Journal of Alzheimer's Disease

Background: Social determinants of health (SDOH) are increasingly recognized as contributors to Alzheimer disease (AD) risk, yet the impact of multidimensional social disadvantage early AD-related pathophysiology remains poorly understood. Methods: We studied 1,466 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with SDOH assessed in early midlife (mean age 40, SD 3.6 years) and plasma AD biomarkers measured 20 years later. A comprehensive SDOH index was constructed from 12 indicators spanning five domains (economic stability, education, neighborhood and physical environment, community and social context, and health care access). We examined associations between SDOH quartile and log-transformed, standardized plasma phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and amyloid-lower case Greek beta42/40 (Alower case Greek beta42/40) using linear regression adjusted for age, sex, race, and estimated glomerular filtration rate. Linear trends across SDOH quartile were also evaluated. Results: Participants in the most disadvantaged SDOH quartile had higher p-tau217, higher NfL and lower Alower case Greek beta42/40 level compared with those in the least disadvantaged quartile (p-tau 217: lower case Greek beta = 0.12, 95% CI 0.03-0.21, p = 0.008; NfL: lower case Greek beta = 0.20, 95% CI 0.05-0.35, p = 0.009; lower case Greek beta42/40: lower case Greek beta = -0.15, 95% CI -0.30-0.00, p=0.05). There was also a significant trend across quartile (p-tau 217: p for trend = 0.012; NfL: p for trend= 0.001). Analyses of individual SDOH domains indicated that lower economic stability, poorer health care access, and lower education were associated with higher NfL, and poorer health care access was associated with higher p-tau217. Conclusions: Greater SDOH disadvantage in early midlife was associated with higher levels of plasma AD biomarkers reflecting AD pathology and neurodegeneration decades later. These findings suggest that social disadvantage during midlife may contribute to early AD-related biological changes and highlight potentially modifiable social factors relevant for dementia prevention.

Background: Cardiovascular health factors are associated with cognitive decline and risk of dementia, including Alzheimer disease (AD); however, this has been mostly studied in late life. We investigated whether vascular and lifestyle factors are associated with AD plasma and imaging biomarkers in midlife. Methods: We investigated 1,406 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with information on vascular and lifestyle factors framed from the American Heart Association (AHA) life's essential 8 (LE8) guidelines for cardiovascular health at early midlife (mean age 45.0 SD 3.6) and AD biomarkers in late midlife (mean age 60 SD 3.5). LE8 was calculated and categorized into poor (0-49), intermediate (50-79), and ideal (80-100) cardiovascular health, based on 8 components including smoking, diet, body mass index (BMI), sleep, fasting glucose, blood pressure, cholesterol, and physical activity. We assessed the AD plasma biomarkers phosphorylated tau 217 (ptau-217) and amyloid beta 42/40 ratio (A{beta}42/40) and the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), an algorithm that characterizes AD-like brain atrophy on brain MRI. We used linear regression to examine the association between LE8 and log-transformed and standardized AD biomarker measures adjusting for age, sex, race, education, and kidney function. Results: Compared to ideal LE8, intermediate (67.9% of participants) and poor (12.6%) LE8 was associated with lower A {beta}42/40 (adjusted mean difference: -2.37, 95% CI: -2.38 to -2.36 and -2.38, 95% CI: -2.40 to -2.36, respectively). There was no association between the LE8 group and ptau-217 level. Moreover, compared to ideal LE8 participants, those with poor LE8 had higher SPARE-AD atrophy pattern (adjusted mean difference: -0.71, 95% CI: -0.81 to -0.62). Conclusion: These findings indicate that poor cardiovascular health in midlife, as defined by the AHA LE8, is linked to less favorable early AD biomarker profiles, particularly reflecting greater amyloid burden and structural brain changes.

