bluuebunny/crossref_metadata_2025 huggingface dataset:
Variable Sleep Quality Is Related to Tau Burden and Worse Memory in Older Women at Risk for Alzheimer’s Disease
Authors: Stiver Jordan , Wang Xin , Lui Kitty K. , Dratva Melanie A , Heyworth Nadine , Pa Judy , Malhotra Atul , Sundermann Erin E. , Banks Sarah
Published: January 2025

Background

Women are more likely to experience sleep problems than men, especially during and after menopausal transition. Sleep disturbances are related to memory decline and the development of Alzheimer’s disease (AD), which is also more common among women. While research on habitual sleep patterns in aging has largely focused on mean sleep outcomes across nights, few studies have examined the potentially harmful effects of night‐to‐night variability in sleep quality on AD biomarkers and memory function. The purpose of this study was to determine how intraindividual variability in nocturnal sleep quality relates to tau burden and memory function in older women at elevated genetic risk for AD.

Methods

Older women (N = 33; Mage = 73.1, SD = 4.0; APOE‐ε4 carriers, n = 17) with mild cognitive impairment and an AD polygenic hazard score ≥50%ile wore an actigraphic device on the wrist for an average of 7.6 nights (range = 5‐13) to objectively measure sleep behavior. Participants also completed neuropsychological tests and 18F‐MK6240 tau‐PET to quantify tau burden. Variability in wake time after sleep onset (WASOv) was calculated as the intraindividual standard deviation of WASO across sleep intervals. Memory was assessed using delayed recall scores from the Logical Memory (LM) subtest of the Wechsler Memory Scale‐Revised, the Rey Auditory Verbal Learning Test (RAVLT), and the Brief Visuospatial Memory Test‐Revised (BVMT‐R). A composite tau‐PET temporal meta‐region of interest was calculated based on standardized uptake value ratios using inferior cerebellar gray matter as the reference region.

Results

After controlling for age, APOE‐ε4 carrier status, and mean WASO, regression models showed that WASOv predicted greater meta‐temporal tau‐PET signal (β = .52, p<.05) and worse delayed recall on LM and BVMT‐R (β = ‐.58 and β = ‐.63, respectively; ps<.01). Results further showed interaction effects, such that WASOv was associated with greater tau as well as worse RAVLT and BVMT‐R performances, especially among APOE‐ε4 carriers (|β| range = .67–.89, all ps<.05).

Conclusions

Variability in sleep quality is associated with greater tau burden and worse memory function in older women at risk for AD, particularly among APOE‐ε4 carriers. Results highlight the possibility that variable sleep quality is a modifiable risk factor in the early pathogenesis of AD and its cognitive sequelae.
Data‐driven Cognitive Composites and APOE ε4 Carriage Predict Progression to Mild Cognitive Impairment in Cognitively Unimpaired Older Adults
Authors: Tallapragada Bhargav , Galna Brook , Shishegar Rosita , Markovic Shaun J. , Brown Belinda M. , Dore Vincent , Laws Simon M. , O’Brien Eleanor K. , Porter Tenielle , Burnham Samantha C. , Weiner Michael S. W. , Morris John C. , Hassenstab Jason J. , Rowe Christopher C. , Jin Liang , Fripp Jurgen , Lim Yen Ying , Doecke James D. , Masters Colin L. , Maruff Paul , Sohrabi Hamid R. ,   the ADOPIC Consortium
Published: January 2025

Background

In cognitively unimpaired (CU) individuals, the PACC is widely used as a cognitive outcome measure and endpoint in observational studies and clinical trials. However, it has drawn criticism for being heavily weighted towards memory. Increasing evidence indicates a decline spanning multiple cognitive domains in CU individuals. Therefore, using principal component analysis (PCA), we derived data‐driven domain‐specific cognitive composites. And subsequently, compared them against their summed z‐score counterparts in predicting progression to mild cognitive impairment (MCI).

Method

Baseline cognitive, demographic, and genotype data of 2,853 CU older adults (aged 41.6 to 98.3) was obtained from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) Consortium. Using varimax‐rotated PCA, tests significantly loading (≥ 0.5) onto each principal component were extracted to derive domain‐specific cognitive composites. The resulting domain scores were normalised to a mean of 0 and SD of 1, with a higher score indicating better cognition. Cox regression was used to assess the association between progression to MCI and baseline demographics, cognition, and APOE ε4 carriage. Akaike information criteria (AIC) was used to compare the fitness of PCA‐derived composites against the zPACC and z‐score domain‐specific composites.

Result

Baseline cohort characteristics are described in Table 1. PCA explained 68% of the variance and resulted in four independent cognitive composites (Figure 1): memory; executive function; attention and processing speed; and global cognition. At 15 years from baseline, 309 participants progressed to MCI, while 2,544 remained CU. Cox regression showed that the four cognitive composites, age and APOE genotype significantly predicted progression to MCI (Concordance = 77%, p < 0.001, AIC = 4105, Table 1). Additionally, the PCA‐derived composites performed comparably, if not better than the summed z‐score counterparts, the PACC (Concordance = 74%, p < 0.001, AIC = 4163) and domain‐specific composites (Concordance = 75%, p < 0.001, AIC = 4142). Baseline older age, APOE ε4 carriage in a dose‐dependent manner (Figure 2) and poorer cognition for each PCA‐composite were independently associated with progression to MCI.

