bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure to Structural Sexism at Birth is Associated with Faster Late‐Life Memory Decline Among Black and White Women in the U.S.
Authors: Avila Justina F , Adkins‐Jackson Paris AJ , Hill‐Jarrett Tanisha G , Brickman Adam M. , Schupf Nicole , Mayeux Richard , Manly Jennifer J.
Published: January 2025

Background

Structural determinants of health may be important drivers of late‐life cognitive decline and dementia risk for women who have a disproportionate burden of Alzheimer’s disease (AD). This study examines how early life exposure to structural sexism influences cognitive trajectories among women racialized as Black and White.

Method

This study analyzed longitudinal data from two cohort studies: the Washington Heights‐Inwood Columbia Aging Project (WHICAP) and the Health and Retirement Study (HRS). Eligible participants were aged 60+, US born, non‐Latinx, and dementia‐free at their baseline cognitive assessment. Confirmatory factor analysis produced a latent variable of state‐level structural sexism comprised of 6 US Census‐derived indicators representing sex/gender disparities in access to economic, political, cultural, and reproductive health resources. Latent variable scores, per US state, were generated for each year between 1902 ‐ 1954 and linked with WHICAP and HRS participants using birth year and state. Cognitive outcomes were level and change in memory performance. Stratified mixed‐effects models were used to examine associations between structural sexism and memory trajectories across women and men. Interaction terms were included to examine associations by racialized group.

Result

Exposure to higher levels of structural sexism was associated with lower baseline memory performance among WHICAP women and a more rapid rate of memory decline among women in both studies. For women, the difference in rate of memory decline between being born in the state with the highest structural sexism versus the state with the lowest structural sexism was equivalent to 8 to 9 years of cognitive aging. Associations between structural sexism and baseline memory were stronger among Black women compared with White women for both studies.

Conclusion

This study provides some of the first insights into the relationship between structural sexism and late‐life cognitive aging outcomes. Results suggest that, among US‐born Black and White women, early‐life exposure to structural sexism negatively impacts late‐life memory trajectories. Structural determinants are actionable risk factors that can be modified through policy changes. A deeper understanding of the pathways linking structural sexism to AD risk can inform the development of future policy interventions to improve late‐life cognitive health among women.
The Modifying Effects of Sex, Race, and Social Relationships on the Association between White Matter Integrity and Dementia Risk: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study
Authors: Eswaran Surabhee , Gottesman Rebecca F. , Knopman David S. , Koton Silvia , Kucharska‐Newton Anna M. , Liu Albert C. , Liu Chelsea , Lutsey Pamela L. , Mosley Thomas H. , Palta Priya , Sharrett A. Richey , Sullivan Kevin J. , Walker Keenan A. , Groechel Renee
Published: January 2025

Background

Weakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.

Method

In 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).

Result

Significant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).

Conclusion

The contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.
Intersectionality of Gender and Social Determinants of Health in Asymptomatic Alzheimer’s Neuropathology
Authors: Besser Lilah M , O'Shea Deirdre , Fuentes Anthony J. , Galvin James E
Published: January 2025

Background

Studies are limited regarding the role of intersectional social determinants of health in asymptomatic Alzheimer’s disease neuropathology (ADNP).

Method

We analyzed data on 3,107 participants in the National Alzheimer’s Coordinating Center’s Neuropathology Dataset who had a visit ≤24 months before autopsy and confirmed ADNP (moderate to frequent neuritic plaques and Braak Stage III‐VI). Groups were defined based on the presence (symptomatic ADNP, n = 2,956) or absence (asymptomatic ADNP, n = 151) of an MCI/dementia diagnosis at the final visit before death. Social determinants included gender (man/women), educational attainment (years), racialized group (Black, White, other), Hispanic ethnicity, living alone, and English/non‐English primary language. Multivariable logistic regression tested associations between these determinants and ADNP classification (asymptomatic vs symptomatic), and additionally, the models were stratified by gender. Models controlled for age at death, apolipoprotein e4 carrier status, informant‐reported memory decline, time between last visit and autopsy, vascular and Lewy body pathology, and comorbidities (i.e., hypertension, diabetes, depression).

Results

Women (versus men) were more likely to have asymptomatic ADNP (OR = 1.02, 95% CI = 1.00‐1.03), as were those with greater years of education (OR = 1.004, 95% CI = 1.004‐1.006), Hispanic individuals (OR = 1.07, 95% CI = 1.03‐1.11), and those living alone (OR = 1.11, 95% CI = 1.06‐1.17). Non‐English primary language speakers were less likely to have asymptomatic ADNP (OR = 0.88, 95% CI = 0.85‐0.92). Gender‐stratified analyses showed that both women and men were more likely to have asymptomatic ADNP if they were Hispanic (women: OR = 1.07, 95% CI = 1.02‐1.11; men: OR = 1.04, 95% CI: 1.00‐1.08) or living alone (women: OR = 1.12, 95% CI = 1.07‐1.18; men: OR = 1.10, 95% CI: 1.02‐1.18). Women speaking a non‐English primary language were less likely to have asymptomatic ADNP (OR = 0.87, 95% CI: 0.83‐0.91), while in men, more years of education was associated with greater odds of asymptomatic ADNP (OR = 1.004, 95% CI: 1.002‐1.007).

