Vascular risk factors contribute to Alzheimer's disease (AD) dementia, but their interaction with AD pathology remains unclear. This study examined systolic blood pressure (SYSBP) and Type 2 Diabetes (T2D) as moderators of the relationship between plasma biomarkers and cognitive and functional impairment in older adults. Data from 479 participants (Table 1.) in the 1Florida Alzheimer's Disease Research Center were analyzed. SYSBP and T2D were assessed, and plasma biomarkers included GFAP, NFL, Ptau181, and Ptau217. Linear regressions and post-hoc simple slopes analyses examined whether SYSBP and T2D moderated biomarker associations with impairment, measured by the Clinical Dementia Rating Scale-Sum of Boxes, controlling for age, sex, education, and APOE status. See table 2. In brief, a significant positive interaction was found between GFAP and SYSBP on impairment ( b  = 0.074, p  = .046), with GFAP significantly predicting impairment at all SYSBP levels (low b  = 0.109, average b  = 0.180, high b =0.250, p  <.001) and a stronger association as SYSBP increased. In contrast, a significant negative interaction was observed between PTau217 and SYSBP (b = −0.091, p  = .007), where PTau217 was significantly associated with impairment at all SYSBP levels but with a weakening effect as SYSBP increased (low b = 0.391, average b  = 0.302, high b  = 0.213, p  <.001). For T2D, a significant positive interaction was found between GFAP and T2D (b = 0.308, p  = .033), with GFAP predicting impairment in both groups but showing a stronger effect in T2D. A significant negative interaction was observed between NFL and T2D (b = -0.410, p  = .044), where NFL predicted impairment in both groups, though the association was weaker in T2D. These findings highlight vascular health as a key modifier of neurodegeneration and inflammation related impairment. The stronger GFAP-impairment relationship at higher SYSBP and in T2D suggests astrocyte activation may drive decline more in individuals with vascular or metabolic comorbidities. In contrast, the weaker effects of PTau217 at high SYSBP and NFL in T2D suggest alternative mechanisms such as hyperperfusion and glycemic dysregulation. Future research should incorporate longitudinal designs, neuroimaging, and refined vascular risk assessments to clarify these relationships.

List-learning tasks (LLTs) are important for characterizing memory in Alzheimer’s disease and related dementias. However, as the Uniform Data Set Neuropsychological Battery (UDS-NB) historically did not require a specific LLT, centers have administered different LLTs. The newest UDS version (v4.0) requires one of two LLTs. To support harmonized UDS memory research, we developed a memory composite incorporating UDS memory tests and multiple LLTs. Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogeneous sample (n = 8716) that completed the UDS-NB and one of five LLTs. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, amyloid/tau PET positivity, and plasma phosphorylated tau. Analyses were replicated in a racially/ethnically diverse cohort (n = 839). Psychometric properties were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity. This composite supports memory research across cohorts that administer the UDS and LLTs. A user-friendly UI is freely available to create the score in other datasets.

Sleep apnea is a potential risk factor for Alzheimer's Disease (AD). Associations between sleep apnea and elevated AD biomarkers like amyloid beta (Aβ) and p -tau have been reported, but it is unclear if or how sleep apnea influences the connection between the two. The link between sleep apnea and AD also has not been extensively studied in the context of relevant demographic, sociocultural, and common genetic factors. Therefore, we assessed the moderating effects of sleep apnea on the association between Aβ-PET and plasma p -tau217 and whether this moderation differed based on sex, ethnicity, or APOE e4 carrier status. We studied 1Florida ADRC participants ( N  = 288) with normal cognition, mild cognitive impairment, or dementia (Table 1). Presence or absence of sleep apnea was determined from the National Alzheimer's Coordinating Center Health History. All participants had plasma samples analyzed for p -tau217 (ALZPath) and completed Aβ-PET with [18F] florbetaben or florbetapir. Global standardized uptake value ratio (SUVR; whole cerebellum reference) was calculated and converted to the Centiloid (CL) scale. We used multiple linear regression to assess the interaction of Aβ-PET and sleep apnea status on plasma p -tau217, controlling for age, sex, and CDR sum of boxes. To determine whether sleep apnea moderator effects differed by APOE e4 carrier status, sex, or ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), we employed three-way interactions. Sleep apnea moderated Aβ-PET associations with p -tau217 (β = 0.26, p  = .022; Figure 1), such that greater amyloid burden related more strongly to higher plasma p -tau217 in those with sleep apnea versus without. A significant three-way interaction of Aβ-PET x sleep apnea x ethnicity on plasma p -tau217 (β = -0.52, p  = .024; Figure 2) revealed that sleep apnea only moderated this association in non-Hispanic/Latino participants. Sleep apnea moderation was not dependent on sex or APOE e4 carrier status. Addressing sleep apnea as a modifiable risk factor may promote slowing or resistance to AD. Larger and longitudinal studies are needed to comprehensively examine sleep apnea in older adults. Exploring sleep apnea effects in more representative samples with consideration of social and structural determinants of brain health will help clarify the role of sleep on AD onset and progression.