Conclusion

Together with APOE ε4 carriage, our PCA‐derived domain‐specific composites performed better than their summed z‐score counterparts at predicting progression to MCI 15 years before symptom onset.
The relationship between amyloid‐b and cognition in young‐onset Mild Cognitive Impairment: the influence of disease duration
Authors: Carbone Chiara , Balboni Erica , Beltrami Daniela , Tondelli Manuela , Gallingani Chiara , Gasparini Federico , Salvatori Davide , Salemme Simone , Vinceti Giulia , Fraternali Alessandro , Marti Alessandro , Chiari Annalisa , Zamboni Giovanna
Published: January 2025

Background

The effect of amyloid‐b brain deposition on cognition is still debated, since it has been shown that its accumulation begins almost 15 years before cognitive symptoms' onset, then reaches a plateau while cognition continues to decline. We studied if there is a parallel between amyloid‐b deposition and cognitive performances in young‐onset Mild Cognitive Impairment (MCI) patients, and if it is associated to symptoms’ duration.

Method

Subjects with a diagnosis of MCI and symptoms’ onset ≤ 65 years underwent neuropsychological assessment, Magnetic Resonance Imaging, and (18F)Flutemetamol‐PET (amy‐PET). FMRIB Software Library was used to assess voxel‐wise correlations between amyloid‐b deposition and cognitive performances, adjusted for age, sex, education, and degree of grey matter atrophy. Correlations were repeated grouping patients depending on whether the duration of their cognitive symptoms had been shorter or longer than the median of the entire group (34 months).

Result

Among the 30 recruited individuals we found a statistically significant correlation between amyloid‐b burden and performance in attentional‐executive (i.e., Trail Making Test [TMT]‐A/B and Stroop Test) and memory (i.e., Free and Cued Selective Reminding Test [FCSRT]‐immediate and delayed free recall, Corsi Supraspan, and Rey‐Osterrieth Complex Figure‐delayed recall) tests.

Patients with short disease duration (n = 15) had even more significant associations relative to patients with longer duration. More precisely, they showed significant linear correlations in widespread brain regions between amyloid‐b burden and cognition in attentional‐executive (i.e., Attentional Matrices, Raven’s Coloured Progressive Matrices, TMT‐A/B) and memory (i.e., Babcock Short Tale‐immediate/delayed recall, FCSRT‐immediate free recall, and Corsi Supraspan) tests.

Conclusion

In young‐onset MCI we found a linear relationship between amyloid‐b deposition and cognitive performance, which is more evident in patients with shorter disease duration. Our results contribute to identifying which cognitive tests are most sensitive to amyloid‐b deposition in the initial stages of dementing diseases.
Cortical Structure of left superior parietal cortex is associated with cognition and dual tasking: a cross‐sectional study of mild cognitive impairment
Authors: Zhang Siyun
Published: January 2025

Background

Individuals with mild cognitive impairment (MCI) commonly exhibit alterations in cortical structures accompanied by a mild decline in cognitive function. While the dual‐task paradigm is utilized for MCI detection, its cortical mechanism remains incompletely understood. This study seeks to explore cortical structural changes and cognitive decline using the dual‐task paradigm in individuals with MCI.

Method

Thirty participants with MCI and thirty healthy controls (HC) were recruited. Magnetic resonance imaging (MRI), cognitive assessments and dual‐task Timed Up and Go (TUG) test were performed. Cortical morphological parameters of cerebral cortical thickness and surface area were computed using Freesurfer software. Correlations analyses were then performed to assessment the relationship between cognitive, motor performance and morphological measures.

Result

The execution time of the dual‐task TUG significantly increased in MCI group, and was negatively correlate with the WAIS Digit Span Forward and Backwards test, total Montreal cognitive assessment (MoCA) score, and its delayed recall subdomain. At the whole brain level, the surface area in left superior parietal cortex (SPC) was significantly reduced in MCI group. No between‐group significant variation was found in cortical thickness was observed. The surface area of the left SPC was positively correlated with total score of the MoCA and its delayed recall subdomain. In the HC group, the cortical thickness was positively correlated with total score and its attention subdomain. Negative correlation between cortical thickness and dual‐task TUG test was also observed.

Conclusion

Individuals with MCI showed decline in attention, short‐term memory, inhibitory control ability and dual‐task performance. The observed structural alterations in the left SPC suggested potential distinctions in this region, which may be associated with cognitive processes and the cognitive demands related to locomotion. This study provides additional evidence supporting the role of the left superior parietal cortex in cognitive and locomotor function in individuals with MCI.
Elevated iron levels in Alzheimer’s disease brain was partially due to increased cytosolic expression of hemoglobin in neurons
Authors: Roberts Blaine Russell , Mukherjee Soumya , Roberts Anne M , Platt Madison E , MacLean Catriona , Bush Ashley I. , Birchall Ian , Masters Colin L.
Published: January 2025

Background

A better understanding of the molecular process that drive Alzheimer’s disease(AD) are required to develop effective biomarkers and therapies. This includes determining how essential elements like Fe, Cu and Zn are involved in the disease. In the literature there is debate over the role of iron in AD and there are reports of increased, decreased and unchanged levels of Fe in AD brain. Most of the studies have use a standard bulk analysis of Fe in brain tissue. However, this does not yield the necessary molecular information required to determine how the metalloenzymes that utilize Fe are affected in the disease.