Conclusion

Our study suggests that gender, education, Hispanic ethnicity, primary language, and living alone, as well as the intersectionality of these factors with gender, may differentially influence MCI/dementia diagnosis prior to death in the presence of ADNP. These findings emphasize the need for future Alzheimer’s disease research to prioritize intersectional social determinants of brain health.
Factors associated with caregivers’ perceptions of advance care planning for people living with dementia
Authors: Zhang Yuchen , Sereika Susan M , Lingler Jennifer H , Seaman Jennifer , Pettigrew Corinne , Albert Marilyn S.
Published: January 2025

Background

People living with dementia (PwD) experience progressive functional decline with increasing dependence on their caregivers. Advanced care planning (ACP) has the potential to promote quality of life, reduce iatrogenic harm, and minimize overutilization of healthcare resources, yet planning ahead in the context of dementia is challenging and requires consideration of numerous factors over an extended period of time. We examined caregivers’ perceptions of current and end‐stage medical care preferences in PwD and the impact of ACP‐related discussions between caregivers and PwD.

Method

This secondary analysis utilized data from the cross‐sectional survey, “Care Planning for Individuals with Dementia”, which was administered by staff at Alzheimer’s Disease Centers across the U.S. Statistical analysis employed binary, ordinal, and multinomial logistic regression. Predicting variables included caregivers’ knowledge about dementia; outcome variables were caregivers’ perceptions of PwD’s goals of medical care; covariates were relationships between caregivers and PwD, the Clinical Dementia Rating of PwD, and demographic characteristics.

Result

Caregivers were mainly white (88.5%) and highly educated (mean = 15.9 years), with a mean age of 78.3 years and high dementia knowledge scores (mean = 8.4/10). Caregivers’ knowledge about dementia was associated with their perceptions about PwD’s medical care. Caregivers with higher total dementia knowledge scores had 1.32 times the odds of endorsing comfort care at end‐stage dementia (p = 0.009). Greater knowledge about severe dementia was inversely associated with perceiving the need for further discussions (knowing a lot: OR = 0.17, p<0.001; knowing some things: OR = 0.37, p = 0.006). Caregivers of PwD in earlier stages were less likely to endorse comfort care as their current preference (no impairment & MCI: OR = 0.17, p<0.001; mild: OR = 0.36, p<0.001), and caregivers of patients with no or mild impairment had 5.24 times the odds of indicating the need for further discussions of treatment preferences (p = 0.02) than caregivers of severe stage patients. Lastly, if caregivers already had ACP‐related conversations with PwD, they were 2.67 times more likely to prefer comfort care for end‐stage disease (p = 0.007).

Conclusion

Our analyses show the importance of providing early dementia‐specific education for PwD and their caregivers on end‐of‐life care. Our findings also highlight ACP as a dynamic and continuous process throughout the disease course.
Inflammatory and Redox Blood Gene Expression Fingerprint of Obstructive Sleep Apnoea in Patients with Alzheimer’s Disease
Authors: ElKhayat Leila Romero , Dakterzada Faride , Huerto Raquel P , Carnes Anna , Targa Adriano , Barbe Ferran , Milanesi Elena , Cuadrado Antonio , Piñol‐Ripoll Gerard
Published: January 2025

Background

Obstructive sleep apnoea (OSA) is the sleep disorder most frequently found in patients with Alzheimer’s disease (AD). The intermittent hypoxia (IH) caused by OSA may participate in AD pathogenesis through increase in oxidative damage and inflammation. We aimed to identify inflammatory and redox genes differentially expressed in the blood from AD patients with severe OSA compared with those with nonsevere OSA.

Method

We included 40 AD patients diagnosed based on clinical manifestations and AD biomarker levels in cerebrospinal fluid (CSF). Severe or nonsevere OSA (apnoea–hypoapnoea index ³ 30/h and < 30/h, respectively) was diagnosed through overnight polysomnography (PSG). The expression levels of 136 inflammation‐related and 84 redox‐related genes were evaluated by whole blood targeted transcriptomics.

Result

We identified three inflammatory genes and six redox genes that were upregulated in AD patients with severe OSA. Of all upregulated genes, TNFSF14 and ALOX12 (inflammatory and redox genes, respectively) were positively correlated with the arousal index. GSR, a redox gene, was positively correlated with the AHI (p<0.05). Finally, we found good correlations between the three inflammatory genes and six redox genes (p<0.05). A pathway enrichment analysis showed a strong enrichment of the serotonergic synapse pathway in severe OSA AD patients.

Conclusion

Our results show an upregulation of nine genes involved in NF‐κB‐mediated inflammation and redox metabolism in the blood of patients with mild AD with severe OSA. Therefore, OSA may worsen the inflammation and oxidative damage that are already altered in patients with AD.
Relationship between Posterior Resting‐State Electroencephalographic Alpha Rhythms and Cerebrospinal Fluid Biomarkers of Neuropathology in Patients with Alzheimer’s Disease Mild Cognitive Impairment
Authors: Percio Claudio Del , Lizio Roberta , Lopez Susanna , Noce Giuseppe , Jakhar Dharmendra , Carpi Matteo , Arnaldi Dario , Güntekin Bahar , Yener Görsev , Babiloni Claudio
Published: January 2025

Background

Patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI) are characterized by abnormalities in resting‐state electroencephalographic (rsEEG) rhythms as measures of brain neural synchronization dysfunction (Babiloni et al., PMID: 33860614). Here, we tested the two following hypotheses that those rsEEG abnormalities: (i) may be higher in ADMCI patients than in patients with MCI not due to AD (noADMCI); and (ii) may be related to the AD diagnostic amyloid‐tau biomarkers derived from cerebrospinal fluid (CSF).