Research on gender and ethnic differences in white matter tracts yields mixed results. Although men show larger global corpus callosum (CC) in absolute values, women have demonstrated larger splenium and isthmus. Additionally, men have shown greater white matter and fractional anisotropy (FA) in multiple regions than women. This study investigates sex and ethnic differences in the corpus callosum and transcallosal white matter tissue microstructure of older individuals with normal cognition and memory disorders. 191 participants (Female n  = 120; Hispanics n  = 115; Non-Hispanics n = 76; Age mean = 71.07; SD = 7.75) were included in the sample from the 1Florida ADRC with cognitively normal ( n  = 75), MCI ( n  = 88), and dementia ( n  = 28) diagnoses. Corpus callosum volumes were collected using a Siemens Skyra 3T MRI scanner and were divided into anterior, mid-anterior, central, mid-posterior, and posterior regions. Also, MRI-based free water diffusion tensor imaging (FW-DTI) measured FW-corrected FA (fwcFA) to assess and compare the integrity of transcallosal tract templates (TCATT) across motor, temporal, parietal, and occipital regions across males and females and ethnic groups. Univariate ANCOVAs controlling for age and clinical diagnosis were performed; females had larger normalized CC volumes in the posterior, F (1, 184) = 8.92, p  = .003, η p 2  = .046, mid-anterior, F (1,184)= 5.68, p  = .018, η p 2  = .030, and anterior, F (1,184)= 14.54, p  < .001, η p 2  = .073, regions, which all survived FDR corrections, with no ethnic differences observed. For transcallosal tracts, females had higher fwcFA in the inferior temporal gyrus, η p 2 Hispanics had higher fwcFA in the premotor cortex, η p 2 η p 2 Sex and ethnicity influence white matter changes during aging independently of age and cognitive diagnosis. However, the effect explained by these demographic variables was very small, suggesting the influence of additional factors.

Abstract INTRODUCTION Multicomponent non‐pharmacological interventions, such as the HABIT Healthy Action to Benefit Independence & Thinking® program, have shown promise for improving emotional well‐being, functioning, and self‐efficacy in both people with mild cognitive impairment (pwMCI) and their care partners. However, limited research has examined whether outcomes differ based on type of care partner who co‐enrolls with the pwMCI. METHODS We analyzed data from 875 pwMCI−care partner dyads who completed the HABIT program. Multivariate linear mixed‐effects regression models evaluated changes from baseline in outcomes by care partner type (spouse vs. non‐spouse) at post‐intervention, 6‐months, and 12‐ months. RESULTS At post‐intervention, pwMCI with spousal care partners demonstrated significant improvements across all outcomes from baseline, whereas those with non‐spousal partners improved in five out of seven outcomes. Across subsequent follow‐ups, pwMCI with spousal care partners showed sustained mean reductions in anxiety (post‐intervention: −2.0; 12‐month: −0.9) and increased compliance (post‐intervention: 5.7; 12‐month: 0.9). Everyday functioning in memory (post‐intervention: −0.9; 12‐months: 1.8) and executive functioning (post‐intervention: −0.7; 12‐months: 4.8) improved at post‐intervention but declined thereafter. Spousal care partners reported reduced anxiety (−1.2) and depression (−1.3) at post‐intervention, but by 12‐months they experienced increased burden, anxiety, and depression relative to baseline. Non‐spousal pwMCI–care partner dyads did not show significant change at 6 or 12‐months. DISCUSSION The HABIT intervention may have more favorable outcomes for pwMCI and care partners in spousal compared to non‐spousal dyads. These findings highlight the potential impact of care partner characteristics on both immediate and long‐term response to behavioral interventions for MCI. Highlights At post‐intervention, people with mild cognitive impairment (pwMCI) with spousal care partners showed significant improvements across all outcomes, while those with non‐spousal partners improved in five of seven outcomes. Gains attenuated over time for both spousal and non‐spousal dyads Spousal care partners reported reduced anxiety and depression at post‐intervention, but by 12 months they experienced increased burden, anxiety, and depression relative to baseline. Non‐spousal pwMCI–care partner dyads did not show significant change at 6 or 12 months.

