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Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well‐characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia‐free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross‐sectional associations of the biomarkers with cognitive domain scores ( N  = 708, 53% female, 22% apolipoprotein E ( APOE ) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all‐cause and AD dementia during up to 20 years of follow‐up were tested. APOE genotype‐stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF‐R, TWEAK, CCL19, IL‐17C, MCP‐4, and TGF‐alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all‐cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline.

INTRODUCTION We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging‐defined subgroups. METHODS We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid‐negative controls. We used voxel‐based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD‐Memory. RESULTS There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD‐Memory, lower left hemisphere GMV for AD‐Language, anterior lower GMV for AD‐Executive, and posterior lower GMV for AD‐Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD‐Language group than any other group (p = 1.15 × 10−10). For overlap between imaging‐defined and cognitively defined subgroups, AD‐Memory matched up with an imaging‐defined limbic predominant group. DISCUSSION MRI findings differ across cognitively defined AD subgroups.

Background Education is a strong predictor influencing the dementia progression. With diminished brain integrity, cognitive reserve (CR) is thought to help preserve cognitive function and delay the symptom manifestation. Yet, scholars have not reached consensus on the extent to which education modifies brain integrity‐cognitive decline associations and how it differs by sex/gender. Method To test the hypothesis about CR on cognitive decline, we used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) sample and included 785 male and 637 female participants, who were cognitively normal or had mild cognitive impairment at baseline (Table 1). We used three global brain integrity measures (cortical thickness (CT), hippocampal volume (HP), and Reversed‐White Matter Hyperintensities (R‐WMH) as well as the language composite score using the item response theory. We applied sex‐stratified random intercept models including the three‐way interaction term (education x CT x time) against the 5‐year language performance. A robust set of contextual confounders was included; intracranial volume (ICV) difference was accounted for in two ways: covariate adjustment vs. normalization. Results The average age was 72.6 (7.0 SD) and 74.3 years (6.8 SD) for female and males, respectively. Males had high average years of education than females. The linear regression models showed that high levels of brain integrity (HP, CT) were associated with high baseline performance and slower decline; education was only associated with higher baseline performance. The estimation of education modifying the association between brain integrity and language was sensitive to ICV correction methods and differed by brain integrity type and sex. For example, education attenuated the relationship between low normalized‐CT and R‐WMH measures and faster decline (i.e., the lower CT or WMH and decline association was weaker with higher education) only in female sample (Figure 1B); such association was not hold when ICV was included as covariate. In both males and females, lower HP and decline association was stronger with higher education, regardless ICV correction methods (Figure 2). Conclusion Incongruence between theory and empirical evidence on education and cognitive reserve may stem from which brain integrity measures are used, and the different approaches to account for ICV.

INTRODUCTION Early‐onset Alzheimer's disease dementia (EOAD) is characterized by more pronounced cognitive decline than late‐onset AD dementia (LOAD). Characteristic performance in spoken language remains undefined. METHOD A cross‐sectional analysis of 1189 people with EOAD and 4646 with LOAD from the National Alzheimer's Coordinating Center (NACC) was conducted. RESULT Based on data from their first NACC visit with AD, there was considerable heterogeneity in language performance across people with EOAD and LOAD. The distribution of naming ability was similar across these groups. On average, people with LOAD performed better than those with EOAD in category fluency, letter fluency, and spoken lexical retrieval, and had lower Clinical Dementia Rating (CDR) Language scores, although there was considerable overlap in the distributions for participants with EOAD and those with LOAD. DISCUSSION At diagnosis, the language profiles of EOAD and LOAD are distinct. There is substantial variability in both groups in multiple aspects of language. Highlights Early‐onset Alzheimer's disease (EOAD) is associated with significantly poorer category and phonemic fluency and global spoken lexical retrieval compared to late‐onset Alzheimer's disease (LOAD) at time of diagnosis. Participants with EOAD dementia show greater severity and variability in clinician‐rated language functioning, as measured by Clinical Dementia Rating (CDR) Language scores. No significant group differences were observed in confrontation naming performance between EOAD and LOAD dementia. Findings support that there are distinct profiles of language performance in EOAD and LOAD at time of dementia diagnosis.