INTRODUCTIONCognitive SuperAgers (SA) are individuals aged 80+ with exceptional episodic memory performance for their age, exceeding middle-aged adult norms. This study integrates family- and association-based methods to identify genetic variants associated with SA in the Midwestern Amish population. METHODS83 Amish SA were grouped into 16 pedigrees for parametric and non-parametric linkage analysis. Variants in linked regions (HLOD/LOD*[≥]3) were tested for association with SA using two contrasts: SA vs. Alzheimers disease (AD; n=40), and SA vs. cognitively unimpaired (CU), age-matched non-SA individuals (CU80+; n=157). RESULTSEvidence of linkage for SA was observed on chromosomes 1, 2, 7, 16, and 20, with the strongest signal around the AD-associated locus WDR12 on chromosome 2. Association analysis for SA vs. AD identified eight variants in HIVEP3 (chromosome 1) that were nominally significant when comparing SA vs. CU80+. DISCUSSIONWDR12 and HIVEP3 are potential candidate genes contributing to SA in the Amish population.

INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases. METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity. RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; ps < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior. DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.

Background: For early detection of Alzheimer's disease, it is essential to identify individuals showing cognitive performance consistent with the mild cognitive impairment (MCI) range during preliminary screening, ideally using methods that extend beyond conventional cognitive assessments. Non-invasive, easily accessible screening tools applicable in daily life are increasingly needed. Facial expressions, particularly during rest, may offer promising biomarkers for MCI level detection. This study aimed to identify specific facial features associated with MCI level during rest to inform development of facial expression-based screening tools. Methods: Participants were classified into an MCI level group and a healthy control (HC) group based on the Montreal Cognitive Assessment (MoCA) scores. Facial Action Units (AUs) were extracted from video recordings of resting-state facial expressions in 31 individuals with MCI level and 14 HC. Two statistical models were employed: a multilevel zero-inflated beta regression model for intensity of 17 AUs and a multilevel logistic regression model for presence or absence of 18 AUs. Results: In the zero-inflated beta regression, the AU relates to upper lip raiser showed a significant group effect (MCI level vs. HC; p <0.001), remaining significant after multiple comparison correction. The logistic regression revealed significant group differences for the AUs related to lip tightener (p <0.001) and lip suck (p <0.001), both remained significant after multiple comparison correction. Conclusions: Distinctive facial action patterns during rest were observed in individuals with MCI level. These findings highlight the potential of resting-state facial expressions as a basis for novel, unobtrusive screening tools for early MCI level detection.

BackgroundCommunity-based clinical-pathologic studies have been instrumental to examine the association of Alzheimers disease and related disorders (AD/ADRD) with age and dementia in very-old non-Latino Whites. Here, we show the age distribution of four AD and three additional common neuropathologies across the adult lifespan and examine their relation to dementia and cognitive impairment in old and young Brazilian adults. MethodsWe examined 5,376 brains from decedents age 18 years or older (52.5% male, 39.8% Black), from the Pathology, Alzheimers and Related Dementias Study (PARDoS), collected between July 2021 and September 2025. Clinical diagnoses were rendered by a clinician who reviewed the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), informant-based Clinical Dementia Rating (CDR) Scale, and other selected data. Four indices of AD including {beta}-amyloid deposits (Thal stage), PHF-tau tangles (Braak stage), neocortical phosphorylated plaques and AD neuropathologic change (ADNC), and three other common neuropathologies, i.e., Lewy-body disease (LBD), chronic gross infarcts, and cerebral amyloid angiopathy (CAA) were assessed. Logistic regression was used for associations of pathologies with clinical diagnoses, adjusting for demographics. ResultsIntermediate to high ADNC were first found as early as the fourth decade. Chronic gross infarcts were found in one-fifth of the brains of young adults. Intermediate to high ADNC, limbic and neocortical LBD, chronic gross infarct and moderate to severe CAA were associated with dementia and cognitive impairment (CI) in older adults with mixed pathologies being the most common. Intermediate to high ADNC was associated with CI but not dementia in young adults, whereas, chronic gross infarcts were associated with both CI and dementia in young adults; overall, mixed pathologies were a small minority. ConclusionIn a community-based, clinical-pathologic study including 5300+ brains from diverse Brazilians, we show that AD and other common pathologies frequently begin in young adulthood. In older adults, mixed pathologies are most commonly associated with dementia, whereas in young adults a single pathology, most commonly chronic gross infarcts rather than ADNC is related to dementia.

