Abstract Introduction Obstructive sleep apnea (OSA) is linked to memory decline and elevated Alzheimer’s disease (AD) risk. Studies consistently show positive associations between sleep disturbances and AD biomarkers in preclinical cohorts, but it is unclear whether AD pathology alters how OSA severity impacts cognition. Here, we examined whether AD biomarkers in Cerebrospinal fluid (CSF) moderate associations between OSA severity and verbal memory. Methods Fifty-eight cognitively unimpaired older adults (61.4±6.3 years, 38 females, 23 AHI≥5) enriched for parental history of AD (n=45) and APOE4 positivity (n=15), and with no prior known history of OSA, underwent clinical polysomnography. Biomarkers were measured using exploratory RocheNeuroToolKit assays. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). PROCESSv5.0 (model 1, SPSS) was used to examine moderating effects of phosphorylated tau-181 (p-tau), neurogranin, and α-synuclein on associations between OSA features (apnea-hypopnea index (AHI), respiratory-disturbance index (RDI), time with < 90% SpO₂) and RAVLT long delay recall performance, while adjusting for sex, age, time between assessments, education years, and body mass index (BMI). P-tau and neurogranin were logarithmically transformed and the reciprocal of α-synuclein was used to maintain normality, and False Discovery Rate (FDR) was implemented for multiple comparisons correction. Results Higher p-tau, neurogranin, and α-synuclein each moderate the association between greater OSA severity and worse long delay recall. Moderations were significant for AHI (p-tau b=–14.3, p< 0.05; neurogranin b=–10.2, p< 0.05; α-synuclein b=2924.1, p< 0.05), RDI (p-tau b=–20.1, p< 0.01; neurogranin b=–11.3, p< 0.05; α-synuclein b=3263.1, p< 0.05), and time < 90% SpO₂ (p-tau b=–15.9, p< 0.01; neurogranin b=–12.4, p< 0.01; α-synuclein b=3550.1, p< 0.01) relationships with RAVLT long delay recall. Conclusion These findings showed that the negative consequences of OSA severity on verbal memory were observed particularly in those with elevated CSF levels of ptau and neurodegeneration markers. These biomarkers may thus help identify those that are more vulnerable to OSA-related memory impairment in the preclinical stage. Support (if any) T35AG076424, T35DK128788, R56AG052698, R01AG027161, R01AG021155, P50AG033514, R01AG037639, K01AG068353, F31AG048732, UL1TR000427