Method

We used a combination of biochemical fraction and size exclusion inductively coupled plasma mass spectrometry to conduct a metalloproteomics analysis of post mortem human brain tissue from control and Alzheimer’s Disease cases.

Result

We observed a significant increase in a single iron containing protein. We used bottom up proteomics and purification to determine the protein was hemoglobin. We further confirmed increase expression of hemoglobin and the binding partner haptoglobin in neurons using immunoshitochemistry. We also use RNAscope to show that neurons express the MRNA for both hemoglobin and haptoglobin which was surprising as these are classic blood proteins.

Conclusion

These results clarify that changes in iron proteins do occur in AD brain and open up a new area of research to understand the role of hemoglobin and haptoglobin in neuronal function.
A CAN‐PROTECT study: The effect of self‐reported and study partner‐reported mild behavioral impairment on quality of life in older adults without dementia
Authors: Warring Ibadat , Guan Dylan X. , Ismail Zahinoor , Smith Eric E.
Published: January 2025

Background

Mild behavioral impairment (MBI) is a syndrome that leverages neuropsychiatric symptoms that emerge in later‐life, and which persist, to identify individuals at high‐risk for incident dementia. Attendant with MBI are changes in quality of life (QoL), which can present concurrent with the onset of cognitive decline or even before. Obtaining information from participants and study partners can provide a broader overview of health and QoL. We investigated the relationship between MBI and QoL in dementia‐free older adults, incorporating both self‐ and study partner reports.

Methods

Data (n = 608) are from the CAN‐PROTECT study. MBI status (±) was determined with a MBI Checklist cut‐off score ≥8 based on self‐ or study‐partner report, resulting in a four‐level categorical variable of MBI positivity/negativity (S‐/SP‐[concordant MBI‐], S+/SP‐[discordant MBI S+], S‐/SP+[discordant MBI SP+], S+/SP+[concordant MBI+]). QoL was assessed using the self‐ and study‐partner‐reported EQ‐5D (higher scores reflecting poorer QoL). Linear regression modelled associations between MBI status (exposure) and EQ‐5D total score (outcome), adjusted for age, cognition, sex, education, ethnocultural origin, marital status, employment status, high blood pressure, diabetes, and heart disease. A sensitivity analysis removed EQ‐5D affective symptoms.

Results

Participants (mean age = 64.8±7.1, 77.0% female) had mean self‐reported scores of 4.6±6.7 for MBI and 6.7±1.8 for EQ‐5D. Study partners reported mean scores of 3.7±5.8 for MBI and 1.4±0.4 for EQ‐5D. Distribution of MBI status was 71.9% for concordant MBI‐, 13.3% for discordant S+, 8.3% for discordant SP+ and 6.6% for concordant MBI+. QoL was poorer in the concordant MBI+ group for self‐reported (b = 2.48, 95% confidence interval [95%CI]: 1.96–3.00, p<.001) (Table 1) and study‐partner reported EQ‐5D (b = 2.63, 95%CI: 2.00‐3.27, p<.001) (Table 2), compared to concordant MBI‐ group. There was a significant association with discordant MBI S+ (p<.001) but not discordant MBI SP+ (p<.81) with self‐reported EQ‐5D. Both discordant groups were significant with study‐partner reported EQ‐5D.

Conclusion

In a mostly cognitively unimpaired community dwelling sample, MBI associations with self‐ and study‐partner‐reported QoL were strongest when MBI symptoms were endorsed by both participants and their study partners. These findings underscore the importance of including study partners brain aging research across the cognitive continuum.
Peripheral Inflammation subgroups in Alzheimer’s disease and related dementias
Authors: Lima Bruna Seixas , Rosa‐Neto Pedro , Phillips Natalie , Borrie Michael , Roncero Carlos Tyler , Lahiri Durjoy , Dori Dvir , Chertkow Howard
Published: January 2025

Background

A growing body of research has focused on inflammation as both a potential biomarker and a risk factor for Alzheimer’s disease (AD). The cytokine Interleukin‐6 (IL‐6) is involved in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. AD has been associated with increased IL‐6 expression in brain, however, increased levels of IL‐6 have also been linked to conditions such as diabetes and hypertension. We examined groups of individuals with AD and related disorders (ADRD) as well as healthy controls to check if elevated levels of IL‐6 (above 1.9 ng/L) were related to the presence of comorbidities.

Methods

We investigated individuals with AD (n = 58); mild cognitive impairment (MCI; n = 139); subjective cognitive impairment (SCI; n = 28); and cognitively unimpaired age matched controls (CU; n = 53). We considered four possible subgroups: Group 0 (defined as individuals with normal IL‐6 levels and without comorbidities that could be linked to elevated IL‐6); Group 1 (individuals with normal levels of IL‐6, despite having comorbidities); Group 2 (individuals with elevated IL‐6 without comorbidities), and Group 3 (individuals with elevated IL‐6 and comorbidities). The comorbidities investigated were hypertension, diabetes, peripheral vascular disease, history of cerebrovascular accident, and rheumatoid arthritis. Logistic regression was used to investigate the relationship between the occurrence of elevated IL‐6, age, sex, history of smoking, body mass index (BMI), Montreal Cognitive Assessment scores (MoCA), nutrition and sleep.