Background and ObjectivesProgression from mild cognitive impairment (MCI) to Alzheimers Disease and Related Dementias (AD/ADRD) varies widely across individuals, yet the mechanisms underlying this heterogeneity remain unclear. Identifying clinical and social determinants influencing this transition could enable earlier intervention. While cardiovascular and social risk factors are established contributors to dementia incidence, their role in progression from MCI to dementia may differ. Few studies using real world clinical data have evaluated these potential determinants of MCI progression. MethodsUsing electronic health records (EHR) from patients with incident MCI at UCSF Health (2010-2024), we evaluated cardiovascular (blood pressure [BP], body mass index [BMI], and type II diabetes) and social (marital status, language preference, race/ethnicity, and neighborhood disadvantage) risk factors for rate of progression from MCI to AD/ADRD. Covariate-adjusted Cox proportional hazards models estimated hazard ratios for incident AD/ADRD, with evaluation of interactions by sex. ResultsAmong 6,529 patients, higher systolic BP was associated with AD/ADRD incidence (HR per 10 mmHg: 1.09, 95% CI: 1.05-1.14). BMI was inversely associated with incidence in both males (HR: 0.94; 95% CI: 0.92-0.97) and females (HR:0.98; 95% CI: 0.96-0.99). Compared to married individuals, widowed patients had a higher hazard of progression (HR: 1.15; 95% CI: 1.00-1.32). Spanish-speaking (HR: 1.38; 95% CI: 1.04-1.81), Chinese-speaking (HR: 1.19; 95% CI: 1.00-1.42), and "Other non-English" speaking patients (HR:1.24; 95% CI: 1.03-1.51) had a higher hazard of progression compared to English speakers. Latinx (HR:1.22; 95% CI: 1.01-1.48) and Asian patients (HR:1.14, 95% CI: 1.00-1.30; p=0.04) also had higher hazards of progression compared to White patients. Neighborhood disadvantage was not significantly associated with disease progression. DiscussionCardiovascular and social factors independently influence dementia progression, with some sex-specific patterns. Integrating clinical and social indicators highlights the potential of EHR data to identify high-risk patients earlier in the care continuum and support equitable dementia prevention.

BackgroundAlzheimers disease (AD) patients are characterized by an early decline of episodic memory due to hippocampal damage. Nonetheless, besides the classical negative symptoms related to episodic memory deficits, i.e. failure to retrieve information, it has been shown that AD patients can also suffer from positives symptoms, i.e. confabulations. Some theoretical accounts have been proposed to explain the cognitive mechanisms underlying confabulation. Yet, even if most of these models have lead to some research trying to validate cognitive deficits in some cognitive domains, in particular executive functions, to our knowledge, none has yet tried to determine the specific cognitive profile of confabulatory patients. In the present study the main aim is to characterize the specific cognitive profile of confabulatory patients. Thus, given that AD patients cognitive profile is well known and documented, we compare mild to moderate AD patients with and without confabulations. Methods37 healthy control (HC) and 35 individuals with mild to moderate AD were recruited at the Pitie Salpetriere University Hospital. All participants were evaluated on Dalla Barbas Confabulation Battery to determine their tendency to produce provoked confabulations. Thus, among AD patients, we distinguish between those who produced confabulations in episodic memory questions, and those who did not. Accordingly 27 AD patients were considered free of confabulations (ADC-), and 8 as confabulators (ADC+) (none HC met the criteria). All participants were assessed on a comprehensive neuropsychological battery. ResultsStatistical analyses showed a significant difference between HC participants and the two groups of AD patients, in almost all cognitive domains assessed. However, when comparing the two AD groups, they did not show distinct profiles. Moreover, regarding the type of confabulations, ADC+ produced significantly more confabulations to the Episodic questions (both concerning past and future). ConclusionsBy not demonstrating cognitive differences between patients with and without confabulations, our results cast doubts on some confabulation models, which assume a unique and sufficient cognitive (e.g. executive) deficit underlying the onset of confabulations. HighlightsO_LIAlzheimers disease patients with or without confabulations do not have otherwise distinct cognitive profiles. C_LIO_LIThe emergence of a confabulatory syndrome does not seem to be the result of a necessary and sufficient executive deficit C_LIO_LIAlzheimers disease patients mainly produce episodic memory confabulations, which involve both the past and the future dimension. C_LI