Method

Datasets in 70 ADMCI patients, 45 patients noADMCI, and 45 normal elderly (Healthy) participants originated from a Eurasian archive. The eyes‐closed rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands and fixed beta and gamma bands. The eLORETA freeware estimated rsEEG cortical sources.

Result

Statistical results showed: (i) compared with the Healthy group, the posterior alpha rsEEG source activities were more reduced in the ADMCI group than in the noADMCI group (p < 0.001; Figure 1); (ii) in the ADMCI group, a strong negative correlation between the CSF phospho‐tau levels and the occipital alpha rsEEG source activities was observed (r = 0.4, p < 0.001; Figure 2). Interestingly, in the ADMCI group, no correlation between the CSF and magnetic resonance imaging (MRI; neurodegeneration) variables was observed.

Conclusion

In ADMCI patients, the abnormalities of cortical neural synchronization mechanisms underpinning brain arousal and vigilance are related to the AD diagnostic phospho‐tau biomarkers and precede a similar relationship between AD amyloid‐tau and neurodegeneration biomarkers. Remarkably, the amyloid‐tau‐neurodegeneration (ATN) AD model may be enriched with those pathophysiological ‘P’ biomarkers as revealed by rsEEG rhythms.
Amyloid and tau PET as well as functional connectivity mediate the association between APOEε4 and neurodegeneration
Authors: Zhang Bing , Xu Xinru
Published: January 2025

Background

It remains unclear to what extent APOEε4 relates to amyloid beta (Aβ) and tau deposition, functional connectivity and neurodegeneration in Alzheimer's disease spectrum.

Method

In 345 participants including subjective cognitive impairment and mild cognitive impairment and Alzheimer disease, We investigate the association of APOEε 4 with Aβ and Tau, functional connectivity and neurodegeneration (cortical thickness and gray matter volume). Using mediation analyses, we tested the indirect effects of APOEε4 on neurodegeneration via Tau deposition (18F‐AV451 positron emission tomography) and interregional functional connectivity (functional MRI) in Braak I‐II and Braak III‐VI.

Result

We observed that increased APOEε4 dose was associated with poorer neurodegeneration in AD typical regional, with the strongest effects observed for medial temporal lobe gray matter atrophy. These relationships were mediated mainly via tau pathology, particularly of the medial parietal lobe, and to a lesser extent serially mediated via Aβ and functional activities in AD signature regions.

Conclusion

In summary, our finding highlight a pathway in which APOEε4 affects neurodegeneration via increased tau pathology and reduced functional connectivity in critical lobe. Examining APOE ε4‐related brain changes through the use of neuroimaging biomarkers in the Alzheimer's disease spectrum provides a unique opportunity to advance our knowledge of the underlying pathophysiology of AD, particularly in the stage of subjective cognitive decline (SCD).
Mapping between the Mini‐Mental State Examination and the Clinical Dementia Rating scale for Patients with Alzheimer’s Disease: An External Validation Study
Authors: Brogaard Niels Juul , Hahn‐Pedersen Julie Hviid , Gundgaard Jens , Polavieja Pepa , Bray Benjamin D , Chan Mei Sum , Hoang Men , Araya Daniel , Trepel Dominic
Published: January 2025

Background

The Clinical Dementia Rating scale Sum of Boxes (CDR‐SB) measure is commonly used in specialist research settings and clinical trials. In clinical practice, shorter cognitive assessments, such as the Mini‐Mental State Examination (MMSE), are commonly used. A targeted literature search identified existing MMSE – CDR‐SB mappings; such as Balsis et al. 2015 and Perneczky et al. 2006. However, neither mapping provided granular translation of these measurements across all Alzheimer’s disease (AD) stages. This study therefore aimed to extend and externally validate existing published mappings between the MMSE and CDR to support the translation of measurements between these tools across all AD stages.

Method

The optimal functional form for the mapping was investigated using power‐transformed univariate regressions, and the modelled mapping was extended to capture the full range of AD stages. External validation of the mapping was conducted using the US National Alzheimer’s Coordinating Centers (NACC) database, stratified by age, sex, education, and AD medication use. Individuals’ most recent visit with valid MMSE and CDR‐SB scores, and concordant AD staging based on clinical diagnoses and global CDR scores were included. Calibration and discrimination metrics were reported, following best practice guidelines for clinical prediction tool validation.