INTRODUCTION:This study aimed to investigate whether sleep quality predicts cognitive/functional decline, and whether Alzheimer's disease (AD) pathology modifies these relationships. METHODS:The Pittsburgh Sleep Quality Index was administered to 326 older adults (113 cognitively normal, 192 mild cognitive impairment, 21 dementia; mean age = 66.4 ± 8.0 years) enrolled in the 1Florida Alzheimer's Disease Research Center. The Clinical Dementia Rating Sum of Boxes (CDR-SB) assessed cognitive/functional decline at baseline and over time. Moderators included hippocampal volume (HV), amyloid beta (Aβ) positron emission tomography, and plasma phosphorylated tau (p-tau)217. RESULTS:Cross-sectionally, longer sleep duration and later wake time were associated with worse CDR-SB, with stronger associations observed among individuals with higher Aβ and p-tau217 levels, and smaller HV. Longitudinally, prolonged sleep duration was associated with faster cognitive decline, particularly in individuals with elevated Aβ or p-tau217 levels and smaller hippocampal volumes at baseline. DISCUSSION:Prolonged sleep duration and later wake times predicted worsening cognitive performance, and these effects were strengthened by greater AD pathology.

INTRODUCTION:Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood. METHODS:Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E (APOE) status, biomarkers, and cognition among older adults with concordant and discordant visual-quantitative Aβ-PET. Discordance was defined as positive visual read (V) of Aβ-PET with below-threshold Centiloid quantification (Q; CL <25; V+/Q-) or negative visual read with CL ≥25 (V-/Q+). RESULTS:We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of APOE ε4 carriers (40%). Black/African American participants were overrepresented in V-/Q+ (40.9%). Both discordant groups had higher plasma phosphorylated tau 217 (p-tau217) and glial fibrillary acidic protein (GFAP) than V-/Q- but lower than V+/Q+. Discordant groups had greater gray matter volume and better cognitive performance than V+/Q+. DISCUSSION:Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Highlights:Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E (APOE) ε4 carriers and Black/African American.Discordant groups had higher plasma phosphorylated tau 217 (p-tau217) and glial fibrillary acidic protein (GFAP) than concordant negative.Discordant groups had less atrophy and better cognition than concordant positive.Centiloid quantification should supplement visual reads in clinical settings.

BackgroundSemantic intrusion errors (SIEs) are associated with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). It is unknown whether accounting for maximum learning capacity still leads to an increase in SIEs when elevated plasma p-tau217, a biological indicator of underlying AD, is present.MethodsOne hundred fifty-eight older adult participants completed the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive cognitive challenge test designed to elicit SIEs. Of these, 108 were clinically diagnosed with amnestic MCI (aMCI). Fifty-eight individuals met or exceeded a plasma p-tau217 positivity of >0.55 pg/ml, while 50 individuals scored below this threshold.ResultsAfter adjusting for demographic covariates and maximum learning capacity, the aMCI p-tau217+ group evidenced more SIEs compared to aMCI p-tau217- on the first (list B1; p = 0.035) and second trials of the competing list (list B2; p = 0.006). Biological predictors such as ApoE ε4 status, higher p-tau217, and older age were predictors of an elevated number of SIEs [list B2: F (3,104) = 10.92; p = 0.001; R = 0.489)].ConclusionsUnlike previous studies that used amyloid PET or other plasma biomarkers, individuals with aMCI p-tau217+ evidenced more SIEs, even after adjusting for their initial learning capacity, a covariate that has not been studied previously. These findings support that SIEs are more prevalent in the presence of underlying AD pathology and occur independent of learning deficits.

With the emergence of anti-amyloid drugs, there is an increased need to determine the presence of brain amyloid in people using non-invasive, cost-effective biomarkers. The goal of this study was to determine the added and stand-alone value of plasma biomarkers for predicting positive amyloid PET in a mixed sample of Hispanic and non-Hispanic older adults. Participants (n=209) from the 1Florida ADRC at Mount Sinai Medical Center, Miami Beach had neurological and neuropsychological evaluations; MRI, rated positive (Hpc+) or negative (Hpc-) for hippocampal atrophy on visual read; amyloid PET brain scans, rated amyloid positive (A+) or negative (A-) on visual read; blood draws for APOE ε4 genotyping (e4+, e4-); and plasma biomarkers including Abeta 42/40 ratio (Quest Diagnostics), p-tau217 (ALZPath), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) (Quanterix). A base logistic regression model including age, sex, APOEε4 status, and hippocampal atrophy was a reference to assess the value of adding plasma markers in predicting A+/A-. Areas under the receiver operating characteristic (ROC) were computed and DeLong’s approach was used to compare ROC curves. Youden’s index was used to identify optimal sensitivities/specificities to discriminate A+ from A- participants. Demographics and clinical data are shown in Table 1. In the base model, the AUC was 0.78 with both APOEe4 and hippocampal atrophy as significant independent predictors of A+ (Table 2). Prediction of A+ was improved by adding all plasma biomarkers (AUC=0.96; 93%/87% sensitivity/specificity), with APOEe4, Abeta42/40, and p-tau217 as independent predictors. Adding either Abeta 42/40 (AUC=0.88) or p-tau217 (AUC=0.94) alone to the base model also improved model prediction. As stand-alone predictors of A+, the optimal specific/sensitivity was 85%/89% for p-tau217 and 77%/81% for Abeta42/40; p-tau217 outperformed Abeta42/40 (AUC=0.92 versus 0.82) (Figure 1). There was a trend for the combination of both biomarkers to outperform p-tau217 alone (AUC=0.94 versus 0.92). Positive amyloid PET status can be predicted with high accuracy in an ethnically diverse population using combinations of biomarkers, APOE genotype, and a measure of hippocampal atrophy. As a stand-alone biomarker, p-tau217 performed better than other biomarkers in predicting amyloid status.