Background Insulin resistance (IR), characterized by reduced insulin responsiveness, has been hypothesized to be related with subsequent cognitive decline beyond the pace of normal aging, increasing the risk for all‐cause dementia. Polygenic risk scores (PRS) can provide a genetic risk profile for IR. This study aimed to cross‐sectionally/longitudinally relate IR genetic liability to memory performance. Method Using summary statistics from a published genome‐wide association study (Oliveri et al., 2024; N = 402,398, UK Biobank) of the triglyceride to high‐density lipoprotein cholesterol ratio (TG:HDL‐C; an indicator of IR), a PRS was built in 22,572 participants from the National Alzheimer's Coordinating Center (NACC) cohort (8,456 variants included with a p‐value threshold of ≤0.001). Linear regression evaluated baseline memory while linear mixed‐effect models assessed baseline interactions with longitudinal memory decline. Models were adjusted for sex, baseline age, Body Mass Index (BMI) (kg/m2), and APOE‐ɛ4 positivity. Restricted cubic splines and scaling accounted for non‐linearity in age and BMI. Missingness in BMI and APOE‐ɛ4 positivity was addressed via multiple imputation. Sensitivity analyses excluded individuals with AD‐related comorbidities (e.g., stroke, cancer, Parkinson's disease, traumatic brain injury, etc.) (N = 8,227) and stratified by APOE‐ɛ4 and APOE‐ε2 positivity. Result A cohort of 10,806 non‐Hispanic White adults (median age 73.5), had mean BMI of 26.7; 38.4% were APOE‐ɛ4 carriers, 52.7% were female, and 37.4% were cognitively impaired at baseline. A positive association was observed between genetic risk for TG:HDL‐C and baseline memory (β=0.019, p = 0.009). Additionally, a higher TG:HDL‐C PRS was associated with slower memory decline (β=0.003, p = 0.040; Figure 1). In sensitivity models, removing participants with comorbidities attenuated associations by 26%, driven primarily by cancer or traumatic head injury. Stratified analyses revealed stronger associations for APOE‐ɛ4 and ɛ2 non‐carriers than carriers for both baseline and longitudinal memory. Conclusion Genetic liability to IR as indicated by a TG:HDL‐C PRS is associated with a small, but significant, association with better memory performance and slower memory decline. However, this effect is modified by comorbidities and APOE‐ɛ4 and ɛ2 non‐carrier status, suggesting a complex interplay between genetic risk for IR, comorbidities, as well as triglyceride and cholesterol metabolism. Future work with larger populations may clarify these relationships

Diffusion and structural brain traits in the medial temporal lobe showed strongest genetic covariance with memory. Top functional brain traits highlighted connectivity in the default mode network. Shared genetic architecture between mid‐life brain imaging traits and late‐life memory parallels Alzheimer's disease vulnerability.

INTRODUCTION The Uniform Data Set (UDS) version 3 neuropsychological battery replaced old tests used in UDS 1&2. Here, we validate domain scores for memory, executive functioning, and language co‐calibrated across UDS eras. METHODS We compared co‐calibrated and harmonized domain scores to traditional equipercentile equating in a crosswalk sample. We also validated domain scores by evaluating associations with magnetic resonance imaging (MRI) findings and APOE genotype across UDS eras. RESULTS We co‐calibrated cognitive domain scores for 49,396 participants, about 25% of whom had data spanning UDS 1&2 and UDS 3 eras. Crosswalk sample (n = 955) correlations between UDS 1&2 and UDS 3 domain scores and equipercentile scores were similar. Harmonized domain scores had statistically significant associations in imaging (n = 2458) and APOE validity assessments (n = 27,857). Significant differences in domain scores were found across UDS eras. DISCUSSION Longitudinal co‐calibrated and harmonized cognitive domain scores bridge the gap across UDS versions and are available from the National Alzheimer's Coordinating Center. Highlights Co‐calibrated domain scores are validated in the NACC crosswalk sample. Co‐calibrated domain scores are validated with neuroimaging measures. Co‐calibrated domains scores are validated with APOE genotype. Co‐calibrated domain scores reveal cognitive performance differences in enrollment visit depending on UDS era. Co‐calibrated domain scores are readily available to investigators utilizing NACC's rich dataset.