OBJECTIVETo assess differences in the severity of Alzheimers disease neuropathological changes in disease epicenters of patients with logopenic variant PPA (lvPPA) with a history of learning differences/developmental dyslexia (LD) versus lvPPA patients without such history (non-LD). BACKGROUNDLearning differences, including developmental dyslexia, are overrepresented in the lvPPA population. It is not known whether a history of developmental differences is associated with a more severe phenotypic expression of Alzheimers disease pathology. DESIGN/METHODSWe quantified the cortical area fraction of phospho-tau immunohistochemistry (IHC) and beta-amyloid IHC in the angular gyrus and superior temporal gyrus of postmortem brains of 15 cases of lvPPA secondary to Alzheimers disease of which 9 non-LD cases (2 males and 7 females), and 6 LD cases (2 males and 4 females). Histological sections were digitally acquired, and foreground IHC-signal was automatically separated and thresholded to quantify the respective tau and beta-amyloid area fractions in each region. RESULTSThere were no differences in the mean age at death between the two groups. Disease duration was longer in the LD group (10.7 {+/-} 1.2 years) than in the non-LD group (8.1 {+/-} 0.8 years), p=0.09. When corrected for sex, age at death and Apo E4 carrier status, the LD group showed higher tau pathology burden in the superior temporal gyrus compared to the non-LD group (0.91% {+/-} 0.37, p=0.03). No differences in tau pathology burden between the groups were observed in the angular gyrus (0.39% {+/-} 0.41, p=0.37). There were no statistically significant differences in the area fraction of beta-amyloid between the two groups of patients in both the angular gyrus and the superior temporal gyrus. CONCLUSIONSOur data suggest that patients with lvPPA secondary to Alzheimers disease and a history of developmental differences have higher tau-pathology burden in the superior temporal gyrus compared to lvPPA-AD patients without such history.

BackgroundAlzheimers disease (AD) is a neurodegenerative disorder marked by cognitive decline, memory impairment, and functional deterioration. Its complex pathogenesis involves factors such as amyloid plaques, tau tangles, neuroinflammation, and synaptic dysfunction, but the precise mechanisms remain unclear, hindering effective treatment. Genetic, environmental, and lifestyle factors contribute to AD risk, yet their interactions are poorly understood. Recent advances in transcriptomics and metabolomics have shed light on the molecular underpinnings of AD, with gene expression alterations and metabolic disruptions implicated in disease progression. These multi-omics disruptions highlight the need for integrative analytical approaches to better characterize AD-relevant biology and advance biomarker discovery. ObjectivesTo integrate genetically imputed whole blood transcriptomics and plasma metabolomics to predict cognitive performance (PACC3) and to identify risk genes and metabolites contributing to prediction, thereby characterizing molecular signatures associated with cognitive performance in AD. MethodsThis study applies a machine learning algorithm to integrate genetically imputed whole blood transcriptomics and measured plasma metabolomics data to predict cognitive performance, as measured by PACC3 score, using data from the Wisconsin Registry for Alzheimers Prevention (WRAP) cohort (N = 1,046). After training a machine learning model on WRAP, the predictive performance was evaluated using an independent dataset from the Wisconsin Alzheimers Disease Research Center (ADRC) cohort (N = 85). Feature importance was assessed to identify genes and metabolites that may play a role as potential risk factors in AD. ResultsThe machine learning model achieved a normalized root mean squared error (NRMSE) of 0.743 {+/-} 0.037 and an R{superscript 2} of 0.311 {+/-} 0.016 across 5-fold holdout test folds in WRAP (p = 5.93 x 10-30), and an NRMSE of 0.915 and an R{superscript 2} of 0.061 when applied to the Wisconsin ADRC cohort. Feature importance revealed transcriptomic biomarkers such as RIPK1, IL6ST, and BIN1 whose higher imputed expression levels were associated with poorer cognitive performance whereas other potential biomarkers including UGP2, NDUFB5, and TMOD2 were associated with better cognitive performance, reflecting mitochondrial energy metabolism and molecular processes associated with cognitive resilience. Several predictive metabolites including benzoate, 3-phenylpropionate, and imidazolelactate also mapped to AD vulnerability signatures, while acyl-carnitine species such as hexanoylcarnitine (C6) and propionate-related metabolites aligned with metabolic resilience. ConclusionIntegrated analysis of transcriptomics and metabolomics demonstrated potential utility for identifying candidate biomarkers associated with cognition in AD. Genes and metabolites reflecting inflammatory signaling, mitochondrial dysregulation, and lipid metabolism emerged consistently among the most influential contributors. These findings align with well-established AD vulnerability pathways and highlight convergent biology across two omics layers. Collectively, this supports the value of multi-omics integration for improving molecular characterization of AD and advancing biomarker prioritization for future mechanistic and translational studies.