Alterations in white matter microstructure (WMM) are associated with reduced cognitive function in patients with Alzheimer’s disease and related dementias, especially of vascular origin. Cardiorespiratory fitness (CRF) and habitual exercise can positively influence brain health; however, the impact on WMM is not clear. The purpose of our study was to assess the relationship between CRF and habitual exercise participation on WMM in healthy older adults. We hypothesized that CRF and habitual exercise would be positively associated with WMM in tracts more susceptible to age-related change or those related to motor function. Older adults free of underlying disease participated in this study (n=23, age=64±5 yrs, M=12, F=11). CRF was assessed using an incremental maximal exercise test on a cycle ergometer (VO2max) and habitual exercise was assessed using the Godin Leisure-Time Exercise Questionnaire (Godin Score). On a separate visit, WMM was measured using neurite orientation dispersion and density imaging (NODDI) MRI scans. Neurite density index (NDI), fraction of isotropic diffusion compartment (FISO), and orientation dispersion index (ODI) were analyzed in twenty-seven white matter tracts defined by the Johns Hopkins Atlas. Associations between VO2max, Godin scores, and WMM in each white matter tract were evaluated using multivariable linear regression while controlling for age and sex. VO2max was a significant predictor of ODI in the genu of the corpus callosum (β=0.714, B=0.001, 95% CI [0.000, 0.002], p=0.007), corticospinal tract (β=0.553, B=0.003, 95% CI [0.000, 0.006], p=0.035), inferior cerebellar peduncle (β=0.558, B=0.001, 95% CI [0.000, 0.003], p=0.024), cerebral peduncle (β=0.566, B=0.001, 95% CI [0.000, 0.002], p=0.040), and uncinate fasciculus (β=0.607, B=0.001, 95% CI [0.000, 0.002], p=0.023). Godin scores significantly predicted ODI in the medial lemniscus (β=0.448, B=0.001, 95% CI [0.000, 0.001], p=0.033). VO2max also significantly predicted FISO of the sagittal striatum (β=0.519, B=0.002, 95% CI [0.000, 0.004], p=0.031). Neither VO2max nor Godin scores were significantly associated with NDI in any of the white matter tracts (p >0.05). Notably, after applying a Benjamini-Hochberg FDR correction for multiple comparisons (q=0.05), neither VO2max nor Godin scores were significantly associated with any WMM variables in any of the white matter tracts. In conclusion, cardiorespiratory fitness was associated with white matter microstructure, especially the orientation dispersion index, in several tracts associated with aging and motor function. However, the significance of these associations depended on the analytical approach. Future studies should examine longitudinal relationships between cardiorespiratory fitness and white matter microstructure to better understand the role of habitual exercise in mitigating risk for Alzheimer’s disease and related dementias. Funding: National Institutes of Health - HL118154 (JNB), HL007936 (KBM) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Cognitive impairment is increasing with global aging, yet mechanisms linking diet, the gut microbiome, and metabolism to cognitive function remain unclear. To investigate a diet-microbiome-metabolome axis associated with cognition, we integrated fecal metagenomics, diet, and multi-platform plasma metabolomics in 505 older adults from four ADRCs. Several microbes broadly associated with circulating metabolites were also linked to multiple measures of cognitive performance. These taxa exhibited coordinated metabolic signatures, with cognition-positive microbes associated with antioxidant, lipid, and microbial-host co-metabolites, and microbes negatively associated with cognition were linked to inflammatory and aromatic amino acid-derived metabolites. Dietary patterns, particularly the Healthy Eating Index Greens and Beans component, were associated with microbial composition and metabolomic structure. Mediation analyses supported a diet-microbe-metabolite-cognition pathway, while metabolites remained associated with cognition after accounting for microbial features. These findings highlight the metabolome as a central integrator of diet, microbial activity, and cognitive function.

Alzheimer’s disease is increasingly viewed as a breakdown of balanced excitation–inhibition (E/I) homeostasis layered atop classical proteinopathy. Restoring circuit-level neural excitation and inhibition is rapidly becoming a tractable therapeutic strategy, guiding trials of circuit-modulating drugs such as levetiracetam. To date, however, findings across species and modalities remain fragmented, and it is unclear how to contextualize AD-focused E/I findings across scales and methodologies. Synthesizing over 150 studies of E/I homeostasis in AD, we organize the results into several prevailing themes: excitatory/inhibitory effects of amyloid and tau, whether hyperexcitation precedes amyloid plaque deposition, progressive oscillatory slowing (a shift of aggregate neural signal frequencies towards lower frequencies) as AD worsens, early preclinical hyperexcitation peaking in MCI and transitioning to hypoexcitation in AD, sex differences in E/I trajectories, APOE4 as a mediating factor, the contribution of neuroinflammation and metabolic dysfunction to E/I imbalance, and E/I-focused trials/experiments, particularly involving levetiracetam. These dominant themes are interpreted in a framework of multidimensional E/I homeostasis, rather than a single-axis imbalance. To support this integration, we first outline the microscale, mesoscale, and macroscale techniques used to assess E/I in AD, ranging from patch clamping and extracellular recordings to EEG/MEG and fMRI. By charting these multiscale E/I shifts, our synthesis offers a unifying framework to guide future experimental work and accelerate the design of biomarker-driven trials of E/I-targeted therapies in Alzheimer’s disease.