Results

We found individuals with and without elevated IL‐6, and with and without comorbidities in all cohorts (Table 1). We found a significant relationship between elevated IL‐6 and aging in all cohorts (Figure 1a). A significant relationship was also found between elevated IL‐6 and greater BMI (MCI group only; Figure 1b), lower nutrition scores (SCI group only, Figure 1c), history of smoking (AD group only; Figure 2a) and sex, whereby males had more elevated IL‐6 (MCI group; Figure 2b).

Conclusions

We found variation in patterns of peripheral inflammation and other common conditions in aging and ADRD. These variations may reflect different mechanistic groups which might help the understanding of variation in clinical features of ADRD, disease progression and response to different therapeutic interventions.
Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease‐related Aβ pathology
Authors: Mancuso Renzo
Published: January 2025

Background

Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies.

Method

To circumvent these issues, here we collected 138,577 single cell expression profiles of human stem cell derived‐microglia from a xenotransplantation model of AD.

Result

Xenografted human microglia adopt a disease‐associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro‐inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Expression of AD risk genes is distributed over this multi‐pronged response to amyloid pathology. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially.

Conclusion

We have identified multiple transcriptomic cell states adopted by microglia in response to AD‐related pathology, which should be taken into account in translational studies.
Tracing senescence in the Alzheimer’s brain through an eigengene‐based analysis of snRNA‐Seq data
Authors: Dehkordi Shiva Kazempour , Zare Habil , Orr Miranda E.
Published: January 2025

Background

Cellular senescence, which can cause significant changes in morphology, metabolism, and function, is a key contributor to aging and diseases including Alzheimer’s Disease (AD). Accurate biomarker identification is essential for detecting senescent cells. Our research aims at defining gene signatures that encapsulate senescence complexity in the brain. Our previous study, highlighted CDKN2D/p19 as a reliable senescence marker in tau neuropathology. This study advances our approach using a new snRNA‐Seq dataset.

Method

We evaluated snRNA‐Seq data from 92 postmortem brains (PMID: 37774680) to validate senescent cell types, utilizing the transcriptional profiles of around 414,000 cells. We used an eigengene‐based approach, where an eigengene is a weighted average expression of genes that summarizes biological signatures with minimal loss of information (PMID: 28298217). Using established weightings from our prior research (PMID: 35531351), we inferred eigengenes indicative of senescence in this dataset. We also recalculated eigengenes for key senescence pathways ‐ the canonical senescence pathway (CSP) which reflects cell cycle arrest, the senescence initiator pathway (SIP) indicating cellular damage and stress, and the senescence response pathway (SRP) representing the toxic senescence‐associated secretory phenotype (SASP) ‐ and assessed the overlap of senescent cells using statistical tests.

Result

Using eigengenes inferred from our previous study, we confirmed that excitatory neurons significantly expressed CSP and SIP signatures in the new dataset. Additionally, microglia and vascular cells in CSP, inhibitory neurons in SIP, and astrocytes and vascular cells in SRP showed significant enrichment (Fig. 1a‐c). Recalculation of eigengenes supported these findings by returning the enrichment of exact cell types within each pathway, demonstrating the method’s robustness in identifying senescent cell types. Furthermore, a substantial number of cells showed overlapping senescence signatures across the CSP, SIP, and SRP (Fig. 2), confirming consistency between inference and recalculated eigengenes.

Conclusion

Our findings validate a computational strategy for detecting senescent cells via eigengene analysis. Consistent identification of senescent cell signatures between inferred and recalculated eigengenes across neural and vascular cells confirms the accuracy of our methods. This approach may direct AD therapeutic development by pinpointing precise senescent cell targets, and uncover new biomarkers of brain cell senescence.
Plasma Aβ42/Aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer’s disease
Authors: Rissman Robert A
Published: January 2025

Background

Our data from several clinical trials of individuals with asymptomatic AD demonstrates that plasma Aβ42/40 quantification by mass spectrometry can serve as a reliable biomarker for predicting elevated brain amyloid as detected by PET. We investigated how adding plasma p‐tau measures to our plasma Aβ42/40 algorithm to streamline identification of eligible participants and reduce burden and trial cost. To determine if the addition of plasma p‐tau181 and/or p‐tau217 concentrations can improve plasma Aβ42/40 algorithms to correctly identify participants with amyloid burden of >20 centiloids with the NAV4694 tracer among individuals screening for participation in the AHEAD preclinical AD trial.

Method

Plasma amyloid and tau were measured using C2N Diagnostics mass spectrometry. Participant samples (N = 1085) collected prior to the incorporation of plasma Aβ42/40 testing during screening were used. Plasma samples consisted of those with adequate amyloid PET levels (n = 364; 33%) to be eligible for AHEAD and those who did not and screen failed (n = 747; 67%). We quantified Aβ (Aβ42/40) and tau species, including the phosphorylated (p‐tau) and non‐phosphorylated (np‐tau) forms of tau181 and tau217. A ratio of p‐tau to np‐tau was calculated (p‐tau181r and p‐tau217r) to normalize inter‐individual differences in np‐tau. We conducted Receiver Operating Characteristic (ROC) curve analyses fagainst amyloid PET status (>20 centiloids). We fit a Mixture of Experts model and included p‐tau181r and p‐tau217r in the predictive algorithm (Aβ42/40, Age and APOE) for amyloid PET status.