INTRODUCTION: Overcoming dementia-related stigma is a global challenge, but tools to assess stigma among family caregivers of people living with dementia remain limited. This study examined the validity and reliability of the Japanese version of the Family Stigma Instrument for family caregivers of people living with dementia (J-FAMSI-dementia), originally developed in the United Kingdom. METHODS: A total of 372 informal caregivers aged 18 to 79 years of family members living with dementia completed an internet survey. The J-FAMSI-dementia comprises five subscales (stigma by association; perceived, affective, and behavioral affiliate stigma; and positive aspects of caregiving), developed through forward and back translations. RESULTS: Confirmatory factor analysis supported an acceptable five-factor model. All subscales showed high internal consistency and moderate to good test-retest reliability. Correlations with dementia attitude, caregiving burden, and depressive symptoms supported construct validity. DISCUSSION: The J-FAMSI-dementia demonstrated acceptable validity and reliability and may help identify dementia-related stigma among family caregivers.

Background and ObjectivesMultifactorial interventions have been reported to be effective in improving cognitive function; however, their long-term effectiveness in community settings remains to be sufficiently examined. This study aimed to investigate the effects of a socially implemented multifactorial intervention program on dementia onset, long-term care insurance certification, and post-intervention cognitive and physical functions. MethodsThis retrospective observational study collected data from three municipalities. The study population comprised individuals suspected of having mild cognitive decline based on cognitive function screening tests conducted by March 31, 2024, and who had been invited to participate in a dementia prevention class, but had not applied for long-term care insurance at the time of the invitation. Participants were classified into class participation and non-participation groups for analysis. Most participants attended the class only once (intervention duration: 4 or 6 months). ResultsData from 104, 218, and 256 individuals were collected from the three municipalities, respectively. No significant association was found between class participation and suppression of dementia onset or long-term care insurance certification in any of the municipalities. Regarding pre-post comparisons among class participants, significant improvements in cognitive function and some physical functions were observed in all the three municipalities. ConclusionsThe multifactorial interventions implemented in community settings showed no effect on dementia onset or health outcomes. However, class participation was associated with improvements in cognitive function and some physical functions. These findings suggest that implementing programs based on evidence can achieve effects similar to those observed in studies conducted under ideal conditions.