INTRODUCTION:Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), but genetic drivers are unclear. METHODS:In 2614 older adults (mean age ± SD: 73.7 ± 9.8 years; 26% cognitively impaired) from seven harmonized cohorts enriched for cognitive impairment, we quantified free-water-corrected diffusion MRI (dMRI) metrics in seven limbic tracts. We estimated single nucleotide polymorphism (SNP) heritability, performed cohort genome-wide association studies (GWASs) with meta-analysis, evaluated shared genetic architecture and enriched pathways, and assessed AD relevance using brain RNA-seq data. RESULTS:Limbic WM is heritable (h2 = 0.26-0.60; pFDR < 0.05). Meta-GWAS identified six loci (p < 5 × 10- 8), including a signal implicating CDH19, an oligodendrocyte-enriched cell-adhesion gene. Additional loci were near the KC6, SENP5, RORA, FAM107B, and MIR548A1 genes. In brain tissue, RORA, FAM107B, and KC6 expression was associated with cognition and AD neuropathology. Results converged on insulin and immune biology and shared genetic architecture with lipid and cardiovascular traits. DISCUSSION:Limbic WM microstructure is genetically influenced and links oligodendrocyte and vascular-inflammatory biology to AD-relevant outcomes.

The social exposome, all social-environmental exposures accumulated over the life course, could partially explain Alzheimer’s disease and other dementias (ADRD) disparities. Measurement and linkage of life course social exposome metrics to biological samples may inform opportunities for intervention. While there is increasing emphasis on the life course social exposome in ADRD research, there is little consensus on its measurement. Vascular brain injury (VBI) is a measure of changes in the cerebral blood vessels associated with increased risk of ADRD, but the extent to which social exposures are associated with VBI is unknown. We evaluated the association between life course social exposome measures and the VBI burden acrosstwo Alzheimer’s Disease Research Center (ADRC) brain banks. Geocoded life course donor addresses were linked to time-concordant national Area Deprivation Index (ADI) rankings, with greater ADI denoting greater county-level disadvantage. Life course social exposome was examined separately as 1, a cumulative measure of the number of years spent above the population median life course ADI, and 2, the change in ADI from youth to adulthood. The outcome was the presence of any of four VBI indicators: infarcts, microinfarcts, hemorrhages, and white matter rarefaction. The association of life course social exposome to VBI burden was evaluated via logistic regression adjusting for sex and age at death. This sample contained 740 donors from two brain banks. The population median ADI was 7.08 (IQR, 5.5) and the mean number of years spent above this threshold was 19.95 (SD, 20.89). More years living in a county above the population median was associated with increased VBI burden (OR, 1.04, 95% CI, 1.03-1.05). A median ADI which increased (OR, 3.67, 95% CI, 3.65-3.70) or remained stably high between youth and adulthood (OR, 3.08, 95% CI, 3.01-3.14) resulted in increased odds of VBI burden. This study shows promise for clarifying the relationship between the social exposome and ADRD brain pathology post-mortem. We found associations between higher life course ADI (greater disadvantage) and VBI burden. Identifying dosages and timing of life course exposures critical for development of VBI allows for future intervention to reduce disparities in ADRD.

INTRODUCTION:White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences. METHODS:To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status. RESULTS:AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure. DISCUSSION:These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults. HIGHLIGHTS:AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system.

AbstractINTRODUCTIONUnderstanding how a research sample compares to the population from which it is drawn can help inform future recruitment planning. We compared the Wisconsin Alzheimer's Disease Research Center (WADRC) participant sample to the Wisconsin state population (WI‐pop) on key demographic, social exposome, and vascular risk measures.METHODSThe WADRC sample included 930 participants. Population statistics were estimated using several national and state data sources. We compared WADRC to WI‐pop for two age groups, 45–64 years and ≥65 years, separately.RESULTSCompared to WI‐pop, WADRC participants were older and included more women, more Black and American Indian individuals, and fewer Hispanic and Asian individuals. WADRC participants had higher levels of educational attainment, consisted of smaller proportions living in rural areas and disadvantaged neighborhoods, and showed lower vascular risks. Greater differences between WADRC and WI‐pop were found for most metrics in the ≥65 group compared to the 45–64 group.DISCUSSIONThe findings revealed opportunities to increase enrollment from the Hispanic/Latino and Asian American populations, to include participants from a broader range of educational backgrounds, and to enroll more residents from rural areas and disadvantaged neighborhoods, which may lead to a broader distribution of cardiovascular risk factors. Expanding sociodemographic and health profiles represented in the participant candidate pool for study selection and including those who are underrepresented in research may potentially reduce selection bias but not eliminate it. Statistical approaches can be applied to address bias and generalize findings from a study sample to its target population by adjusting for their differences in the joint distribution of covariates. Although research centers have different regional populations and specific recruitment focuses for scientific reasons, evaluating their participant characteristics may help plan engagement efforts to improve the inclusion of underrepresented groups and collaboratively support generalizable research nationwide.Highlights We compared the characteristics of Wisconsin Alzheimer's Disease Research Center (WADRC) participants with the Wisconsin population. Metrics of comparison included demographics, social exposomes, and vascular risks. WADRC participants are different from the Wisconsin population. We explored the implications and causes of the differences. We discussed strategies for engaging and recruiting underrepresented groups.