Result

A linear MMSE to CDR‐SB mapping (see Figure 1 for equation) was found to have the optimal functional form and demonstrated high goodness of fit (Adjusted = 0.989). When externally validated on the NACC population (n = 25,768; Table 1), the mapping satisfied all validation metrics (Somers’ D = 0.705, R2 = 0.739; above the prespecified 0.7 threshold), and deciles of patients by CDR‐SB were generally well‐calibrated (Figure 1). The mapping also demonstrated acceptable discrimination between no/mild AD dementia versus moderate AD dementia (AUC = 0.885; 95%CI: 0.879‐0.891) and between moderate AD dementia versus severe AD dementia patients (AUC = 0.756; 95%CI: 0.743‐0.769). The mapping accurately predicted AD stage across the overall NACC database and when stratified by subgroups (Table 2).

Conclusion

This extended mapping for MMSE to CDR‐SB demonstrated good performance, especially in less severe AD stages. The findings can support the translation of AD severity assessments between datasets using CDR‐SB and MMSE, bridging a common information gap between clinical trials and real‐world evidence studies.
Eye movement combined machine learning methods for three‐classification diagnosis of Alzheimer's disease
Authors: Song Jiaqi , Yu Weihua , Lü Yang
Published: January 2025

Background

Alzheimer's disease (AD) is a chronically progressive neurodegenerative disease, and mild cognitive impairment (MCI) is a transitional stage between normal cognition and AD. Multi‐classification of AD poses a challenging task, and currently, only a few algorithms have achieved an accuracy above 60%. This study was designed to construct a diagnostic model based on eye movement parameters to distinguish dementia due to AD, MCI and normal cognition.

Method

Eye movement data were collected from 258 subjects, comprising 66 individuals with normal cognition, 81 patients with MCI and 111 patients with dementia due to AD. Machine learning methods were used to construct classification models. Pearson's correlation analysis was used to detect correlations between the five most important eye movement indicators and neuropsychological scales.

Result

Among all the machine learning classifiers, the gradient boosting classifier model demonstrated the best classification performance, achieved 68.2% of accuracy and 66.32% of F1‐score. Additionally, correlation analysis indicated that the eye movement parameters exhibited a significant correlation with various cognitive functions, including general cognitive status, attention, visuospatial ability, episodic memory, language and instrumental activities of daily life.

Conclusion

Eye movement parameters in conjunction with machine learning methods achieve satisfactory overall accuracy, making it an effective and less time‐consuming method to assist clinical diagnosis of AD.
Targeted Multiplexed MALDI MS Platform Enables Detection of Novel Pathogenic Forms of Tau, Amyloid Beta and Alpha Synuclein
Authors: Bergo Vladislav
Published: January 2025

Background

The rapidly growing pipeline of target‐specific Alzheimer’s Disease (AD) therapeutic candidates requires accompanying tests that can identify patients likely to have a beneficial response. The growing importance of multiple pathologies in determining AD progression and treatment response underscores this need. Our work focuses on establishing analytical capability to expand detectable forms of major protein drug targets for AD: Tau, amyloid beta (Ab) and a‐Synuclein (aS) proteoforms as potential personalized molecular signatures.

Method

Novel analytical workflow (BAMS™) based on single bead immunoaffinity capture, enrichment and mass spectrometry (MS) quantification was applied to measure distinct species of CSF Tau, Aβ and αS. Samples from cognitively normal (CN) and AD subjects were acquired from a biobank and measured either non‐digested or after digestion with LysC protease. MS data was collected on Bruker Autoflex Max MALDI TOF instrument and processed using in‐house developed software.

Result

BAMS™ has detected >40 CSF Aβ peptides, comprising N‐terminal AβX‐40/42 (X= 1, 3, 5, 7, 10, 11) and C‐terminal Aβ1‐X (X between 6 – 43) truncation series. The latter included previously unreported peptides Aβ1‐6‐Aβ1‐11, Aβ1‐21‐Aβ1‐26, Aβ1‐31 and Aβ1‐32. Many peptides including amyloid plaque pathology markers Aβ1‐40 and Aβ1‐42 were measured with CVs under 10%. A survey of CN and AD subjects reveals major differences within Aβ1‐X patterns likely reflecting different amyloid metabolism. Total and phospho‐Tau (tTAU and pTAU) probes revealed extensive endogenous proteolysis in the Proline Rich Domain with multiple detected fragments terminating at distinct proline sites. The pTAU probe detected hyperphosphorylated sequences containing up to 3 and 5 modified sites in CN and AD, respectively, which unambiguously differentiated normal from diseased samples. Three αS probes have been developed that measure: (1) total protein abundance, (2) C‐terminal fragmentation and (3) relative abundance of monomer and dimer species of isoforms SNCA140, SNCA126 and SNCA112.

Conclusion

Healthy and diseased human CSF may contain a wider range of Tau, Aβ and αS proteoforms than previously recognized. BAMS™ can simultaneously measure multiple protein targets and multiple proteoforms via independent probing of distinct protein regions. The broad sequence coverage enables screening of multiple biomarker candidates for accurate molecular profiling of tau tangles, amyloid plaques and Lewy bodies.
Survival and time till nursing home admission in persons with dementia: a systematic review and meta‐analysis
Authors: Brück Chiara C. , Mooldijk Sanne S. , Kuiper Lieke M. , Wolters Frank J.
Published: January 2025

Background

Accurate prognosis after a dementia diagnosis is important for patient information and advanced care planning, but available information is fragmented, with inconsistent estimates that are often restricted to survival. We aimed to summarise the literature to assess survival times and time to nursing home after dementia diagnosis and determine the impact of clinical characteristics and study design.