Background and ObjectivesAlzheimers disease (AD) is characterized by early disruptions in brain connectivity. However, how genetic and biological markers of AD risk relate to dynamic functional connectivity (dFC) remains unclear. This study examined whether AD-related pathology, genetic risk, and blood-based biomarkers (BBMs) of neurodegeneration are associated with local and distant resting-state dFC patterns, and whether these relate to cognitive performance in cognitively normal older adults. Research Design and MethodsWe analyzed baseline data from 86 cognitively normal older adults (71.6 {+/-} 3.9 years; 60.5% female) enrolled in the AGUEDA trial (NCT05186090). Participants underwent A{beta}-PET imaging, APOE4 genotyping, and plasma quantification of BBMs (A{beta}42/40, BD-tau, GFAP, NfL, p-tau181, p-tau217). Resting-state fMRI was used to compute voxel-wise local and distant dFC using a stepwise connectivity framework. General linear models tested associations between AD pathology, APOE4 status, and BBMs with dFC, adjusting for age, sex, and education. Additional models examined links between dFC and six cognitive domains ResultsA{beta}-positive individuals and APOE4 carriers showed lower local connectivity in frontal regions, while APOE4 carriers exhibited higher distant connectivity in the superior motor area, inferior frontal gyrus, and anterior insula. Among BBMs, only neurofilament light chain (NfL) was associated with both lower local (insula, cingulate) and higher distant (precuneus, putamen, thalamus, supramarginal, superior motor area) connectivity. Regions showing higher distant connectivity related to APOE4 or NfL were associated with poorer cognitive performance. Discussion and ImplicationsDynamic functional connectivity reveals early network alterations in AD risk, characterized by reduced local and elevated distant connectivity--patterns linked to poorer cognition and potential early neurofunctional vulnerability in aging.

Background: Estimates from high income countries suggest that approximately 40% of dementia cases may be attributable to modifiable risk factors across the life course. However, most evidence informing these estimates originates from high income settings, and population level estimates from sub Saharan Africa remain limited. We aimed to estimate population attributable fractions (PAFs) for modifiable dementia risk factors in the Democratic Republic of the Congo (DRC). Methods: We conducted a cross sectional analysis of community dwelling adults aged 65 years and older enrolled in the Etude du Vieillissement Cognitif et de Demence en Republique Democratique du Congo (EVCD RDC). Prevalence estimates of dementia and associated exposures were derived from prior epidemiological studies in this population. Odds ratios were estimated using logistic regression, and population attributable fractions were calculated by integrating exposure prevalence with effect size estimates. To account for correlations between exposures, communality weights were applied when estimating combined PAFs across risk factors. Findings: Combined modifiable risk factors were estimated to account for 37.3% (95% CI 14.3 to 55.6) of dementia cases in this sample. Poverty had the largest weighted PAF (18.4%, 95% CI 13.3 to 22.8), followed by low educational attainment (11.3%, 95% CI 7.3 to 15.3) and depression (5.8%, 95% CI 2.8 to 8.6). Additional contributors included traumatic events (5.4%), war exposure (2.1%), diabetes (1.3%), and hypertension (1.1%). A hypothetical 15% proportional reduction in these risk factors was estimated to reduce dementia prevalence by 6.4% (95% CI 2.1 to 10.8), corresponding to approximately 10 700 cases prevented in the DRC by 2025. Interpretation: Modifiable risk factors account for a substantial proportion of dementia burden in the DRC, with structural determinants such as poverty and education contributing the largest fractions. Dementia prevention strategies in low and middle income countries may therefore require broader public health approaches that address socioeconomic and structural determinants alongside conventional clinical risk factors.

INTRODUCTION: Bilingualism may confer resilience via enhanced neural integrity. However, evidence for bilingualism's neuroprotective effect is mixed, and studies across Alzheimer's disease (AD) variants are scarce. This study examined gray matter volume (GMV) differences between bilinguals and monolinguals with amnestic AD and logopenic variant primary progressive aphasia (lvPPA). METHODS: In 136 amnestic AD and 88 lvPPA participants with neuropsychological assessments and structural MRI, we analyzed differences between monolinguals and bilinguals within each variant, controlling for demographic covariates. RESULTS: Amnestic AD bilinguals exhibited less GMV in hippocampal, fusiform, and occipital regions compared to monolinguals. LvPPA bilinguals had less temporal and occipital volumes, but they had greater volumes in inferior parietal regions, which are considered a disease epicenter in lvPPA. Cognitive performance in monolinguals and bilinguals was comparable within variants. DISCUSSION: Bilingualism may support cognitive reserve (preserved cognition despite reduced GMV) in both AD variants, with additional brain reserve in lvPPA.