Result

Plasma samples from N = 1085 composed of 67% Female, 13.5% Hispanic, 3.7% Black or African American with a mean age of 67.6 (SD = 6.1) years. 45% of participants had at least one APOE4 allele. The Area Under the Curve (AUC) for Aβ42/40 was 0.87 (95% CI; 0.84, 0.89), consistent with prior reports. For plasma tau, we found AUCs of 0.74 (95% CI; 0.71, 0.77) with p‐tau181, to 0.91 (95% CI; 0.90, 0.93) with p‐tau217r. The model including covariates p‐tau217r, Aβ42/40, Age and APOE improved AUC to 0.95 (95% CI; 0.93, 0.96).

Conclusion

Our data suggests that plasma p‐tau217r in addition to Aβ42/40 ratio can significantly improve anti‐amyloid clinical trial screening burden and timelines for recruitment.
C9orf72 repeat expansions increase risk for secondary symptom development in amyotrophic lateral sclerosis and behavioral‐variant frontotemporal degeneration
Authors: Spencer Barbara E , Xie Sharon X , Elman Lauren , Quinn Colin , Amado Defne A , Baer Michael , Lee Eddie B , Van Deerlin Vivianna M , Dratch Laynie , Massimo Lauren , Irwin David J , McMillan Corey T
Published: January 2025

Background

In amyotrophic lateral sclerosis and behavioral‐variant frontotemporal degeneration, the presence of secondary cognitive‐behavioral or motor symptoms, respectively, is associated with shorter survival. However, factors influencing the risk of secondary symptom development remain largely unexplored and time‐to‐event characterization for developing secondary symptoms is important for prognostic clinical decision‐making.

Method

We performed a retrospective evaluation of the entire disease course of individuals in the Penn Integrated Neurodegenerative Disease Database with a primary clinical phenotype of amyotrophic lateral sclerosis (n = 173) or behavioral‐variant frontotemporal degeneration (n = 69). All individuals were evaluated for C9orf72 expansions (>30 repeats). Only individuals who had neuropathological confirmation of a TDP‐43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or primary clinical phenotype.

Result

Binary logistic regression and Cox proportional hazard analyses revealed increased odds (odds ratio = 4.26 [1.98‐9.18]; p<0.001) and an increased hazard (hazard ratio = 4.79 [2.33‐ 9.82], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Primary phenotype, age at symptom onset, and sex were not associated with risk for secondary symptom development.

Conclusion

These findings highlight the need for clinician vigilance to detect the onset of secondary cognitive‐behavioral and motor symptoms in patients carrying a C9orf72 repeat expansion, regardless of primary phenotype, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.
Deletion of α5 integrin in endothelial cells ameliorates age–associated cognitive decline and increases survival in mice
Authors: II Gregory W Hall , Ismael Saifudeen , Bix Gregory J
Published: January 2025

Background

Levels of inflammatory components gradually rise in tissues and blood as we age. This “inflammageing” process is often debilitating and even fatal. Cognitive impairment is one example of inflammageing’s incapacitating nature. Excessive permeation of inflammatory markers in the brain gradually erodes the blood‐brain barrier (BBB) over time. Consequently, enhanced cerebral inflammatory processes contribute to neurological senescence. Neurological inflammageing may be partly due to α5 integrin, a receptor found primarily in brain endothelial cells during brain development, cerebrovascular injury (e.g. stroke), neuroinflammation and neurodegenerative disease (e.g. ALS). We hypothesize that deletion of α5 integrin in endothelial cells helps maintain BBB integrity and leads to improved cognitive performance with age. In the past we have shown that endothelial cell selective α5 knockout (α5‐EC‐KO) mice are more resilient to ischemic stroke. Enhanced stroke recovery in α5‐EC‐KO mice is due to less α5‐related BBB deterioration and subsequently less brain edema and infiltration of peripheral inflammatory cells. Therefore, we used aged α5‐EC‐KO and wild type (WT) litter mate mice to investigate how α5 integrin influences cognitive performance and survival probability over time.

Methods

25‐32‐month‐old male and female α5‐EC‐KO mice and aged‐matched WT mice were used in the study. Cognitive function was analyzed using Y‐maze and open field. Additionally, Kaplan Meier curves were used to assess probability of survival.

Results

For Y maze, results indicate a trend towards greater alteration rate and total alteration for α5‐EC‐KO mice. Open field test shows greater center time and less peripheral time for α5‐EC‐KO. WT and α5‐EC‐KO mice have nearly identical mean speed. Additionally, Kaplan‐Meier curves indicate a greater probability of survival for α5‐EC‐KO mice between the ages of 26 to 30 months. Interestingly, 26‐30 months is the average life expectancy of a lab mouse.

