bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep experiences and longitudinal brain changes in cognitively normal older adults
Authors: Choi Jung‐Min , Byun Min Soo , Yi Dahyun , Jung Joon Hyung , Sohn Bo Kyung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Lee Dong Young ,   KBASE Research Group
Published: January 2025

Background

Disturbed sleep has been associated with Alzheimer’s disease (AD) dementia. Nevertheless, limited information is yet available for the relationship between sleep experiences and longitudinal changes of brain pathologies related to AD. This study aimed to investigate the association between late‐life sleep experiences and the prospective changes of in vivo AD pathologies and cerebrovascular injury over 2 years in cognitively normal (CN) old adults.

Method

A total of 225 CN older adults who participated in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) study between 55 and 90 years of age were included. All participants were also systematically interviewed using a structured interview form to determine sleep duration and subjective sleep quality at baseline. All of them underwent a comprehensive clinical assessment, [11C] Pittsburgh Compound B positron emission tomography (PET), [18F]fluorodeoxyglucose (FDG)‐PET, and magnetic resonance imaging at baseline and 2‐year follow‐up. A subset of participants (n = 44) also underwent [18F]AV‐1451 PET at baseline and 2‐year follow‐up. All analyses were adjusted for age, gender, education, apolipoprotein E ε4 status, vascular risk score, Hamilton Depression Rating Scale score, and use of sleep medication.

Result

Poor sleep quality at baseline was significantly associated with both higher baseline global Aβ retention and its longitudinal increase over 2 years, but not with other AD neuroimaging markers including tau deposition, AD‐related neurodegeneration, and white matter hyperintensity (WMH) volume. There was no significant relationship of sleep duration with any AD neuroimaging markers and WMH volume.

Conclusion

Our findings suggest that poor sleep quality in late life may predict or contribute to prospective increase of brain amyloid deposition in the near future.
A nano‐ to microscale, complex and multifactorial computational model of Alzheimer’s disease
Authors: Duchesne Simon , Chamberland Éléonore , Moravveji Seyedadel , Doyon Nicolas
Published: January 2025

Background

While individual etiological hypotheses for AD are researched, few large‐scale theoretical integrative efforts linking entities involved in these dysfunctions have been attempted. Experimentally, assessing such a global theory is logistically near impossible to achieve as the number of variables is substantial. Alternatively, computational neuroscience allows for the joint study of multiple entities at this scale, the generation of predictions, and their validation with real data. In this work, we present a theoretical computational model describing the progression of AD through an individual’s lifespan covering more than 50 different entities.

Method

Our computational model is a system of 19 ordinary differential equations (cf. Figure 1). The equations describe the evolution of proteins at the nanoscale (Aβ monomers, oligomers and plaques; tau filaments and tangles, anti‐inflammatory cytokines, insulin) and cell populations at the microscale (neurons, astrocytes, macrophages, microglia). Equations were parametrized according to sex and APOE status, and initial conditions chosen from the literature. Our key outcomes of interest were the accumulation of recognized pathological markers of AD (Aβ monomers or plaques, tau filaments or tangles) and neuronal death. The model was solved in daily increments over a 50‐year lifespan.

Results

The evolution of every variable of our model is shown in Figure 2. For the different forms of amyloid, the curves for APOE4‐negative men and women mostly overlap. This is also observed for APOE4‐positive individuals. However, it is important to note that despite the overlap, there are noticeable variations in the curves between different groups. Neuronal loss occurs earlier in individuals with an APOE4 allele regardless of sex. We obtain losses of 10.9% and 11.7%, for APOE4‐ and APOE+ women respectively, and of 10.9% and 12.1% for APOE4‐ and APOE4+ men respectively, which are commensurate with the literature. We also observe a transition to a proinflammatory state occurring around 50 years of age, with women who are APOE4+ experience this transition earlier, followed by APOE4+ men, APOE4‐ women, and finally APOE4‐ men.