Introduction. There is consistent evidence of a disadvantage in bilinguals' speech production compared to monolinguals in healthy individuals, but studies investigating this phenomenon in clinical populations such as Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) are scarce. Given that both clinical groups are characterized by wordfinding difficulties, understanding how bilingualism influences speech production in these populations is essential. Methods. Early and highly proficient Catalan-Spanish bilinguals (active bilinguals) were compared to Spanish-dominant speakers with low proficiency in Catalan (passive bilinguals) using a picture-naming task. The study included 58 older adults, 66 patients with AD, and 124 individuals with MCI. Reaction times, accuracy, and error types were collected in the naming task in each individual's dominant language. Results. First, active bilinguals demonstrated faster naming latencies than passive bilinguals, particularly for low-frequency words. Second, active bilinguals with MCI exhibited more naming errors than passive bilinguals with MCI, including a higher incidence of crosslanguage intrusions and anomia. Third, passive bilinguals with MCI and AD showed more semantic errors than active bilinguals. Discussion. These findings underscore the impact of second language use on naming performance in MCI and AD. Moreover, they provide insight into the potential mechanisms underlying lexical retrieval differences in bilinguals, including lexico-semantic processing and language control.

aStructured abstractO_ST_ABSBACKGROUNDC_ST_ABSOver the past couple of decades, the role of infections, as well as the involvement of the immune system, have been highlighted in the development of dementia. METHODData from the Wisconsin Registry for Alzheimers Prevention cohort were utilized for the analysis. A history of medical conditions was searched across the cohort, and known infections and autoimmune conditions were recorded for each participant. These conditions were then compared with the diagnosis and cognitive performances of each participant. Furthermore, plasma markers were analyzed using two different protein quantification methods. RESULTSOur analysis revealed poorer cognitive performances among participants with listed medical conditions. In plasma samples, Ab42/ICAM1 was identified as a protein ratio with significant variation across condition statuses. DISCUSSIONOur study confirmed that infections and autoimmune conditions contribute to cognitive decline. Ab42/ICAM1 was identified as a relevant marker.

IntroductionAlzheimers disease (AD) disproportionately affects women, with accumulating evidence suggestion a contributary role of hormones in this disparity. Given the known influence of hormones on brain health and cognition, characterizing specific profiles in dementia is crucial. In addition, sex-stratified hormonal alterations in AD and other dementias remain poorly understood. MethodsWe quantified nine steroid hormones: 11-deoxycortisol, 17-hydroxyprogesterone, aldosterone, cortisol, dihydrotestosterone, estrone, progesterone, testosterone and estradiol. The hormones were quantified in cerebrospinal fluid (CSF) and plasma from 204 participants across five cognitive categories: no cognitive impairment (n=32), mild cognitive impairment (MCI) non-AD (n=38), MCI due to AD (n=21), AD dementia (n=81), and vascular dementia (VaD) (n=32). Participants were recruited at the Danish Dementia Research Centre, Copenhagen University Hospital, Copenhagen, Denmark. Hormone levels were measured using liquid chromatography-tandem mass spectrometry. Sex-stratified generalized linear models were adjusted for age. Overall, 50.5% of participants were women with a mean age of 69 (SD = 9.8) compared to men with a mean age of 70 (SD = 9.1). ResultsIn women with AD, CSF cortisol and 11-deoxycortisol were significantly elevated compared to women with no cognitive impairment (Fold Change (FC) (95% CI) = 1.13 (1.01-1.27), p-value = 0.04 and (FC (95% CI) = 1.01, (1.00-1.01), p-value = 0.03, respectively). Plasma progesterone was decreased (FC (95% CI) = 0.90 (0.81, 0.99), p-value = 0.04). Women with VaD exhibited reduced CSF estradiol (FC (95% CI) = 0.86 (0.74, 0.98), p-value = 0.03). In men with AD, plasma aldosterone was elevated (FC (95% CI) = 1.19 (1.06, 1.33), p-value = 2.81e-03). Correlation analyses revealed that CSF cortisol in women was significantly correlated with CSF AD pathology markers in amyloid-beta 42 (r = -0.29, p-value = 3.02e-03) and phosphorylated tau (r = 0.2, p-value = 0.04). The increase of cortisol was validated in an external cohort where t-test showed significant difference in cortisol between people with AD and cognitively healthy controls (CN), this difference was larger in women (mean AD = 0.26 vs mean CN = 0.21, p-value = 1.79e-06) than men (mean AD = 0.23 vs mean CN 0.21, p-value = 0.04) ConclusionOur findings demonstrate sex-dependent dysregulation of steroid hormone in dementia. Specifically, cortisol and aldosterone are highlighted, which are potential modifiable targets.