Method

We systematically searched MEDLINE and EMBASE for studies reporting time from dementia diagnosis to nursing home admission or death. Two reviewers independently extracted information on study design, patient population, disease characteristics, and outcomes, including semi‐automated quantification of Kaplan‐Meier survival curves. We used a modified Newcastle‐Ottawa Scale for study appraisal and performed meta‐regression analyses to identify determinants of prognosis.

Result

Of 212 included studies, 188 reported on survival (1,255,916 participants) and 70 on nursing home admission (229,925 participants). Overall, median survival was 4.7 years (interquartile range: 3.4‐6.0), and this differed substantially with patient demographics and disease characteristics. Survival varied with age and was on average 6.6 years among studies with a median age of 65 years, and 3.7 years with a median age of 85 (Figure 1A). Shorter observed survival among women than men was explained entirely by later disease onset in women. Survival was longer among patients with Alzheimer’s disease compared to all‐cause dementia (Figure 2), and longer in more recent studies (1.3 years comparing studies ≥2010 to <1990). Patients in Asia lived longer after diagnosis than their counterparts in the U.S. and Europe (1.1‐ and 1.3‐years difference, respectively). Survival probabilities were 88%, 69%, 52% and 26% after 1, 3, 5 and 10 years of follow‐up, respectively (Figure 3A). Taken together, variation in methodology and clinical characteristics explained 50% of heterogeneity in survival among studies. Median time to nursing home admission was 3.3 years (IQR 2.2‐4.0; Figure 1B), with 15% of patients being admitted after 1 year, increasing to 36% at 3, and 57% at 5 years from diagnosis (Figure 3B), which was influenced only by age.

Conclusion

Patients with dementia have an average life‐expectancy of five years at time of diagnosis, of which two years are lived in nursing homes.
The incidence of all‐cause dementia and Alzheimer’s disease from around the world: data from the COSMIC collaboration
Authors: Vella Ashleigh S. , Visontay Rachel , Lipnicki Darren M. , Nichols Emma , Steinmetz Jamie , Lipton Richard B. , Llibre‐Rodriguez Juan J. , Katz Mindy J. , Scarmeas Nikolaos , Guerchet Maëlenn , Preux Pierre‐Marie , Ritchie Karen , Carriere Isabelle , Petersen Maria Skaalum , Skoog Ingmar , Rolandi Elena , Kim Ki Woong , Riedel‐Heller Steffi G. , Shahar Suzana , Ganguli Mary , Anstey Kaarin J. , Lobo Antonio , Crawford John D. , Mewton Louise , Sachdev Perminder S. ,   other COSMIC authors
Published: January 2025

Background

High‐income countries (HICs) are over‐represented in current global dementia incidence rates, skewing estimates. Variance in diagnostic methods between HICs and low‐ and middle‐income countries (LMICs) is speculated to contribute to the regional differences in rates. Cohort Studies of Memory in an International Consortium (COSMIC) offers a unique opportunity to address these research inequalities by harmonising data from international studies, including representation from LMICs. This study aimed to identify dementia incidence rates by age and sex in various regions worldwide, where data for dementia diagnosis were available.

Method

Data were obtained from 36 members of COSMIC, representing 28 countries across 6 continents (HICs: Australia, Canada, Faroe Islands, France, Germany, Greece, Italy, Japan, Netherlands, South Korea, Spain, Sweden, & USA; LMICs: Brazil, China, Cuba, Dominican Republic, Ecuador, Indonesia, Malaysia, Mexico, Nigeria, Peru, Philippines, Republic of Congo, & Tanzania). For each member study, we calculated incidence rates for all‐cause dementia. Findings from 14 studies, with a consensus diagnosis are presented in the results. Using an Item Response Theory approach, we are currently calculating a comparable incidence rate for those studies without a consensus diagnosis.

Result

Consistent with previous trends, incidence rates (per 100 person‐years) increased with age, from 65‐70 years‐old to 85‐90 years‐old, for both males (i.e., Republic of Congo, 4.41 to 19.57; France, 0.46 to 3.89; USA, 0.17 to 3.22; Spain, 0.31 to 4.22; 65‐70 & 85‐90 cohorts respectively) and females (i.e., Republic of Congo, 3.57 to 15.31; France, 0.45 to 3.72; USA, 0.22 to 4.25; Spain, 0.36 to 4.96; 65‐70 & 85‐90 cohorts respectively). There were no sex differences in incidence rates in younger age groups (60‐65). Among older age groups, however, women tended to have higher incidence rates than men, in some countries (Faroe Islands, Germany, Sweden, and USA).

Conclusion

Geographical differences in dementia incidence rates likely represent inherent variation among countries, beyond methodological considerations. We are working to expand the range of studies and regions for which we calculate dementia incidence rates. This involves the development of approaches to classify and harmonise incident dementia in studies lacking consensus diagnoses. Doing so will bolster LMIC representation.
The Common Marmoset as a Preclinical Primate Model for Alzheimer’s disease
Authors: Silva Afonso C
Published: January 2025

Background

Our limited understanding of the mechanisms that trigger the emergence of Alzheimer’s disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that developing a nonhuman primate model of AD will be an essential step toward overcoming the limitations of other model systems and is crucial for investigating primate‐specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD.