INTRODUCTION:The interpretation of plasma phosphorylated tau (pTau) levels may be influenced by metabolic conditions, such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, and kidney function. We examined the extent to which metabolic factors are associated with plasma pTau concentrations (pTau181, pTau217, pTau231) and the contribution of these factors on analytical outcomes. METHODS:We analyzed data from 287 participants using partial Spearman's rho, Mann Whitney U, ROC analysis, and linear mixed models. RESULTS:Concordance between plasma pTau217 and amyloid PET was not influenced by IR or estimated-glomerular-filtration-rate (eGFR). Accounting for eGFR improved concordance of pTau181 and pTau231 with amyloid PET. Age, binarized waist-to-hip ratio, and amyloid status were associated with all longitudinal pTau concentrations, and eGFR associated with longitudinal pTau231. DISCUSSION:Metabolic health may influence the interpretation of some plasma pTau biomarkers, potentially necessitating adjustments for metabolic factors in research and clinical settings.

APOE is the greatest genetic risk factor for AD, however, other smaller genetic effects are often ignored. In this work, endophenotype-informed polygenic scores (PGS) that exclude the APOE region were tested along with a separate, previously published, APOE neuropathology-based score ( APOE score). The APOE score serves as a more nuanced quantification of APOE genetic risk that considers the effects of the different haplotypes. PGS and APOE score were compared to amyloid positivity, determined via PET imaging, which is used as a measure for AD risk and progression. Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with genetic data and Florbetapir ( 18 F-AV-45) amyloid PET summary SUVR (whole cerebellum reference region) values were included in analyses. Amyloid positivity (A+) was defined as SUVR > 1.11. PGS were calculated using the weights from genome-wide association studies (GWAS) of CSF Aβ 42 (amyloid-PGS) or ptau 181 (ptau-PGS), after excluding the APOE region (±500kb). APOE effects were accounted for using the APOE score that was calculated following Deming et al (2023). 1094 participants (618 A+) were included in the analyses (Table 1). The APOE score was significantly associated with A+ after accounting for sex and age at scan (OR = 2.931, P = 6.38e-45; Table 2). The amyloid-PGS was also significantly associated with A+ (OR = 0.492, P = 0.026), whereas the ptau-PGS did not quite reach significance (OR = 3.218, P = 0.054). After adding the APOE score, the effect of amyloid-PGS on A+ remained but did not quite reach significance (OR = 0.515, P = 0.072) and ptau-PGS was not significant (OR = 1.845, P = 0.375). These results validate the utility of the APOE score with PET amyloid as well as the potential value of including non- APOE genes in quantifying the genetic risk for amyloid accumulation and AD. The significant association between amyloid-PGS and A+, and near significance after adding the APOE score, demonstrates the existence of additional genetic effects outside of APOE that have an impact on amyloid accumulation. While the ptau-PGS did not reach significance, possibly due to sample size, the OR (3.218) was greater in magnitude than the amyloid-PGS (1/OR = 2.033). Future work will explore these relationships in other cohorts and with other PET AD biomarkers.