Hypertension is a known modifiable risk factor for Alzheimer’s disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013–12/31/2016), to identify apparent treatment‐resistant hypertension (aTRH), and hypertension‐control levels (well‐controlled hypertension, intermediate‐controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD‐9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson–Aalen estimator and log‐rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234–1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time ( P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837–0.956) and fixed‐dose combination medications (OR: 0.804, 95% CI: 0.732–0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.

BACKGROUND:Sleep apnea is a potential risk factor for Alzheimer's Disease (AD). Associations between sleep apnea and elevated AD biomarkers like amyloid beta (Aβ) and p-tau have been reported, but it is unclear if or how sleep apnea influences the connection between the two. The link between sleep apnea and AD also has not been extensively studied in the context of relevant demographic, sociocultural, and common genetic factors. Therefore, we assessed the moderating effects of sleep apnea on the association between Aβ-PET and plasma p-tau217 and whether this moderation differed based on sex, ethnicity, or APOE e4 carrier status. METHOD:We studied 1Florida ADRC participants (N = 288) with normal cognition, mild cognitive impairment, or dementia (Table 1). Presence or absence of sleep apnea was determined from the National Alzheimer's Coordinating Center Health History. All participants had plasma samples analyzed for p-tau217 (ALZPath) and completed Aβ-PET with [18F] florbetaben or florbetapir. Global standardized uptake value ratio (SUVR; whole cerebellum reference) was calculated and converted to the Centiloid (CL) scale. We used multiple linear regression to assess the interaction of Aβ-PET and sleep apnea status on plasma p-tau217, controlling for age, sex, and CDR sum of boxes. To determine whether sleep apnea moderator effects differed by APOE e4 carrier status, sex, or ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), we employed three-way interactions. RESULT:Sleep apnea moderated Aβ-PET associations with p-tau217 (β = 0.26, p = .022; Figure 1), such that greater amyloid burden related more strongly to higher plasma p-tau217 in those with sleep apnea versus without. A significant three-way interaction of Aβ-PET x sleep apnea x ethnicity on plasma p-tau217 (β = -0.52, p = .024; Figure 2) revealed that sleep apnea only moderated this association in non-Hispanic/Latino participants. Sleep apnea moderation was not dependent on sex or APOE e4 carrier status. CONCLUSION:Addressing sleep apnea as a modifiable risk factor may promote slowing or resistance to AD. Larger and longitudinal studies are needed to comprehensively examine sleep apnea in older adults. Exploring sleep apnea effects in more representative samples with consideration of social and structural determinants of brain health will help clarify the role of sleep on AD onset and progression.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy specific to individuals with repetitive head trauma. Traumatic encephalopathy syndrome (TES) is the proposed clinical syndrome resulting from CTE with or without other contributing neuropathologies. Pathophysiological mechanisms driving CTE and underlying TES symptoms are not understood. Using network-based bioinformatics, we conducted the first large-scale analysis of the plasma proteome in TES and CTE. We leveraged a proximity extension assay (Olink Explore) to quantify 2,778 plasma proteins in 34 TES, 39 biomarker-confirmed Alzheimer’s disease (AD), and 44 controls (HC; Table 1). TES was subdivided on Aβ-PET status (23 TES Aβ- , 11 TES Aβ+ ). Secondary analyses focused on antemortem plasma ofrom brain donors with autopsy-confirmed CTE (N=8) and without (N=12). Differential abundance and network analyses of proteomic signatures were annotated via gene ontology and cell type enrichment. Protein co-expression modules were age- and sex-adjusted, and compared between groups using analysis of variance (Tukey’s post-hoc with Cohen’s d). Within TES Aβ- , differential Spearman’s correlations examined individual protein associations with cognitive composites (memory, executive function, language, visuospatial) and co-expression modules were tested for overrepresentation of cognitive-associated proteins using Fisher’s exact tests with false discovery rate (FDR) correction. Differential abundance analysis revealed a bias towards increased plasma protein abundance in TES Aβ- , with enrichment for mitochondrial proteins (e.g., MECR, TOMM20). Network analysis identified 9 protein co-expression modules (M1-M9), of which 5 were elevated in TES Aβ- , but not TES Aβ+ or AD, compared to HC (M1-cell division/mitochondrion, d=1.4; M2-TNF signaling/cell adhesion, d=0.72; M4-cell metabolism, d=0.90; M5-chemokine, d=0.80; M8-muscle, d=0.88; Figure 1). Metabolic and immune-linked signals in TES Aβ- were replicated when comparing autopsy-confirmed CTE to plasma of brain donors without CTE or those living with AD and HC. Within TES Aβ- , M2-TNF signaling was highly enriched for proteins negatively associated with memory (FDR-p=8.5e-08) and executive function (FDR-p=2.3e-6). Network-based proteomics identified elevated peripheral molecular signatures that differentiated TES and autopsy-confirmed CTE from healthy older adults and biomarker-confirmed AD. Mitochondrial and inflammatory pathway dysregulation may be uniquely upregulated in CTE and underly cognitive changes in TES. Future protein-specific assessment (Figure 2) will inform biomarker and therapeutic targets in older adults at greatest risk for CTE.