Method

The consortium successfully generated viable founders carrying PSEN1 mutations. in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community.

Result

The consortium successfully generated viable founders carrying PSEN1 mutations. in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community.

Conclusion

By establishing marmoset models of AD, we will be able to investigate primate‐specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.
Deciphering the Protective Interplay between Cancer and Alzheimer’s: Advancing Drug Repositioning Strategies for Alzheimer’s Disease Treatment
Authors: Zhao Hong , Vasquez Matthew , Ahn Ju Young , Dong Wenjuan , Sheng Jianting , Yin Zheng , Wong Stephen T.C.
Published: January 2025

Background

Global epidemiological studies involving over nine million participants have shown a 35% lower incidence of Alzheimer’s Disease (AD) in older cancer survivors compared to those without a history of cancer. This inverse relationship, consistent across recent studies with methodological controls, suggests that cancer itself, rather than cancer treatments, may offer protective factors against AD. This insight opens avenues for novel therapeutic strategies targeting early AD by harnessing cancer‐associated protective factors.

Methods

To investigate the potential protective effect of cancer against Alzheimer’s Disease (AD), we developed “cancer‐in‐AD” mouse models. These models involved injecting a small number of breast cancer cells into young AD‐model mice (5xFAD) and monitoring amyloid plaque progression. Additionally, we introduced extracellular vesicles (EVs) from breast tumor‐bearing mice into similar AD models. Using spatial transcriptomics, we analyzed brain tissue gene expression and cell‐cell interactions, focusing on the astrocyte‐microglia‐oligodendrocyte network near amyloid plaques. This approach helped identify potential drugs for repurposing in AD treatment.

Results

The study found a significant reduction in amyloid burden within the brains of the cancer‐in‐AD mouse models compared to age‐matched cancer‐free AD mice. The administration of EVs from cancer animal’s plasma to the AD mice prompted the release of various inflammatory cytokines and chemokines. A key discovery was an activated astrocyte‐microglia‐oligodendrocyte signaling network that regulates amyloid‐beta homeostasis in these mouse brains. Out of 49 FDA‐approved drugs identified to induce this cancer‐induced signaling, 11 showed promise in improving AD symptoms and reducing amyloid and tau accumulations, in both preclinical and clinical studies.

Conclusions

The study reveals a notable decrease in amyloid levels in AD mice with cancer or exposed to tumor‐derived EVs, linked to immune system reprogramming and glial network activation. This supports the study’s drug repositioning approach and sets the stage for further research into the anti‐AD properties of these drugs, focusing on identifying crucial signaling elements for enhanced drug repositioning and combination treatment strategies.
Social Condition and Cognitive Function Among Boston Area Puerto Ricans
Authors: Palacios Natalia , Ekaterina Shishova , Scott Tammy , Falcon Luis , Tucker Katherine L
Published: January 2025

Background

This study aimed to assess associations between socioeconomic condition and cognitive function among Puerto Rican adults residing in the greater Boston Area.

Methods

We assessed the relationship between a score of social condition, encompassing education, income‐to‐poverty ratio, perceived stress, food security, and psychological acculturation, and cognitive function in a cohort of Puerto Rican Adults residing in the greater Boston area. The score was assessed over more than 12 years of follow‐up and ranged from 0 (best social condition) to 15 (poorest social condition). We examined the varying contributions of traditional (education and income) vs. psychosocial (perceived stress, food security, and psychological acculturation) in relation to cognitive function.

Results

After adjusting for covariates, poorer 12‐year average social condition was associated with poorer cognitive function (β = ‐ 0.52, 95% CI = [‐ 0.66, ‐ 0.38; P trend = 5.7×10−14 for highest vs. lowest disparity category). The association was stronger for traditional (β = ‐ 0.53, 95% CI = [‐ 0.67, ‐ 0.40] P trend = 5.7×10−14) than psychosocial (β = ‐0.20, 95% CI = [‐ 0.34, ‐ 0.06] P trend = 0.05) measures, but both were significantly associated with cognitive function.

Conclusions

Our findings in US‐mainland Puerto Rican adults suggest that socioeconomic condition, both traditional and psychosocial, are associated with cognitive function. This work highlighting the importance of addressing and reducing social disparities to promote better cognitive health outcomes.
The role of volunteer older adults in the exercise programme of the Comprehensive Resilience‐Building Psychosocial Intervention (CREST) for people with dementia
Authors: Casey Dympna , Smyth Siobhán , Doyle Priscilla , Gallagher Niamh , Whelan Barbara
Published: January 2025

Background

The CREST intervention included three components one of which was an eight‐week exercise programme. The aim of the programme was to increase the exercise capacity of people with mild to moderate dementia and facilitate social engagement with volunteer older adults from the community supporting a person with dementia, raising awareness and understanding of dementia. We explore the experience of volunteer older adults’ participation in the exercise component of the CREST intervention following a five‐hour training on dementia awareness and the CREST exercise programme.

Method

Qualitative semi‐structured focus groups and individual interviews were conducted with the older adults, people with dementia, their carers and the facilitators of the exercise programme. Data were analysed thematically. Older adults also completed the Dementia Attitude Scale (DAS) and the Dementia Knowledge Twenty (DK‐20) questionnaire pre‐ and post‐intervention.