INTRODUCTION:Impaired cerebrovascular reactivity (CVR) is common in type 2 diabetes (T2D) patients and is a risk factor for dementia. However, most prior functional magnetic resonance imaging (fMRI) studies in T2D disregarded the impact of impaired CVR on brain activation patterns. This study investigated the relationship between CVR and brain activation during an fMRI task in T2D patients. METHODS:Seventy-four T2D patients underwent a working-memory (WM) fMRI task. CVR was measured by the breath-holding index test using transcranial Doppler (TCD). Regression analyses examined associations between CVR and brain activation and between glycated hemoglobin (HbA1c) and activation with/without adjusting for CVR. RESULTS:An association between CVR and brain activation was found in the left middle and inferior frontal gyri. Adjusting for CVR led to a different pattern of HbA1c-related activation. DISCUSSION:The findings highlight methodological implications, emphasizing the importance of accounting for impaired CVR when analyzing and interpreting fMRI data in T2D patients. Highlights:The study found that cerebrovascular reactivity impacts brain activation patterns during a working memory task in type 2 diabetes patients.Accounting for cerebrovascular reactivity altered the brain regions showing activation related to working memory and glycemic control.The findings highlight the importance of considering vascular factors when interpreting fMRI data in populations with vascular dysfunction.

The timing of neurodegeneration in relation to the onset of Alzheimer’s disease pathology is not fully known. This study examined the association of longitudinal atrophy derived from T1-weighted MRI with 1) cerebrospinal fluid (CSF) amyloid-tau (AT) groupings and 2) Pittsburgh compound B (PiB) PET-derived estimates of amyloid duration among cognitively unimpaired (CU) individuals. CU participants in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center (N = 297) underwent longitudinal MRI, APOE genotyping, and lumbar puncture to determine CSF Aβ42/40 (A) and pTau181 (T) concentration at baseline using in-house cutoffs. CSF measurements were performed using the NeuroToolKit, a panel of robust prototype biomarker assays (Roche Diagnostics International Ltd). Image segmentation was performed using a longitudinal pipeline in SPM12. Grey matter volumes from AD-associated regions (adjusted for intracranial volume) were z-scored according to age-associated predictions from a robust longitudinal A-T-/APOE4-/CU control group. Differences in longitudinal atrophy relative to controls were tested in linear mixed-effects models using contrasts between A+T- and A+T+ groups and A-T- controls and interactions with time (years from baseline). In the PiB PET subset, sampled iterative local approximation was used to estimate time-to-positivity at baseline relative to a PiB DVR threshold of 1.16. CSF A+ individuals were grouped as CSF A+ only, early PiB+ (PiB+ <= 5 years), and established PiB+ (PiB+ > 5 years). Differences in longitudinal atrophy were tested with A+ group/A-T- contrasts and interactions with time. All analyses were FDR-corrected. See Table 1 and Figure 1 for participant characteristics and model details. Based on CSF assays, both A+ groups showed longitudinal atrophy relative to controls in a majority of ROIs, suggesting that A+, regardless of pTau+, is associated with neurodegeneration. Further analysis incorporating PET showed that CSF A+ in the absence of PiB+ was not associated with atrophy, but early PiB+ was associated with atrophy in medial temporal ROIs and precuneus. The largest and most widespread atrophy was observed in the established PiB+ group (Figure 2). Neurodegeneration appears to begin soon after the onset of PET-measurable amyloid-positivity. Clinical intervention at the earliest signs of amyloid deposition may be needed to delay neurodegeneration.

Residence in highly socioeconomically disadvantaged neighborhoods has recently been associated with Alzheimer’s disease (AD) neuropathology at autopsy, cognitive decline, and magnetic resonance imaging (MRI) markers of volumetric brain atrophy in cognitively unimpaired adults. Furthermore, there is mounting evidence that markers of brain microstructure derived from diffusion-weighted MRI (DWI), including neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), are sensitive to AD-related neurodegeneration. In this study, we used linear mixed-effects (LME) modeling to investigate the hypothesis that neighborhood-level disadvantage is associated with mixed-longitudinal trajectories of microstructural neurodegeneration in 539 late-middle-aged participants across the AD continuum. 539 participants (Table 1) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged between 1 and 5 times with multi-shell DWI (constituting 865 total scans). For each scan, average NDI, ODI, and ISO values were extracted from the hippocampus, anterior parahippocampal gyrus, and whole brain cortical gray matter. Geocoded participant addresses were linked to neighborhood disadvantage as measured by the Area Deprivation Index, a marker derived from 17 census indicators of education, employment, poverty, and housing quality. Statewide ADI was binarized for each participant (the highest quintile/most disadvantaged or lowest 4 quintiles/least disadvantaged) and used as a predictor of DWI metrics in LME models with age, sex, diagnosis, education level, and interactions between ADI and age and ADI and diagnosis as covariates. NDI—a measure sensitive to axonal and dendritic loss—was significantly lower (denoting more neurodegeneration) in the most disadvantaged group in all three assessed brain regions (P Corrected < 0.05), and there was a significant interaction between ADI and age (P Corrected < 0.05) for hippocampal NDI (Figures 1-2). No other ADI-DWI associations or ADI interactions survived Benjamini-Hochberg correction for multiple comparisons. Our findings suggest that living in a disadvantaged neighborhood is associated with neuronal degeneration, evidenced by the apparent loss of neurites, and that this process accelerates with age across the AD continuum. As a result, addressing disparities in the social determinants of health may have the potential to reduce the likelihood of neuronal injury in aging adults.

