserve (years of education, socioeconomic status; SES) and brain reserve (brain-predicted age difference, and a volumetric AD signature). We hypothesized that greater structural brain integrity, higher education, and higher SES would attenuate the association between greater AD pathology and poorer cognitive performance.
Methods
This cross-sectional study analyzed baseline data from a multisite randomized clinical trial, which was conducted at 3 US universities and enrolled cognitively unimpaired, physically inactive, community-dwelling adults. AD pathology was measured via plasma assays for phosphorylated tau (p-tau)-217 in the whole cohort, and PET for β-amyloid (Aβ) in a subset of participants as a secondary analysis. The primary outcome of cognitive function was evaluated by a comprehensive cognitive assessment. SES was measured via the MacArthur Socioeconomic Status Index, and magnetic resonance imaging was used to calculate brain-predicted age difference (brain-PAD) and a volumetric AD signature. Data were analyzed using linear regression models with interaction terms for moderation analyses.
Results
A total of 621 participants (aged 69.9 ± 3.8, 71% female) had available data for the main analyses and 355 had PET Centiloid data available. Brain-PAD moderated the association between AD pathology (measured by p-tau217) and multiple cognitive domains, including episodic memory (β = −0.09 [−0.16 to −0.02]), processing speed (β = −0.08 [−0.15 to −0.01]), working memory (β = −0.10 [−0.18 to −0.03]), and executive function/attentional control (β = −0.08 [−0.15 to −0.01]). Specifically, the negative association of greater AD pathology with poorer cognition was weakest in individuals with younger appearing brains. A latent SES score also moderated the relationship between p-tau217 and episodic memory (β = 0.08 [0.01–0.16]), but this did not survive correction for multiple comparisons. Neither years of education nor the volumetric AD signature moderated pathology-cognition associations.
Discussion
These results support the hypothesis that higher cognitive and brain reserve may help buffer the cognitive consequences of AD pathology. Strategies to increase both cognitive and brain reserve could help to boost resilience against emerging AD pathology; however, longitudinal studies are needed to confirm these conclusions.

A substantial proportion of dementia risk may be attributable to modifiable factors, yet these are often examined in isolation despite their interrelated nature and tendency to co-occur. It remains unclear whether the relationship between modifiable factors and dementia risk is influenced by individual characteristics such as sex and genetic susceptibility. We investigated longitudinal associations between the Lifestyle for Brain health (LIBRA) score and risk of dementia, cognitive performance, and brain structure, and whether relationships differed by sex and APOE ɛ4 carrier status.Participants were aged > 50 years, dementia-free at baseline, 50% female and predominantly (97%) white/Caucasian. The LIBRA score included 11 modifiable factors (e.g., hypertension, obesity, physical inactivity). Magnetic resonance imaging estimated brain volume, domain-specific cognitive composite scores were calculated, and dementia diagnoses were determined based on self-reported and linked healthcare data.Across a mean follow-up of 10.2 years, a higher LIBRA score was associated with greater odds of developing dementia (OR = 1.20, 95% CI 1.18-1.22). This association was stronger in APOE ɛ4 non-carriers compared to ɛ4 carriers. Cross-sectionally, higher LIBRA scores related to poorer cognition, smaller whole-brain gray and white matter volumes, and increased ventricular cerebrospinal fluid (CSF), however, only the association with increased ventricular CSF persisted longitudinally (mean follow-up 3.4 years).Each one-point increase on the LIBRA score was associated with 20% increased odds of developing dementia. These results reinforce the need to target modifiable dementia risk factors and to tailor dementia prevention strategies to individual risk profiles to maximize the impact on brain health.

Background Physical activity and sleep are both related to brain health, and these lifestyle factors also share a bi‐directional relationship. However, in the context of cognitive function, sleep and physical activity are seldom considered together in cross‐sectional studies, and the influence of each lifestyle factor in the context of interventions (e.g., exercise) remains unclear. The purpose of this research is to investigate whether sleep and physical activity may interact to influence brain health in older adults. Method This will present data from two studies. The first is a previously unpublished cross‐sectional study in healthy older adults (n = 589; 69.8 ±3.7 years). Sleep was measured via the Pittsburgh Sleep Quality Index (PSQI) and both sleep and physical activity were measured via 24‐hour actigraphy for 7 days. We investigated the moderating influence of physical activity on associations between sleep and cognitive function in five domains. Secondly, we will present published data from a randomized controlled trial which was a 6‐month, supervised exercise intervention in 89 cognitively unimpaired older adults (68.76±5.32 years). We investigated the influence of baseline sleep, measured by PSQI, on exercise‐induced cognitive improvement across the course of the intervention. Result Cross‐sectionally, moderate‐to‐vigorous physical activity (MVPA) moderated the association between self‐reported sleep efficiency and episodic memory, processing speed, EF/attentional control, and working memory (β[range] = ‐0.10 – ‐0.17, all p < .05). Light physical activity moderated the association of actigraphy‐measured WASO with EF/attentional control and processing speed (βs = 0.10, all p < .05). The direction of these results was such that the association between lower sleep efficiency and greater WASO with poorer cognitive performance was stronger in those with low physical activity levels. From our exercise intervention study, we found that that those with poorer sleep efficiency at baseline showed the greatest exercise‐induced improvements in episodic memory from pre‐ to post‐intervention (β=−0.024, p = 0.004). Conclusion Our results suggest that physical activity and sleep interact to influence cognitive function, and the efficacy of exercise interventions to improve cognition may be influenced by sleep. Taken together, our data suggest that physical activity may compensate for some negative influences of poor sleep on cognition.