Result

Overall, the older adults (n = 9), people with dementia (n = 9), their carers (n = 9) and the programme facilitators (n = 2) were positive about the inclusion of the older adults in the exercise programme. Most commented on the role of the older adults in encouraging and supporting the people with dementia with the exercises and the social aspect. Two of the people with dementia highlighted difficulties in personality but they found a way to work together as the weeks progressed. While the majority of older adults felt that the training they received prior to the intervention prepared them sufficiently to support the person with dementia, there were only slight improvements in attitudes and knowledge scores about dementia based on the DAS (baseline M = 105; SD = 9.68; post‐intervention M = 109; SD = 8.80) and DK‐20 (baseline M = 11.3; SD = 4.74; post‐intervention M = 14.2; SD = 2.59).

Conclusion

The volunteer older adults actively contributed to the exercise program, providing encouragement and support to the people with dementia, and enhancing the social dynamics of the sessions. There were modest improvements in the attitudes and knowledge scores about dementia among the volunteer older adults, suggesting a potential positive impact of the intervention on their awareness and understanding.
Development of a Dementia Intensive Advanced Practice Provider Fellowship
Authors: Arthur Anne K , Gillen Lindsey , Fikru Samantha , Malcolm Jessica , Vidoni Eric D
Published: January 2025

Background

The aging population is driving an unprecedented increase in the number of individuals with Alzheimer’s disease and related dementias (AD/ADRD). Currently, there is limited availability of specialists in AD/ADRD and a growing need in the United States for new access points to treat the estimated 7.2 million people with AD/ADRD expected in 2025. Care access disparities are particularly apparent in the Central Plains states, most of which are considered “Neurology Deserts”. In response, the University of Kansas has developed an Advanced Practice Provider (APP) Brain Health Fellowship to increase sustainable access to AD/ADRD care.

Methods

The KU Alzheimer’s Disease Research Center (KU ADRC) and the KU School of Nursing developed a 6‐month AD/ADRD fellowship to train APPs to recognize, diagnose and treat AD/ADRD. Learning modules and rotations were selected by an expert panel, including our neurology and APP clinical fellowship directors, and cover relevant topics and departments encountered during the diagnosis and treatment of AD/ADRD. Examples include AD/ADRD treatments, neuropsychology, neuroimaging, biomarkers, social work support, end of life care planning, and research. The weekly schedule includes didactics, precepted clinics, mentored clinics, and specialty clinics. The program director and fellow review evaluations, clinical progress, and career planning monthly. The fellow completes pre‐ and post‐fellowship competence and dementia knowledge surveys developed by the program. The fellow receives a competitive salary, laptop, and education materials.

Results

To date, one fellow has completed the program. Pre‐ and post‐test results showed an 85% increase in AD/ADRD knowledge. The fellow, on average, rated the preceptors and program at “Above Average” to “Excellent”. Feedback during and after the fellowship has been incorporated into ongoing programming. The first fellow was hired by the KU ADRC.

Conclusions

The KU ADRC APP Brain Health Fellowship is a first‐of‐its‐kind approach to develop clinicians trained to care for the growing number of individuals with AD/ADRD. Our preliminary results suggest the fellow increased AD/ADRD care competence and the program was valued by the fellow. The immediate post‐program employment of the fellow is evidence of potential benefit to increasing access to care. The fellowship will continue in 2024 and train two more fellows.
Accurate diagnosis of Alzheimer’s disease using specific volatile organic compounds from breath
Authors: Shen Lu , Zhang Sizhe , Liu Haokun , Ouyang Ziyu , Xu Tianyan , Yang Qijie , Zhu Yuan , Wan Meidan , Xiao Xuewen , Yang Xuan , Yuan Li , Bei Yuzhang , Wang Junling , Guo Jifeng , Chen Haibin , Tang Beisha , Jiao Bin
Published: January 2025

Background

Existing biomarkers including cerebrospinal fluid and positron emission tomography for Alzheimer’s disease (AD) diagnosis are relatively invasive and expensive. Application of exhaled breath collection and volatile organic compound (VOC) detection for AD diagnosis remains unclear.

Method

In this cross‐sectional study, high‐pressure photon ionization time‐of‐flight mass spectrometry (HPPI‐ToF‐MS) was used to detect VOCs from breath in three datasets and patients diagnosed as Parkinson’s disease (PD). Plasma p‐tau181 was quantified using ultra‐sensitive Simoa technology. GC x GC TOF‐MS was used to detect VOCs in plasma. Near‐infrared spectroscopy was carried out to elucidate alterations of brain metabolism.