INTRODUCTION:Early-onset Alzheimer's disease (EOAD) may have distinct biomarker and clinical features from late-onset AD (LOAD). EOAD is understudied in ethnically heterogeneous populations. METHODS:We studied EOAD (N = 44, age 64.7 ± 5.5, 55% female, 52% Hispanic/Latino), LOAD (N = 113), early-onset non-AD (EOnonAD, N = 114), and clinically normal (CN, N = 93) individuals from the 1Florida Alzheimer's Disease Research Center. Group differences and demographic interactions were evaluated in plasma (phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain), neuroimaging (amyloid positron emission tomography, brain magnetic resonance imaging), and global function (Mini-Mental State Examination, Clinical Dementia Rating Sum of Boxes). RESULTS:AD-related biomarkers and global function were consistently worse in EOAD than EOnonAD and CN, and similar or worse than LOAD. Among EOAD, younger age related to greater amyloid burden among non-Hispanic/Latino individuals only. AD-related biomarker changes were more severe in females than males among non-Hispanic/Latino EOAD, but more severe among males in Hispanic/Latino EOAD. DISCUSSION:The biological and clinical features of EOAD may differ by sex and ethnicity. Highlights:Alzheimer's disease (AD) biomarkers and global functional measures were measured in Hispanic and non-Hispanic individuals with early-onset AD (EOAD).Overall, AD-related biomarkers and global function were consistently worse in EOAD than non-AD cognitive decline and controls, and similar or worse than late-onset AD.Younger age related to greater amyloid burden among non-Hispanic EOAD, but not Hispanic EOAD.Hispanic EOAD males had more severe changes than females, contrasting findings in non-Hispanic EOAD (females more severe than males).

Objectives:The primary aim of the current analysis was to evaluate the cumulative effect of different social determinants of health (SDoH) factors on vascular burden, cognition, and physical functioning. Methods:We conducted a secondary data analysis of the Midlife in the United States (MIDUS 2) cross-sectional study using data from participants aged 55 and older. Measures derived from the Framingham Stroke Risk Profile, Brief Test of Adult Cognition by Telephone, and physical functioning scores from the Medical Outcomes Study - Short Form 36 items (MOS-SF36) were used to represent vascular burden, cognition, and intermediate activities of daily living, respectively. SDoH variables included education, income, health insurance, stress, and support from family and friends. Associations were evaluated using a composite-based structural equation model (c-SEM) embedded in an overall SEM. Findings:Among MIDUS participants with no clinical diagnosis of cognitive impairment or neurological disorder (N=568; mean age=64.6), higher education, less stress, and higher income significantly contributed to the SDoH composite. Positive SDoH was associated with better physical functioning (beta=-0.21, p<0.001) and higher cognition (beta=0.54, p<0.001). Significant direct effects of SDoH on vascular burden (beta=-0.12, p<0.05) and cognition (beta=0.51, p< 0.001) and of vascular burden on cognition (beta=-0.28, p<0.001) were found. Mediation analysis indicated that the unique effects of SDoH on cognition remained significant after controlling for vascular burden (beta=0.04, p< 0.05). After accounting for vascular burden and cognition, SDoH did not have a significant unique effect on physical functioning. Conclusion:Our results support the disablement theory, suggesting that factors outside of the disease model (such as SDoH factors) impact diseases that underlie physical and functional limitations.