Emerging evidence underscores the significant influence of diet on risk for Alzheimer’s disease and related dementias (ADRD). In particular, a Western dietary pattern associates with increased risk for ADRD, with proposed mediation via inflammatory mechanisms, among others. Although a Western dietary pattern associates with gut microbiome alterations, it remains unclear whether microbial alterations mediate Western diet-associated inflammation and neurodegeneration. To begin to investigate these relationships, this study assessed whether the gut microbiome mediates associations between fast food consumption and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, glial activation, and Alzheimer’s disease (AD). Cognitively unimpaired adults (n=86, Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center) underwent lumbar puncture, provided a stool sample, and reported average weekly fast food consumption over the past year via questionnaire. Participants were an average of 67 years of age and 62% of participants (n = 53) were female. Fecal microbiome composition was characterized using 16S rRNA sequencing. A QIIME2/Phyloseq pipeline was used to complete denoising, feature classification, filtration of rare taxa and agglomeration at each taxonomic rank. CSF biomarkers were quantified using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Multiple regression tested associations between fast food consumption and CSF biomarkers of neurodegeneration, glial activation, and AD. Phylogenetically-informed mediation (PhyloMed; Hong et al, 2021) was performed at each taxonomic rank to identify bacterial clades mediating the relationship between fast food and the CSF Aβ42/40 amyloid pathology test. A significant association between fast food and CSF Aβ42/40 was observed, such that more frequent fast food consumption associated with lower levels of CSF Aβ42/40 (Figure 1), but no significant mediating effects of gut microbiome were observed (Table 1). No significant associations between fast food consumption and other CSF biomarkers were observed (Table 2). While associations between fast food consumption and CSF biomarkers were expected to be partially mediated by gut microbial alterations, few individuals reported consuming fast food more than once each week. Further evidence is needed to characterize the influence of fast food and its nutritional components on neurodegeneration and development of AD pathology preclinically.

Importance:It is unclear whether the duration of amyloid-β (Aβ) pathology is associated with neurodegeneration and whether this depends on the presence of tau. Objective:To examine the association of longitudinal atrophy with Aβ positron emission tomography (PET)-positivity (Aβ+) and the estimated duration of Aβ+ (Aβ+ duration), controlling for tau-positivity. Design, Setting, and Participants:Data for this longitudinal cohort study were drawn from the Wisconsin Registry for Alzheimer Prevention and the Wisconsin Alzheimer Disease Research Center Clinical Core Study. Participants who had 2 or more magnetic resonance imaging (MRI) visits, 1 Pittsburgh compound B (PiB) PET visit, and 1 MK-6240 PET visit with other covariates available were included. A replication analysis was conducted using data from the OASIS-3 dataset. All data were collected between June 1, 2009, and January 22, 2025. Follow-up times ranged from 1.0 to 13.0 years (median [IQR], 8.8 [5.9-10.6] years). Exposures:Sampled iterative local approximation (SILA)-estimated PiB PET uptake at baseline MRI was used to estimate Aβ+ and its duration at baseline MRI. MK-6240 PET uptake in the entorhinal cortex was used to create tau-positive and tau-negative groups using a threshold of 1.27 standardized uptake value ratio. Main Outcomes and Measures:SILA-based modeling of PiB PET data was used to obtain estimated Aβ+ duration at baseline MRI age. Linear mixed-effects models tested differences in atrophy between Aβ+ vs Aβ- individuals and with Aβ+ duration, controlling for individuals who were tau-positive (measured via MK-6240 tau PET) at their most recent PET scan within their MRI visits. Z-scored volumes in temporo-parietal regions of interest associated with AD dementia were assessed via a robust normative approach. Results:A total of 95 Aβ+ (median [IQR] age, 66.4 [61.1-70.4] years; 59 female [62.11%]) and 275 Aβ- (median [IQR] age, 60.2 [55.7-64.6] years; 183 [66.55%] female) individuals were included. Aβ+ (partial η2, 0.015-0.043) and tau-positivity (partial η2, 0.018-0.100) were independently associated with neurodegeneration, with generally small effect sizes. Aβ+ duration was associated with atrophy in a greater number of regions of interest than Aβ+ status alone with somewhat larger effect sizes (partial η2, 0.013-0.056). Results were mostly similar in the OASIS-3 dataset. Conclusions and Relevance:In this longitudinal cohort study, subtle neurodegeneration was observed soon after the onset of Aβ pathology. These results may be consistent with Aβ pathology as a pathological state.

