Kelsey Sewell

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.

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.

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.

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.

Background
The development of Alzheimer's disease (AD) involves accumulation of brain pathology; however, some individuals appear to maintain cognitive and day-to-day function in the presence of neuropathology better than others. One likely contributor to this resilience is the maintenance of structural brain integrity to a greater extent than expected based on age-related norms, i.e., a younger ‘brain age’. In this study we examined whether brain age moderated the association between AD-related blood biomarkers and cognitive function.

Method
We utilized baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE) study. Cognitively unimpaired older adults (n = 648, aged 69.9±3.8, 71% female) completed a comprehensive cognitive assessment and an MRI scan where T1-weighted images were used to calculate brain age using brainageR. The difference between chronological age and brain age was used to calculate the brain-predicted age difference (brain-PAD). Assays were completed for plasma-based biomarkers phosphorylated tau (p-tau) 217 and neurofilament light (NfL) measured on the SIMOA platform.

Result
After covarying for age, sex, site, BMI, image quality and education, brain-PAD moderated the association of p-tau217 with episodic memory (β=-0.09, SE = 0.04, p = .017), processing speed (β=-0.07, SE = 0.04, p = .046), working memory (β=-0.10, SE = 0.04, p = .005), and executive function/attentional control (β=-0.08, SE = 0.04, p = .035), but not visuospatial processing. The direction of these interactions was such that the association between higher p-tau217 and poorer cognitive performance was strongest in those with higher brain-PAD (i.e., accelerated brain aging). We do not find evidence of a significant moderation effect of brain-PAD on the association between NfL and cognitive performance in any domain (all p >.05).

Conclusion
Our results suggest that maintenance of structural brain integrity (slower brain aging) may help protect against cognitive deficits in the face of AD pathology (i.e., p-tau217) in cognitively unimpaired individuals. These results provide support for the concept of brain maintenance, however, should be further tested in samples across the AD trajectory (i.e., mild cognitive impairment and AD). Understanding these mechanisms could inform strategies to promote resilience and delay AD-related cognitive decline in aging populations

Introduction
This study examined longitudinal associations between self-reported exercise and cognition, with moderation by sex, in individuals with autosomal dominant Alzheimer's disease (ADAD) mutations. We also examined whether changes in exercise over time differed in ADAD mutation carriers versus non-carriers in the years preceding first cognitive symptom onset.

Methods
Participants (n = 491) were ADAD mutation carriers (63%) and non-carriers (37%) from the Dominantly Inherited Alzheimer Network aged 37.6 ± 11.1 years. Participants reported their average time partaking in various leisure-time exercise activities over the past 12 months.

Results
Greater baseline exercise predicted better longitudinal cognitive performance. Sex did not moderate these associations. In the years preceding first cognitive symptoms or last follow-up visit, mutation carriers showed a decline in their exercise engagement compared to mutation non-carriers.

Discussion
Self-reported exercise is associated with preserved cognitive function in those with ADAD mutations; however, AD-related pathways may influence the level of engagement in exercise prior to cognitive symptom onset.

Highlights
• Greater weekly exercise predicts slower cognitive decline in ADAD mutation carriers.
• These associations varied dependent on closeness to estimated symptom onset.
• These associations were not moderated by sex.
• Weekly exercise declined in ADAD mutation carriers compared to non-carriers.
• Results may suggest a bidirectional relationship between exercise and AD risk.

INTRODUCTION
The relationships between 24-h time-use composition (i.e., sleep, sedentary behavior, light physical activity, and moderate-to-vigorous physical activity [MVPA]) and brain morphology in older adulthood remain poorly understood. We examined associations between 24-h time-use composition and brain age using compositional data analysis, predicting that 24-h time use would be associated with brain age and that a greater amount of time engaged in MVPA would drive associations with younger brain age.

METHODS
Baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE; n = 648) were analyzed. Brain age was estimated using T1-weighted magnetic resonance imaging data. Time-use composition was derived from wrist-worn triaxial accelerometers. Regression models examined associations between 24-h time-use composition (expressed as isometric log ratios) and brain age, adjusting for age, sex, apolipoprotein E4 (APOE4) carriage, education, body mass index, image quality, and site. Compositional isotemporal substitution evaluated how hypothetical reallocations of time between behaviors related to brain age.

RESULTS
The final sample included 573 adults (69.8±3.7 years, 407 females). It was found that 24-h time-use composition was associated with brain age (F = 2.72, p = 0.004). Post hoc modeling indicated that time spent in MVPA primarily drove these associations, such that less MVPA was associated with greater brain age, irrespective of whether time was taken from sleep, sedentary behavior, or light physical activity.

DISCUSSION
These results suggest that 24-h time use, especially time spent in MVPA, relates to structural brain age in late adulthood. Maintaining or increasing MVPA may help preserve younger brain age, irrespective of which behaviors this time was reallocated from. Future research should examine whether systematically shifting 24-h time use toward MVPA alters brain aging trajectories.

INTRODUCTION
Arterial stiffness (carotid-femoral pulse wave velocity [cfPWV]) and plasma neurofilament light (NfL), markers of vascular and neuroaxonal aging, are linked to cognitive decline. Whether higher cfPWV amplifies the NfL–cognition relationship remains unclear.

METHODS
Cognitively unimpaired older adults (N = 570) were assessed using composite cognitive scores from confirmatory factor analysis. cfPWV was dichotomized at the median. Plasma NfL was quantified on a Single Moleculte Array-High Definition, model X (SIMOA-HD X).

RESULTS
Higher NfL correlated with poorer performance across all cognitive domains (p < 0.05), and higher cfPWV was linked to worse episodic memory, working memory, and processing speed (p < 0.05). NfL× cfPWV interactions were significant for episodic (β = 0.289, p = 0.048) and working memory (β = 0.287, p = 0.025), with stronger NfL–cognition associations in the higher cfPWV group (episodic memory: β = -0.324, p < 0.01; working memory: β = -0.343, p < 0.01).

DISCUSSION
Greater cfPWV amplified the association between NfL-related axonal degeneration and cognitive decline.