Result

A total of 861 participants were enrolled. Patients with AD were diagnosed according to the 2011 NIA‐AA diagnosis criteria and further confirmed in dataset 1 (n=30) based on the A+T+N+ framework. Datasets 1 and 2 were used to recognize the different VOCs between patients with AD and controls. The diagnostic power of VOCs for AD was confirmed separately in train datasets 1 and 2 and independent test dataset 3. The specific VOCs in AD diagnosis were further compared with patients with PD. Among all participants, no statistical difference was observed in demographic characteristics for dataset 1. Six VOCs, including ethanol (m/z = 46), isopropanol (m/z = 60), chloroethane (m/z = 64), pyrrole/3‐butenenitrile (m/z = 67), 1‐butanol (m/z = 74), and benzene (m/z = 78), were significantly different between the two groups in dataset 1 and were verified in dataset 2 and dataset 3. Ethanol (m/z=46) and pyrrole/3‐butenenitrile (m/z=67) presented areas under the ROC curve (AUCs) values of 0.907 and 0.895, respectively, in datasets 1 and 2 and 0.849 and 0.974, respectively, in dataset 3 (community). The six VOCs were associated with cognitive decline as reflected by neuropsychological tests, five (m/z = 46, 64, 67, 74, and 78) were correlated with plasma p‐tau181 levels, and five (m/z = 46, 60, 67, 74, and 78) showed consistent alteration in plasma. Moreover, five (m/z = 46, 60, 67, 74, and 78) were associated with altered brain connectivity.

Conclusion

Specific breath VOCs may be used as simple biomarkers for AD detection.
Investigating the APOE4‐associated heterogeneity of imaging biomarkers across AD diagnostic stages
Authors: Mares Jason , Sharma Anurag , Guo Jia , Nuriel Tal
Published: January 2025

Background

Carriers of the apolipoprotein E ε4 (APOE4) allele are at an increased risk of developing Alzheimer’s disease (AD) and display an earlier age of onset compared to non‐carriers who develop the disease. While researchers have extensively characterized the impact of APOE4 on the susceptibility of AD, little is known about the differences in disease etiology and presentation in APOE4 carriers vs. non‐carriers.

Method

In order to investigate these differences, we performed a broad analysis of imaging biomarkers in APOE4 carriers vs. non‐carriers present in the ADNI cohort.

Result

We observed differences between APOE4 carriers vs. non‐carriers in several imaging readouts, including Ab‐PET, Tau‐PET, FDG‐PET, and structural MRI measures. These differences were variable based on sex and amyloid positivity. Interestingly, when we compared cognitively normal ADNI participants who converted to MCI or AD to those who did not, we observed APOE4‐dependent differences that may point to specific pathologies that mediate MCI/AD conversion in APOE4 carriers vs. non‐carriers.

Conclusion

These observations of pathological heterogeneity between APOE4 carriers vs. non‐carriers reveal significant differences in disease pathogenesis between these two groups, which may have important implications with regard to the diagnosis and treatment of AD in different genetic cohorts.
Evaluation of Two Plasma pTau217 Simoa Assays Against Amyloid‐PET
Authors: Figdore Daniel , Bornhorst Joshua A , Graff‐Radford Jonathan , Vemuri Prashanthi , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Algeciras‐Schimnich Alicia
Published: January 2025

Background

Tau phosphorylated at threonine 217 (pTau217) is one of the most promising blood‐based biomarkers of Alzheimer’s disease (AD). This study compares the performance of two plasma pTau217 immunoassays on the Simoa platform for detection of abnormal amyloid‐PET.

Method

Plasma samples from 112 individuals without cognitive impairment and 114 with mild cognitive impairment (MCI) or AD related dementia were evaluated. Testing was performed on the Quanterix Simoa® HD‐X Analyzer using the ALZpath Simoa® pTau217 and the Simoa® ACC pTau217 (Janssen antibodies) commercial assays. Amyloid‐PET imaging was performed using 11C‐Pittsburgh Compound B and a standard uptake value ratio (SUVR) cutoff of ≥1.52 (≥25 Centiloid) was used for abnormal (n= 147) vs. normal (n= 79) classification. Passing‐Bablok regression analysis and Spearman’s correlation coefficient (rho) were used to estimate bias and correlation between the assays, respectively. Correlation of each assay with Amyloid‐PET SUVR was evaluated. Amyloid‐PET status as the outcome and plasma pTau217 as predictor was used to estimate the area under the receiver operating characteristic (ROC) curve (AUC).

Result

The pTau217 concentrations between the two assays showed an excellent correlation (Spearman’s rho= 0.94 [95% CI= 0.93 to 0.96, p<0.0001]). However, the Passing‐Bablok regression analysis equation for ALZpath (x‐axis) and ACC (y‐axis) was y= 0.1324x ‐ 0.0019, showing that measured pTau217 concentrations with the ALZpath assay were higher (∼87%) than with the ACC assay (concentrations ranged 0.057 to 3.5 pg/mL and 0.003 to 0.5 pg/mL, respectively). Correlations between amyloid‐PET SUVR and the two pTau217 immunoassays were almost identical with Spearman’s rho= 0.70 (95% CI= 0.62 to 0.76, p<0.0001) for ALZpath and 0.69 (95% CI= 0.61 to 0.75, p<0.0001) for ACC. The AUC for detection of an abnormal amyloid‐PET among the MCI/AD group was 0.88 (95% CI= 0.81 to 0.95) for ALZpath, and 0.89 (95% CI= 0.83 to 0.96) for ACC.

Conclusion

Analytically, the two Simoa® pTau217 assays correlate well with each other, but results are not interchangeable due to a significant proportional bias. Clinically, the performance of the assays was largely equivalent for the detection of abnormal amyloid‐PET by AUC analysis based on their almost identical correlations with amyloid‐PET SUVR.