Structured AbstractO_ST_ABSBACKGROUNDC_ST_ABSPositron emission tomography (PET), cerebrospinal fluid (CSF), and plasma assessments are used to measure amyloid abnormality in Alzheimers disease (AD). However, it remains unclear if these three measures are similarly associated with brain structure and cognitive measures. METHODSLinear regressions examined the relationship between amyloid levels measured by PET, CSF, and plasma and brain volumes, white matter hyperintensities (WMHs), and cognitive measures. RESULTSModerate correlations were found between PET and CSF amyloid measurements and PET and plasma measurements, while weak correlations were found between CSF and plasma. PET, CSF, and plasma amyloid measurements differed in their associations with brain volume, WMHs, and cognition. DISCUSSIONUsing different measurement methods, amyloid was not consistently associated with volumetric or cognitive measures. Our findings also suggest that plasma markers may not be associated with cognitive and brain changes in the same manner as CSF and PET.

Background and ObjectivesAssociations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism to explain these is cerebral amyloid-beta (A{beta}) aggregation as a defence in response to infection, with subsequent tau accumulation. However, few studies have assessed associations of infections with tau and A{beta} pathology. We investigated associations of serological measures of several common infections with plasma p-tau217 and A{beta} status measured by neuroimaging in the 1946 British birth cohort. MethodsCirculating antibodies against 14 pathogens, measured at age 60-64 years, were modelled as pathogen serostatus (indicating lifetime exposure to an agent), pathogen burden indices (measuring cumulative exposure to 2+ pathogens), and seroreactivity tertiles (indicating recent immunological activity against pathogens). Associations of these were tested with plasma p-tau217 (primary outcome) and A{beta} status measured by positron emission tomography imaging (A{beta}-PET; secondary outcome), measured approximately 7 years after serology measurements. Modelling used multivariable quantile and logistic regression, respectively. Model 1 adjusted for sex and ages at serology and outcome assessment, models 2 and 3 additionally adjusted for APOE {varepsilon}4 carriage and education, respectively. We also tested for interactions in associations with APOE {varepsilon}4 carriage and education, and for interactions between herpes simplex virus 1 (HSV1) exposure with both cytomegalovirus (CMV) and varicella zoster virus (VZV) exposure. Results1356 and 424 individuals had complete data for p-tau217 and A{beta}-PET analyses, respectively. Mean age at p-tau217 was 69.9 years (SD 0.7) and 51.3% of participants were female. No notable associations were observed for either outcome in main models, with the exception being an unexpected relationship between seropositivity for herpes simplex virus 2 and lower p-tau217 at the 75th quantile. There was also some evidence for potential interactions in p-tau217 associations by APOE {varepsilon}4 carriage (for Helicobacter pylori and CMV) and by educational attainment (for Helicobacter pylori serostatus). DiscussionThese findings are not supportive of associations between exposures to many common infections and aggregation of core AD neuropathology measures. The possibility that some pathogens might interact with APOE {varepsilon}4 carriage and education in relation to AD neuropathology warrants further study.