Abstract INTRODUCTION This study examined the association of longitudinal atrophy with baseline cerebrospinal fluid (CSF) amyloid beta (Aβ, A) and phosphorylated tau (p‐tau, T) biomarkers (Aβ42/40, p‐tau181) in 406 cognitively unimpaired (CU) individuals (6.670 years of follow‐up on average, up to 13 imaging visits) to assess whether A+ is associated with Alzheimer's disease–like atrophy and whether this depends on p‐tau181 levels. METHODS An A‐T‐ CU group free from abnormal neurodegeneration (N) was identified using a robust normative approach and used to model normal age‐related atrophy via z‐scoring. Linear mixed‐effects models tested differences in longitudinal atrophy between A+ and A‐T‐N‐ individuals and between A/T subgroups. RESULTS A+ was associated with worse atrophy within and beyond the medial temporal lobe, even at low levels of p‐tau181. DISCUSSION Neurodegeneration likely begins soon after the onset of abnormal Aβ pathology. Clinical intervention at the earliest signs of Aβ pathology may be needed to mitigate further neurodegeneration. Highlights An A‐T‐N‐ control group was identified using a robust normative approach A+ was associated with accelerated atrophy in cognitively unimpaired individuals Atrophy was observed even at low p‐tau181 levels

Plasma pTau217 (tau phosphorylated at threonine 217) assays will expand access to screening for Alzheimer’s disease (AD). However, clinical interpretation is not well-established, particularly during the preclinical window when interventions may be most effective. Using plasma samples from primarily late-midlife, cognitively unimpaired Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Center (WADRC) participants, we investigated pTau217 agreement with amyloid and tau PET then compared trajectories between participants grouped by baseline pTau217. EDTA plasma samples from 428 participants were analyzed using the ALZpath pTau217 Simoa assay on a Quanterix HD-X (Table 1). Amyloid and tau positivity were defined as global [ 11 C]-PiB DVR>1.19 (21.6 centiloids) and [ 18 F]-MK6240 temporal meta-ROI SUVR>1.3, respectively. In separate receiver operating characteristic (ROC) analyses using pTau217 to classify amyloid and tau PET, the area under the curve (95% CI) and optimal (Youden) cutoffs were, respectively: 0.91 (0.87-0.94), 0.37 pg/mL; and 0.89 (0.83-0.94), 0.53 pg/mL. To characterize pTau217 rates of change based on baseline measurements, participants were clustered into low (≤0.37 pg/mL), intermediate (0.37 < pTau217 < 0.53 pg/mL), and high (≥0.53 pg/mL) groups according to the ROC thresholds. Linear mixed models were then run with group and age as fixed effects and including random person-level intercept and age slopes. Mean pTau217 concentration was 2.5 times higher for amyloid positive participants compared to amyloid negative (Figure 1A; p < 0.001). Significant differences were also observed between CU, MCI, and dementia groups (Figure 1B; CU-MCI: p < 0.001, CU-MCI: p<0.001, Dementia-MCI: p<0.001). Mixed effects models indicated that pTau217 increased at a higher rate in the high group compared to other groups (Figure 2; simple slopes low-high: t(361)=-7.010, p<0.001, intermediate-high: t(318)=-5.712, p < 0.001). No differences were observed between simple slopes for low and intermediate groups (t(235)=-0.314, p=0.9470). These results suggest that plasma ALZpath pTau217 is a very good proxy for molecular PET for detecting AD pathology prior to symptoms. Strategies such as assigning an indeterminate zone for secondary confirmation (Brum, W., et al, 2023) would improve accuracy and lessen the burden on existing resources while expanding access to the broader community.