Conclusions

Observations from Y maze and open field tests suggest that α5‐EC‐KO mice have improved spatial memory and less anxiety behavior when compared to aged‐matched WT mice. Moreover, the Kaplan‐Meier curves depict a greater probability of survival for aged α5‐EC‐KO mice. Thus, α5 integrin expression may significantly influence age‐related cognitive decline. Preliminary data suggests that inhibition of α5 integrin may improve symptoms of age‐associated cognitive impairment.
The pTau217 interactome in human Alzheimer’s disease brain tissue from APOE3 and APOE4 carriers
Authors: Kavanagh Tomas , Ponce Jackeline , Thierry Manon , Ueberheide Beatrix , Wisniewski Thomas , Drummond Eleanor
Published: January 2025

Background

Hyperphosphorylated tau (pTau) in Alzheimer’s disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated on up to 55 epitopes. Emerging studies suggest that phosphorylation of specific epitopes may alter the role of tau. The role of specific pTau species can be explored through protein interaction (“interactome”) studies. These provide knowledge about the role of individual pTau species and critical context for tau‐focused biomarker and drug‐discovery studies. The aim of this study was to analyse the interactome of pTau217, which biomarker studies suggest is one of the earliest accumulating tau species in AD.

Methods

pTau217 interactors were identified in fresh‐frozen human brain tissue from 10 cases of advanced AD using affinity purification‐mass spectrometry. Cases were balanced for ApoE ε3/ε3 and ε4/ε4 genotypes (n = 5 each) to explore if ApoE influences pTau protein interactions. Results were compared to our previous pTauS396/S404 interactome dataset generated using the same cases to determine if individual pTau species have different interactomes.

Results

579 proteins were significantly enriched by pTau217 co‐immunoprecipitation in comparison to control IgG (p < 0.05; fold change >1.5). Of these, 23 proteins were identified as bona fide pTau217 interactors (SAINT score > 0.65), including known pTau interactors SQSTM1 and ubiquitin. Phosphorylation analysis of tau enriched by pTau217 vs pTau396/S404 co‐immunoprecipitation confirmed enrichment of a different pools of tau, with pTau217 displaying fewer phosphorylated epitopes, hinting that pTau217 may be an earlier generated species. Despite these differences, 15 bona fide pTau217 tau interactors also interacted with pTauS396/S404 suggesting close similarities in interactomes (Fisher’s exact p = 2.3 × 10‐14). Common interactors notably included five subunits of an E3 ubiquitin ligase not previously been linked to tau or AD. 46 and 28 pTau217 interactors were identified in ApoE ε3/ε3 and ApoE ε4/ε4 cases respectively and these significantly overlapped (16 common interactors; Fisher’s exact p = 4.3 × 10‐24).

Conclusions

pTau217 interacts with many similar proteins to pTauS396/S404. Our results highlight a strong interaction between multiple pTau species and a novel E3 ubiquitin ligase, which may have an important role in AD and potentially tau degradation.
Disrupted Sleep at Night Is Associated with a Higher Level of Agitation Throughout the Week in People Living with Cognitive Decline
Authors: Au‐Yeung Wan‐Tai M. , Miller Lyndsey M. , Lindauer Allison , Beattie Zachary T , Mattek Nora , Steele Joel S. , Kaye Jeffrey A
Published: January 2025

Background

Agitation is one of the most challenging behaviors exhibited by people with cognitive decline, causing distress in caregivers, earlier placement into long‐term care and faster disease progression. In order to better manage agitated behaviors in people with cognitive decline, it is important to identify associated factors. The MODERATE (Monitoring Dementia‐Related Agitation Using Technology Evaluation) study aims to characterize agitation using technology and identify precipitants (behavioral or environmental) of agitation.

Method

People living in the greater Portland, Oregon, USA area were recruited into the study. The inclusion criteria were a diagnosis of mild cognitive impairment or dementia, currently residing with a family caregiver within their own home, and caregiver endorsement of symptom(s) of agitation, irritability/lability, motor disturbance, nighttime behaviors and/or disinhibition in the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q). Bed pressure mats (Emfit) were deployed as part of the ORCATECH platform in their homes, which measure participants’ sleep behaviors and their physiological signals through ballistocardiography. The weekly agitation levels of the participants were reported by their family caregivers through modified Cohen‐Mansfield Agitation Inventory‐Short Form questionnaires as part of weekly online surveys.

Result

Data from the first 8 participants (mean age(SD) = 70 (10)) with bed pressure mats were analyzed. A subset of bed pressure mat outputs was selected to provide a holistic picture of participants’ sleep behaviors and their physiology while avoiding multicollinearity. Monitoring period was for a mean (SD) of 315 (190) nights. An individual mixed linear model was built with each included bed pressure mat output and week as the predictors and total agitation level as the model output. After false discovery rate correction, higher duration of wake after sleep onset was a significant predictor of their weekly total level of agitation. The caveats of these results include small sample and varied follow‐up time ranging from 4‐85 weeks of observations per participant.

Conclusion

Disrupted sleep (measured objectively by bed pressure mat) are positively associated with participants’ weekly level of agitation. Future work with larger sample sizes is needed to confirm findings. Unobtrusive identification of behavioral factors associated with agitation can potentially help manage this challenging behavioral symptom.
Association between mediterranean‐like diet, longitudinal cognitive decline, and medial temporal atrophy over time in cognitively unimpaired older adults with or without SCD
Authors: Kuhn Elizabeth , van Lent Debora Melo , Stark Melina , Kleineidam Luca , Yakupov Renat , Peters Oliver , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Düzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Jessen Frank , Wagner Michael ,   for the DELCODE study group
Published: January 2025

Background

Previous findings evaluating longitudinal cognition in relation to the MeDi diet are inconsistent, and few studies have examined it in relation to the presence/absence of subjective cognitive decline (SCD). Our current aims are to test whether adherence to the MeDi diet is associated with the risk of clinical progression, future cognitive decline, and atrophy over time in Alzheimer’s disease (AD)‐sensitive regions in cognitively unimpaired (CU) older adults with or without SCD.