Neuropsychological testing is an essential tool in clinical settings engaged in detecting, treating, or preventing neurocognitive disorders around the world. There is a need for accurate norms across cultures, including Latinx/Hispanic communities. We reviewed studies published in English or Spanish focused on acquiring normative data for Spanish-speaking individuals in the United States (U.S.), Latin America and the Caribean (LAC), and Spain. We searched available studies from Embase, PubMed, PsycINFO APA, Science Direct, and ProQuest up to October 31, 2024. Studies were imported to COVIDENCE and reviewed by two Spanish–English bilingual reviewers and one proficient English reviewer. Ultimately, 75 articles were included and categorized into U.S. (n = 23), LAC (n = 21), Spain (n = 23), and multiregional (n = 8) based. Overall, most studies included a cognitively normal/healthy sample to establish the normative data, adjusting or stratifying for age, education, and sex. In Spanish speakers, cognitive performance improved with advancing age in children and adolescents and declined with age in adults. Higher education was also associated with better performance on tests across regions. While this review highlights the increasing accumulation of norms for Spanish-speaking populations, there is a continued need to expand norms to other Spanish-speaking populations not included in this analysis. Future research should add variables, such as acculturation and bilingualism, to aid normative rigor. This review works as a tool to facilitate and improve the understanding of current normative data.

The severity of white matter hyperintensities (WMHs) is known to be linked to Alzheimer's disease (AD) and vascular dementia. Ethno-racial differences in how WMH volumes relate to cardiovascular (CV) risk factors or AD pathology have not yet been shown. Only 30% of U.S. studies have compared WMH severity between ethnic groups, with Hispanics included in only 17%. We analyzed the contributions of demographic, cultural, CV risk factors, and plasma and brain AD biomarkers to the severity of WMHs in Hispanics and non-Hispanic Whites (Non-HW). Participants were from the 1Florida ADRC study, including 252 Hispanics and 172 Non-HW (No Cognitive Impairment = 63, Non-Amnestic Mild Cognitive Impairment = 49, Amnestic MCI = 233, Dementia = 79). Linear regression models used a quantified visual rating of MRI WMH volume as the dependent variable. Independent variables included ethnicity, age, sex, education level, CV factors (see bottom of Table 1 for listing these factors), hippocampal and cortical atrophy, amyloid PET status, and plasma p -tau217. The Hispanic group also included Language proficiency and acculturation as individual predictors. No significant differences were observed in CV risk factors between ethnic groups (Table 1). In the entire group, individual predictors of higher WMH scores included older age, positive amyloid PET status, p -tau217, severity of hippocampal and diffuse cortical atrophy, cognitive diagnosis, and higher CV risk scores (Table 2). Ethnicity, education, and sex were non-significant. In the multiple regression model for the total sample, only age, hippocampal atrophy, and diffuse cortical atrophy remained significant predictors (Table 3). In the Hispanic group, only diffuse cortical atrophy was associated with WMH (language proficiency and acculturation were not significant predictors in the bivariate regression models; therefore, they were not included in the multiple regression model). Adjusted R 2 values were 0.153 for the whole sample and 0.150 for Hispanics. The strongest predictors of WMHs were age and measures of atrophy but not cardiovascular risk. No differences in WMHs or CV risk factors were found between WH and NHW. Results suggest that WMHs are associated with neurodegeneration, regardless of ethnicity.

The Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list-learning paradigm. ADCs often supplement the UDS with their own preferred list-learning task. Given the importance of list-learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list-learning tasks. We applied item-banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking-items) and one of five list-learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list-learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD-biomarker+ MCI (n = 26), and AD-biomarker+ dementia (n = 98). In a subsample with amyloid- and tau-PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs. Model fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43-0.93). Differences in list-learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly ( p ’s<.001) correlated with younger age (β = -0.18), lower CDR Box Scores (β = -0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid-PET positivity was associated with lower composite scores, but was not statistically significant (β = -0.34; p = 0.25; d = 0.40). Tau-PET positivity was associated with worse performance, demonstrating a large effect size (β = -0.75; p<0.002; d = 0.91). The harmonized memory score developed in a large national sample was stable regardless of contributing list-learning task and its validity for cross-cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross-cohort ADRD research.