Synaptic density loss is a major correlate of cognitive functioning in adults with and without significant impairment. It is also a feature of clinical Alzheimer’s disease (AD) and suspected to co-occur with neurofibrillary tau (NFT) accumulation. Previous studies using [ 11 C]UCB-J for in-vivo analysis of synaptic density have been restricted to unimpaired (CU) A- and impaired (CI) AD (A+) participants where within group analyses have shown no association between synaptic density and NFT. There is also little known about the relationship between synaptic density and NFT in AD without cognitive impairment. Here we evaluated the association between synaptic density and NFT in CU and CI AD. Participants were recruited from ongoing AD-related studies (Wisconsin Registry for Alzheimer’s Prevention, ADRC) at UW and from the community and underwent comprehensive clinical and cognitive evaluation to determine cognitive status. Pearson’s r was used to determine associations between synaptic density ([ 11 C]UCB-J DVR) and neurofibrillary tau ([ 18 F]MK-6240 SUVR) across all participants and within amyloid and cognitive groups. Participant demographics are reported in Table 1. Across all participants, synaptic density and ERC, Hp NFT were well correlated (ERC NFT: r = -.46, p < .001; Hp NFT: r = -.49, p < .001). Within groups, only the CU A+ correlation between synaptic density and NFT remained significant (ERC NFT: r = -.49, p = .02; Hp NFT: r = -.59, p = .003) with CI A+ showing only a moderate (insignificant) relationship with Hp NFT (ERC NFT: r = -.16, p = .44; Hp NFT: r = -.31, p = .14) (Figure 1). In agreement with previous work, CI AD has lower Hp synaptic density than CU A-, and no significant relationship between Hp synaptic density and NFT. However, CU AD participants showed a significant relationship between NFT and synaptic density. This may be explained by a floor effect of Hp synaptic density that is reached by participants with clinical AD, but not yet in preclinical AD, or the existence of non-AD pathologies contributing to synapse loss. These results can help better understand the process of neurodegeneration in AD as participants progress from preclinical to clinical AD.

Amyloid burden impacts cognitive decline in the pre-dementia stages of Alzheimer's disease (AD), but there remains significant variability in cognitive trajectories that may be explainable by markers of synaptic function and neurodegeneration. Leveraging longitudinal data from two harmonized, at-risk but predominantly unimpaired cohorts, we examined how several proteins measured from cerebrospinal fluid (CSF) differ by amyloid status, cognitive status, and impact cognitive decline measured using a Preclinical Alzheimer's Cognitive Composite. Four hundred and thirty-four individuals provided CSF biomarkers of amyloid-beta42 (ab42), phosphorylated tau (181), from which we identified Aβ + individuals using a cutoff based on a p-tau181/Aβ42 ratio. Other markers of neurodegeneration (N) included neurofilament light, neurogranin, SNAP-25, and NPTX2. Most biomarkers of N were higher in the Aβ + group and lower in cognitively unimpaired individuals, though NPTX2 exhibited the opposite pattern. Even in the face of Aβ+, NPTX2 was higher in individuals who showed slower rates of cognitive decline, suggesting NPTX2 may be associated with cognitive resilience. Moreover, a SNAP-25/NPTX2 ratio of synaptic dysfunction explained more variance in cognitive decline than other biomarkers alone. This work provides support for potentially useful biomarkers of synaptic function implicated in the clinical syndrome of AD, aiding in future diagnosis and staging efforts.