Background The hippocampus, vital for memory processing, is one of the first regions affected by Alzheimer's disease (AD). APOE‐ε4 (risk) and APOE‐ε2 (protective) alleles are key genetic drivers of AD risk and cognitive decline. This study aimed to assess the modifying effect of the APOE genotype on the association between hippocampal volume and memory performance. Furthermore, we considered the modifying effects of sex, self‐reported race, and clinical diagnosis. Methods Data were obtained from 6,895 participants (mean age at baseline=75.2 years; 21% AD, 43% male, 81% non‐Hispanic white (NHW), 12% APOE‐ε2 carriers, and 40% APOE‐ε4 carriers) from four cohorts of aging and AD: ADNI, NACC, ROS/MAP/MARS, and WRAP. MRI data, processed with deep learning MUSE, included left and right hippocampal volumes, harmonized for batch differences using Longitudinal Combat. Memory composite scores were harmonized across cohorts using latent variable modeling. Linear regression on baseline memory assessed two‐way interactions between total hippocampal volume×sex, total hippocampal volume×APOE (modeled dominantly), and three‐way interactions that included sex, race, or diagnosis. Mixed effects regression models assessed these interactions on memory trajectories and included fixed and random effects for intercept and the slope (years from baseline). Results The association between hippocampal volume and memory performance is stronger in females than in males, whereby females with larger hippocampi outperform males with larger hippocampi (p = 7.47×10‐13; R2=0.007; Figure 1). APOE haplotype also interacted with hippocampal volume on baseline memory, whereby the association is stronger in ε4(p = 6.07×10−13; R2=0.004) carriers and attenuated in ε2 carriers (p = 3.22×10−5; R2=0.001), particularly among individuals with mild cognitive impairment (p = 0.048; b=5.41×10‐5). Notably, APOE interactions with hippocampal volume were consistent across NHW and non‐Hispanic black (NHB) participants. In longitudinal analyses, we found a significant three‐way interaction between APOE‐ε2, AD diagnosis, and hippocampal volume on memory (p = 0.0001; R2c=0.8; R2m=0.5), driven by a stronger interaction among participants with AD (p = 0.036; R2c=0.5; R2m=0.04). Conclusion While hippocampal volume is a potent predictor of memory performance, sex, and APOE modify this association with the most pronounced effects observed among APOE‐ε4 carriers, women, and participants with AD. These results emphasize the importance of considering genetic, clinical, and demographic factors in AD research.