Methods

This longitudinal study includes 171 controls and 228 SCD patients recruited from memory clinics in the DELCODE study. All participants underwent serial neuropsychological assessments and MRI scans for up to 7 years, and had available MeDi adherence scores based on the clustered Food Frequency Questionnaire (range: 0‐9). Clinical progression to incident‐MCI status was determined by consensus diagnosis, global cognitive decline was assessed using the PACC5 cognitive composite, and medial temporal lobe (MTL) gray matter volume was estimated using the Freesurfer longitudinal pipeline. We used multivariate Cox regression and linear mixed‐effects modeling to address our objectives. Gray matter volumes were corrected for total intracranial volume, and all analyses were adjusted for demographics.

Results

In SCD patients, we found that higher adherence to the MeDi diet was associated with a lower risk of clinical progression to incident‐MCI (Fig. A2), and less global cognitive decline (Fig. B2), and MTL atrophy over time (Fig. C2; mainly driven by less parahippocampal and amygdala atrophy). Higher adherence to the MeDi diet was also associated with better baseline cognition and MTL volumes in these patients. This was not significant in the HC group (Fig. A1‐C1), possibly because they experienced less cognitive decline over time than the SCD group (both p<0.001; not significant for MTL atrophy). Further adjustment for kcal intake, body mass index, and physical activity yielded similar results, although sometimes only at trend levels.

Conclusion

In SCD patients seeking medical help, better adherence to a MeDi diet pattern may reduce future cognitive decline and MTL atrophy. These novel data provide a rationale for dietary intervention studies in this population, and support counseling SCD patients on the benefits of MeDi (and other lifestyle factors) for cognitive health.
Abnormal cortical neural synchronization mechanisms in quiet wakefulness in patients with Symptomatic Huntington and Dementia due to Alzheimer’s disease
Authors: Jakhar Dharmendra , Tucci Federico , Noce Giuseppe , Lopez Susanna , Lizio Roberta , Percio Claudio Del , Carpi Matteo , Salamone Enrico Michele , Güntekin Bahar , Yener Görsev , De Tommaso Marina , Delussi Marianna , Babiloni Claudio
Published: January 2025

Background

Huntington’s disease (HD) is a progressive neurodegenerative disorder phenotypically manifested by motor, cognitive and psychiatric symptoms (Novak and Tabrizi, 2011). These patients are also characterized by vigilance abnormalities. This has been demonstrated by electrophysiological measures (Wiegand et al., 1991). In particular, previous studies have shown that HD patients have reduced alpha amplitude (de Tommaso et al., 2003; Bellotti et al., 2004) and increased resting delta activity (Bylsma et al., 1994). These electroencephalographic changes resemble those observed in patients with Alzheimer’s dementia (Babiloni et al., 2020). To date, there have been only a few studies on the specific pathophysiological changes that are the cause of the above changes in brain rhythms. In our opinion, the comparison of these two populations could be an enrichment of the physiological model that explains the electroencephalographic changes that have been observed in HD patients.

Method

Clinical and EEG datasets in 21 ADD (Dementia due to Alzheimer Disease), 16 S‐HD (Symptomatic Huntington Disease) and 39 Healthy (Nold) individuals matched for demography, education, and gender were taken from an Eurasian database. The rsEEG frequency bands were individual delta, theta, alpha as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz). The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions.

Result

As core findings, we have showed that global delta source activities (and central, parietal, and occipital delta source activity) are significantly greater in S‐HD than in ADD (p<0.05 Bonferroni corrected) and that frontal and temporal alpha 2 source activities are significantly lower in S‐HD than in ADD (p<0.05 Bonferroni corrected) Showed in Figure 1.

Conclusion

The present findings showed more abnormalities in delta source activities in HD patients if compared to the ADD patients, possibly related to an abnormal functioning of dopaminergic ascending neuromodulation of basal ganglia in HD subjects. Moreover, the HD peculiar alterations in alpha source activities could be related to more alterations in the cholinergic system impinging upon basal ganglia if compared with ADD patients.
Diversity in Sociodemographic and Linguistic landscape: Perspectives from Chinese American, Mexican American, and Indian Cohorts
Authors: Tee Boon Lead , Alladi Suvarna , Thanissery Nithin , Babulal Ganesh M. , O'Bryant Sid E. , Petersen Melissa , Allen Isabel Elaine
Published: January 2025

Background

Nearly half the world’s population is bi‐ or multilingual, where diverse interpretations of bilingualism with varying associated sociodemographic factors may lead to inconsistent conclusions in bilingualism and cognitive research and thus our study aimed to further examine this.

Method

We examined the sociodemographic features and bilingualism phenotypes among monolingual and bilingual individuals across three cohorts: Chinese American (CA) from UCSF Memory and Aging Center (n = 517), Mexican American (MA) from HABS‐HD project (n = 1,166), and Indians (ID) from National Institute of Mental Health and Neuroscience (NIMHANS) (n = 1,233), encompassing individuals with normal cognition, mild cognitive impairment (MCI), and Alzheimer’s dementia (AD). We compared group differences between monolinguals and bilinguals via Student’s t‐test for continuous variables and with Pearson’s Chi‐squared test for categorical variables. Group comparison of bilingualism phenotypes across cohort were analyzed using ANOVAs for continuous variables (with Bonferroni correction for multiple comparisons).