Background Physical activity (PA) may be a potent strategy to preserve cognitive function and reduce dementia risk, though critical questions regarding effectiveness, dosing, and mechanisms remain. Identifying the clinical impact and biological pathways of PA will help direct new preventive approaches and improve the precision of behavioral interventions. We present preliminary cross‐sectional and longitudinal findings from a phase 3 clinical trial of aerobic exercise on cognition and brain health in older adulthood. Methods The Investigating Gains in Neurocognition in an Intervention Trial of Exercise(IGNITE) study is a 12‐month randomized dose‐response exercise trial in 648 older adults (69.88 ± 3.75 years [range 65‐80]; 71% female; 25% non‐white) consisting of three conditions: (1) 150 minutes/week moderate‐intensity aerobic exercise, (2) 225 minutes/week moderate‐intensity aerobic exercise, or (3) 150 minutes/week light‐intensity stretching/toning (control). We obtained a comprehensive cognitive assessment, brain MRI, PET amyloid, Alzheimer's Disease(AD)‐related blood biomarkers (ptau217, GFAP, NfL, Aβ1‐42/Aβ1‐40), accelerometry and cardiorespiratory fitness (CRF) data at baseline and 12‐months. Results Higher baseline fitness (CRF) was associated with greater volume of select hippocampal subfields, preserved white matter microstructural integrity, and better performance across multiple cognitive domains including executive function, processing speed, and episodic memory. Greater baseline moderate‐to‐vigorous PA (MVPA) was associated with better multi‐domain cognitive performance and decelerated brain aging. Higher fitness and MVPA were also related to lower NfL levels, particularly among Aβ‐positive individuals, suggesting that maintaining higher fitness may help offset neurodegenerative changes in the setting of preclinical AD pathology. In longitudinal analysis, total adverse event risk was low, emphasizing general safety of aerobic exercise in this large community‐based sample. During this talk, we will also share preliminary interventional findings on the impact of exercise on executive function and other cognitive processes, dose‐response relationships, and specific demographic, health, and genetic factors that may influence the potency of exercise effects on cognitive outcomes. Conclusions Preliminary findings emphasize the relationship of fitness and PA to cognition, multiple aspects of brain morphology, and AD‐related blood biomarkers in cognitively unimpaired older adults. This research also identifies multiple moderators of these relationships, which may help inform individualized exercise prescriptions to optimize cognitive and brain health in older adulthood.

Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers. METHODS Here, we leveraged a novel analysis framework capable of resolving individual fiber populations at the within-voxel level-fixel-based analysis (FBA)-to analyze three metrics of white matter organization from diffusion-weighted MRI scans: fiber density (FD), fiber cross-section (FC), and their combined measure (FDC). Using a cross-sectional sample of 636 cognitively unimpaired older adults aged 65 to 80 years (mean age = 69.8 years; 71% female), we hypothesized that FBA metrics would be associated with CRF and that this variation in FBA metrics would mediate associations between CRF and cognitive performance. RESULTS In whole-brain analyses, higher CRF was associated with greater FD, FC, and FDC. Furthermore, these FBA-derived metrics statistically mediated the relationship between CRF and cognitive performance in the domains of visuospatial abilities, processing speed, working memory, and executive function/attentional control, but not episodic memory. DISCUSSION These findings highlight the potential for CRF in the preservation of multiple aspects of cognition as a function of white matter micro- and macro-structural properties. Our results provide novel insights into the neurobiological mechanisms of fitness-related cognitive resilience. Highlights Higher cardiorespiratory fitness (CRF) is linked to better white matter integrity in older adults. Fixel-based analysis reveals CRF associations with fiber density and cross-section. White matter properties mediate CRF effects on cognition, excluding episodic memory. Findings suggest CRF supports cognitive resilience via white matter organization.