BACKGROUND:Mild cognitive impairment (MCI) is a clinical diagnosis representing early symptom changes with preserved functional independence. There are multiple potential etiologies of MCI. While often presumed to be related to Alzheimer's disease (AD), other neurodegenerative and non-neurodegenerative causes are common. Wider availability of relatively non-invasive plasma AD biomarkers, such as p-tau217, can provide invaluable insights into MCI clinico-pathology and the associated implications for symptom etiology, prognosis (e.g., risk for progression to dementia), and treatment options. OBJECTIVES:The main goal of this study was to evaluate differences between individuals with MCI with and without plasma p-tau217 biomarker evidence of AD (MCIAD+ and MCIAD-) as well as a control group of clinically normal older adults with negative AD biomarkers (CNAD-). We evaluated group differences in demographics, recruitment, clinical scales, fluid biomarkers, and brain imaging. We further probed these factors as independent contributors to symptoms among MCIAD- participants, for whom symptom etiology is most poorly understood. Lastly, in a subset of participants followed longitudinally, we investigated how these factors related to odds of clinical progression to dementia. DESIGN:We conducted an observational cross-sectional and longitudinal clinical research study. Study groups were compared cross-sectionally on demographics, recruitment, clinical measures, and biomarkers (chi square analyses, analyses of covariance). Contributors to functional changes were evaluated with multiple linear regression. Factors associated with the odds of progression from MCI to dementia longitudinally were evaluated with binary logistic regression. SETTING:1Florida Alzheimer's Disease Research Center. PARTICIPANTS:Cross-sectional analyses included 378 older adults classified as CNAD- (N = 76, age 66.1 ± 7.2, 63.2% female, 23.7% non-Hispanic/White), MCIAD- (N = 198, age 68.9 ± 7.9, 51.5% female, 29.3% non-Hispanic/White), or MCIAD+ (N = 104, age 73.9 ± 7.4, 52.9% female, 49.0% non-Hispanic/White). Longitudinal analyses focused on 207 participants with MCI (68.5% of cross-sectional MCI sample) followed for an average of 3 years. MEASUREMENTS:Demographics (age, sex, years of education, self-identified race and ethnicity, primary spoken language), National Alzheimer's Coordinating Center-defined clinical phenotypes (Clinically Normal, Impaired - Not MCI, Amnestic MCI, Nonamnestic MCI, Dementia), recruitment source (clinic-based versus community-based), genetics (APOE genotype), functional evaluation (Clinical Dementia Rating scale), global cognition (Mini Mental State Exam), vascular history (Vascular Burden Score), neuropsychiatric symptoms (NPI-Q Total score), plasma biomarkers (ALZPath p-tau217, Quanterix Simoa-based GFAP and NfL), and brain imaging (grey matter volume in select AD-relevant regions of interest, global white matter hyperintensity volume). RESULTS:Among those with MCI, 104 (34.4%) had plasma biomarker evidence of AD. MCIAD+ participants were more frequently recruited from clinic-based settings than MCIAD- (74.8% vs. 47.5%, p<.001). Over half (51.5%) of MCIAD+ carried at least one APOE e4 allele compared to 26.6% of MCIAD- and 29.4% of CNAD- (p<.001). Both MCIAD+ (p<.001, Cohen's d = 0.93) and MCIAD- (p<.001, d = 0.75) reported more severe neuropsychiatric symptoms than CNAD. MCIAD+ had higher plasma GFAP and NfL than both MCIAD- (GFAP: p<.001, d = 0.88, NfL: p<.001, d = 0.86) and CNAD- (GFAP: p<.001, d = 0.80; NfL: p<.001, d = 0.89). For the AD signature region of interest, MCIAD+ had lower volume than both CNAD- (p<.001, d = 0.78) and MCIAD- (p=.018, d = 0.39). For the hippocampus, both MCIAD+ (p<.001, d = 0.87) and MCIAD- (p<.001, d = 0.64) had lower volume than CNAD-. Longitudinally, older age (OR=1.14 [1.06-1.22], p<.001), higher levels of p-tau217 (OR=10.37 [3.00-35.02], p<.001) and higher neuropsychiatric symptoms (OR=1.19 [1.02-1.39], p=.023) were associated with higher odds of progression to dementia. CONCLUSIONS:MCI is etiologically heterogeneous. The presence of Alzheimer's pathology defined by elevated plasma p-tau217 in individuals with MCI significantly worsens prognosis. Neuropsychiatric symptoms may contribute to cognitive complaints and risk for progressive decline irrespective of AD pathology. Plasma p-tau217 can inform our understanding of base rates of different MCI phenotypes on a larger scale. As with other AD biomarkers, frequency of elevated plasma p-tau217 and odds of progression to dementia requires careful consideration of recruitment source (clinic- vs. community-based), especially across ethno-racially diverse older adults. Ongoing integration of emerging neurodegenerative disease biomarkers with detailed clinical evaluations will continue to improve treatment specificity and prognosis.