The hippocampus, vital for memory processing, is one of the first regions affected by Alzheimer's disease (AD). APOE-ε4 (risk) and APOE-ε2 (protective) alleles are key genetic drivers of AD risk and cognitive decline. This study aimed to assess the modifying effect of the APOE genotype on the association between hippocampal volume and memory performance. Furthermore, we considered the modifying effects of sex, self-reported race, and clinical diagnosis. Data were obtained from 6,895 participants (mean age at baseline=75.2 years; 21% AD, 43% male, 81% non-Hispanic white (NHW), 12% APOE-ε2 carriers, and 40% APOE-ε4 carriers) from four cohorts of aging and AD: ADNI, NACC, ROS/MAP/MARS, and WRAP. MRI data, processed with deep learning MUSE, included left and right hippocampal volumes, harmonized for batch differences using Longitudinal Combat. Memory composite scores were harmonized across cohorts using latent variable modeling. Linear regression on baseline memory assessed two-way interactions between total hippocampal volume×sex, total hippocampal volume×APOE (modeled dominantly), and three-way interactions that included sex, race, or diagnosis. Mixed effects regression models assessed these interactions on memory trajectories and included fixed and random effects for intercept and the slope (years from baseline). The association between hippocampal volume and memory performance is stronger in females than in males, whereby females with larger hippocampi outperform males with larger hippocampi (p = 7.47×10 ; R =0.007; Figure 1). APOE haplotype also interacted with hippocampal volume on baseline memory, whereby the association is stronger in ε4(p = 6.07×10 ; R =0.004) carriers and attenuated in ε2 carriers (p = 3.22×10 ; R =0.001), particularly among individuals with mild cognitive impairment (p = 0.048; b=5.41×10 ). Notably, APOE interactions with hippocampal volume were consistent across NHW and non-Hispanic black (NHB) participants. In longitudinal analyses, we found a significant three-way interaction between APOE-ε2, AD diagnosis, and hippocampal volume on memory (p = 0.0001; R c=0.8; R m=0.5), driven by a stronger interaction among participants with AD (p = 0.036; R c=0.5; R m=0.04). While hippocampal volume is a potent predictor of memory performance, sex, and APOE modify this association with the most pronounced effects observed among APOE-ε4 carriers, women, and participants with AD. These results emphasize the importance of considering genetic, clinical, and demographic factors in AD research.

Background White matter (WM) abnormalities are prevalent in aging and neurodegenerative cognitive decline. This study compares single‐shell free‐water (FW) imaging and multi‐shell NODDI Isotropic Volume Fraction (ISOVF) in assessing WM microstructure and their associations with cognitive decline. Methods FW and ISOVF were quantified across 48 white matter tracts in cognitively unimpaired (CU) and impaired (MCI and AD dementia) individuals from ADNI and VMAP. Multi‐shell dMRI data (b=1000, 2000 s/mm2) were collated from 139 ADNI‐3 participants (age=75.9 ± 6.7; 56.8% female; 92.1% NHW) and 437 VMAP participants (age=65.8 ± 9.3; 57.0% female; 78.0% NHW). Memory and executive function composites were harmonized using ComBat. Covariates included age, sex, years of education, race, clinical status, and ApoE‐ε4 positivity. Analyses included linear correlations between FW and ISOVF, group comparisons, and age modeling via general linear models. Linear regression examined associations between tract‐specific metrics and cognitive composites, with bootstrapped comparisons testing differences in R2adj values between FW and ISOVF models. Results FW and ISOVF showed strong correlations across key white matter tracts (Figure 1), particularly in transcallosal (TC) pathways, with the highest correlations in the calcarine sulcus TC (r=0.784), lingual gyrus TC (r=0.780), and ILF (r=0.775). Group‐wise analyses revealed significant CU vs. MCI differences in all 48 tracts, most notably in the ILF (FW: p = 1.05×10‐15) and temporoparietal SLF (ISOVF: p = 4.36×10‐14). Age effects were significant across all 96 measures, with FW explaining marginally greater variance than ISOVF. The highest R2adj values were in the ILF for FW (54.82%) and ISOVF (47.73%). FW in the lateral (42.93%) and anterior (47.84%) orbital gyri TC best explained memory variance, while FW in the ILF (51.98%) and ISOVF in the inferior parietal lobule TC (51.59%) best explained executive function. Bootstrapped comparisons identified significant R2adj differences between FW and ISOVF in 10 tracts for memory and 14 tracts for executive function, including the ILF, SLF, UF, and superior temporal gyrus TC. Conclusion Both bi‐tensor FW and NODDI ISOVF showed robust associations with age and cognitive performance, varying in magnitude and tract specificity. FW and ISOVF provided largely comparable insights, highlighting their complementary value for understanding white matter health in neurodegenerative research.