Result

Educational disparities were significant between monolinguals and bilinguals across all cohorts (all p<0.001), with the exception of MCI (monolinguals: 8 ±1.8 years, bilinguals: 9.6 ±6.3 years, p = 0.104) and AD groups (monolinguals: 4.4 ± 6.7 years, bilinguals: 5.5 ± 6.1 years, p = 0.722) at NIMHANS. Notably, a greater prevalence of illiteracy among monolinguals emerged in the NIMHANS (monolinguals: 10%, bilinguals: 2%, p<0.001) and HABS‐HD cohorts (monolinguals: 4%, bilinguals: 2%, p = 0.034), a trend absent in the UCSF group (monolinguals: 0%, bilinguals: 0%). In HABS‐HD, monolinguals with normal cognition (p<0.001) or MCI (p = 0.019) resided in neighborhoods with greater deprivation, whereas those in NIMHANS control group indicated lower socioeconomic status in monolinguals (p<0.001), a distinction not found in UCSF. Additionally, bilinguals in the UCSF CA and NIMHANS ID cohorts were observed to speak a greater number of languages (p<0.001) that largely belonging to different language families. Naturally, when examining the maximum spoken language distance of bilingual participants, UCSF CA and NIMHANS ID bilinguals had significantly higher language distances compared to bilinguals in the HABS‐HD cohort (p<0.001).

Conclusion

These findings emphasize the diverse bilingualism phenotypes and associated sociodemographic factors within distinct populations and underscore the imperative need for a comprehensive characterization of language history in bilingualism research.
The role of impaired oxidative base lesion repair in Alzheimer’s disease
Authors: Egiazarian Milena A , Abentung Andreas , Sakshaug Teri S , Karabeika Emily E , Hanumaihgari Priyanka R , Grøntvedt Gøril Rolfseng , Sando Sigrid B , Bjørås Magnar , Scheffler Katja
Published: January 2025

Background

Accumulation of oxidative DNA damage and its inefficient repair is a contributing factor to Alzheimer’s disease (AD), yet the underlying mechanism remains largely unknown. Novel AD mouse models deficient for oxidative DNA damage repair were developed and characterized to better understand their impact on AD progression. In addition, vascularized cerebral organoids from AD patients were generated to translate findings to a human model of AD.

Method

AD mice deficient for oxidative DNA repair enzymes were collected at different ages and amyloid β (Aβ) accumulation quantified by enzyme‐linked immunosorbent assays and immunostaining. Astrocytes and microglia numbers were quantified by immunostaining and inflammatory responses determined by gene expression analyses. DNA damage was measured by mass spectrometry and immunostaining of DNA damage marker. Behavioral analyses were performed to assess cognitive function. Cerebral organoids were fused with vessel organoids generated form AD patients and healthy controls. Vascularization and AD pathology was determined by immunostaining of specific vessel marker and mesoderm‐derived microglia, and Aβ and neuronal marker, respectively.

Result

Aβ accumulation was significantly altered upon loss of oxidative DNA repair in AD mice in an age‐ and sex‐dependent manner. Microglia and astrocyte number changed significantly during disease progression and were either reduced or increased dependent on the oxidative DNA repair enzyme deficiency and sex of the mice. Level of DNA damage in the brain was only moderately increased or not affected. Cognitive function was significantly impaired in AD mice deficient for oxidative DNA repair enzymes. Cerebral organoids fused with vessel organoids developed vascular structures and showed integration of microglia cells. Aβ accumulated specifically in AD patient‐derived organoids compared to healthy controls and showed signs of neurodegeneration.

Conclusion

The repair of oxidative DNA damage is critical for processes associated with AD pathogenesis, in particular neuroinflammation and important to maintain cognitive function. AD patient‐derived vascularized cerebral organoids are immunocompetent and recapitulate AD pathology which will be advantageous to translate findings from mice to humans.
Multiple pathological mechanisms of Bin1 for tau aggregation and propagation
Authors: Tomita Taisuke
Published: January 2025

Background

Recent genome‐wide association analysis has identified Bridging Integrator 1 (BIN1) as one of the genetic risk factors for late‐onset AD. In AD patients, single nucleotide polymorphisms in BIN1 correlate well with tau pathology, suggesting the involvement of BIN1 in the formation and propagation of tau accumulation pathology, but the molecular mechanism and point of action remain unclear.

Method

To comprehensively clarify the effects of BIN1 on two pathological events, tau aggregation and propagation, we analyzed BIN1 knockout mice.

Result

Using transgenic mice and seed injection model, we found that BIN1 knockout facilitated the cell‐autonomous tau accumulation in neurons but reduced the tau pathology induced by extra‐neuronal tau seeds. In the primary neuron‐glia co‐cultures, but not neuronal cultures, BIN1 knockout accelerated the degradation of the extracellular tau seeds. The present study suggested that BIN1 has different effects on tau metabolism in neurons and glial cells; the loss‐of‐function of BIN1 promotes the aggregation and accumulation in neurons, while BIN1 knockout enhanced the degradation mechanism of tau in glial cells.

Conclusion

The present study implicates that BIN1 has different effects on tau metabolism in neurons and glial cells.