While intrusions in verbal memory tests are known to indicate a cognitive decline in aging, their role in verbal fluency (VF) tasks remains underexplored. Aims: to determine if intrusion percentages in phonemic (PF) and category (CF) VF tasks differ across cognitive diagnoses, longitudinally (across 3 years), and if they are associated with frontal lobe, temporal lobe, and hippocampal volumes. Participants were from the 1Florida Alzheimer's Disease Research Center (ADRC), including 102 CN, 160 MCI, and 34 dementia participants at year 1 ( M (age) = 72.17; 62.66% female; Table 1), with year 2 and year 3 follow-ups. The Clinical Dementia Rating (CDR-GS) global score was used to determine cognitive status, (i.e. normal [CDR-GS = 0], MCI [CDR-GS = 0.5], or dementia [CDR-GS = 1 ≥1]). Intrusion percentages from PF and CF tasks (collected every 15.36 months, on average) were analyzed alongside brain volumes (one-time MRI scans collected at baseline). Two separate MANCOVAs revealed intrusion percentages on VF tasks at baseline (year 1) significantly differed across year 2 diagnostic groups, as well as year 3 diagnostic groups (Figure 1), after controlling for demographic variables. This indicated intrusion percentages were significantly associated with diagnostic outcomes at year 2 and at year 3. Individuals with dementia exhibited higher intrusion percentages than cognitively normal individuals. Negative correlations were found between baseline VF intrusion percentages and brain volumes in frontal (left frontal pole and CF: r (296) = -.161, p  = .005; left rostral midfrontal & CF: r (296) = -.151, p  = .009; left caudal midfrontal & PF: r (285) = -.151, p  = .010; right frontal pole & CF: r (296) = -.159, p  = .006) and temporal regions (left inferior & CF: r (296) = -.158, p  = .006: right middle and PF: r (296) = -.157, p  = .008), after Bonferroni corrections. Regression analyses revealed higher baseline VF intrusion percentages were significantly associated with reduced left frontal pole and left caudal mid-frontal volumes (Table 2). Intrusion percentages in VF tasks may be a sensitive marker of cognitive decline in aging and structural changes in the left frontal lobe.

Plasma P-tau217 demonstrates strong sensitivity and specificity for Alzheimer’s disease (AD) neuropathological change, but existing studies are often ethnically homogeneous. Assumptions about how well plasma P-tau217 relates to key AD-related cognitive outcomes like memory may not generalize. We assessed whether the association between plasma P-tau217 and memory depended on ethnicity in a sample of Hispanic/Latino and non-Hispanic/Latino White older adults. We studied 273 1Florida ADRC participants with normal cognition, mild cognitive impairment (MCI), or dementia (Table 1). All participants had plasma samples analyzed for P-tau217 (ALZPath) and neuropsychological assessments. Using Pearson’s correlations, we first evaluated the bivariate association between P-tau217, Craft Story verbatim recall (verbal memory), and Benson Figure recall scores (visual memory) overall and stratified by ethnicity. To determine whether ethnicity moderated the effects of P-tau217 on memory, we used multiple linear regression to assess the interaction of P-tau217 and ethnicity (Hispanic/Latino vs. non-Hispanic/Latino) controlling for age, sex, education, and testing language. Post hoc sensitivity analyses separately evaluated individuals below and above internal Aβ PET-derived P-tau217 cutoffs for “AD positive” concentration. Higher P-tau217 was significantly associated with worse verbal (r= -0.38, p < 0.001) and visual memory (r= -0.31, p < 0.001) overall and separately in Hispanic/Latino (r= -0.56, r= -0.57; p’s <.001) and non-Hispanic/Latino White participants (r= -0.30, r = -0.34; p’s < 0.001). Ethnicity significantly moderated P-tau217 associations with verbal (β= -0.38, p= 0.001) and visual memory (β = -0.38, p= 0.001). The negative relationship between P-tau217 and memory was significantly stronger for Hispanic/Latino than non-Hispanic/Latino participants. P-tau217 and demographic covariates explained more variance in verbal (R2= 0.39) and visual memory (R2= 0.37) for Hispanic/Latino than non-Hispanic/Latino Whites (R2= 0.16 and R2= 0.19, respectively). Post hoc analyses suggested these findings were driven by individuals on the AD continuum. AD pathology, measured via plasma P-tau217, may more strongly relate to memory function in Hispanic/Latino than non-Hispanic/Latino Whites. Findings have implications for the potential roles of co-pathology or unexplored risk factors in explaining memory loss beyond AD across demographic subgroups. Ethnically representative studies will improve translation of AD biomarkers and inform anticipated AD-directed treatment effects.