Conclusion

Computational models represent an essential initial step toward constructing a complex, predictive framework, and hold significant potential for identifying effective therapeutic targets in the fight against AD.
Prospective Study of Endogenous Estrogen History and Cognitive Decline in the Nurses' Health Study
Authors: Juramt Namuunaa , Kang Jae H. , Wang Dong D. , Vyas Chirag M. , Peng Cheng , Curhan Sharon , Warner Erica T. , Zeleznik Oana A. , Rosner Bernard A. , Wang Molin , Stampfer Meir J. , Okereke Olivia I. , Eliassen A Heather
Published: January 2025

Background

Endogenous estrogen history across the life course may be associated with better cognitive maintenance. Few large longitudinal studies have evaluated this prospectively, and results have been inconsistent. We assessed the association of reproductive span, an indicator of endogenous estrogen history, with cognitive change in older women.

Method

We followed 13,419 Nurses’ Health Study participants who were free of stroke, were ≥70 years old as of 1995‐2001, reported natural menopause or bilateral oophorectomy and had information on ages at menarche and menopause. Reproductive span was defined as age at menopause minus age at menarche. Four telephone‐based cognitive assessments were administered (at 1.5‐2 year intervals). The primary outcome was the global composite score, averaging z‐scores of 6 tests measuring general cognition (the Telephone Interview of Cognitive Status, TICS), verbal memory, category fluency, and attention. Linear mixed‐effects models, adjusted for age, education, depression, menopausal hormone therapy (MHT) within 10 years of menopause, surgical menopause, and other lifestyle and health variables, were used to estimate the differences in annual rate of change over time by quintiles (Qs) of reproductive span. We examined interactions with menopause type, MHT duration and apolipoprotein E (APOE) e4 allele (among 5,434 women).

Result

The mean baseline age was 74.3 years, the mean follow‐up was 6.6 years, and the mean reproductive span was 36.4 years (range = 7‐46 years). Longer reproductive span was significantly associated with more favorable cognitive change: compared with women with the shortest reproductive span (Q1: ≤33 years), women with the longest reproductive span (Q5: ≥41 years) demonstrated better maintenance in global cognition (difference in annual rate of changeQ5vs.Q1 = 0.007; 95% CI: 0.00001, 0.01; p‐trend = 0.02); this difference was equivalent to that observed in women 1.4 years apart in age. We observed similar trends with TICS and verbal memory (p‐trends≤0.04), but not category fluency (longer reproductive span was associated with better baseline performance, p≤0.01; but not differences in rates of decline) and attention (no associations found). We observed no interactions with surgical menopause, MHT, or APOE e4.

Conclusion

Longer reproductive span, an indicator of greater endogenous estrogen history, was significantly associated with more favorable cognitive maintenance in older women.
Suboptimal seizure control is associated with increased risk of MCI among Adult Patients with Epilepsy
Authors: Shen Jia Yi , Soh Chirin , Chew Wee Jin , Siew Rachel , Saffari Seyed Ehsan , Koh Pei Xuan , Tan Yee Leng , D/O Srinivasan Sheila , Tan Nigel Choon Kiat , Loh Ngai Kun , Tan Louis CS , Ng Kok Pin
Published: January 2025

Background

Epilepsy is associated with increased risk for dementia, which adversely impacts the quality of life for patients and their families. Mild cognitive impairment (MCI) is the prodromal stage of dementia offering an important window for intervention. However, the epilepsy related risk factors for MCI are not well understood. The ongoing Mild Cognitive Impairment among Adult Patients with Epilepsy (MCAPE) study is a longitudinal study evaluating the prevalence and risk factors for MCI amongst adult patients with epilepsy (PWE). This abstract summarizes the interim findings.

Method

Adult PWE were recruited from outpatient clinics at a tertiary centre, the National Neuroscience Institute, Singapore. Patients with previous stroke, known dementia, or intellectual disability were excluded. Participants underwent a self‐administered questionnaire on their lifestyle risk factors and epilepsy‐specific factors, followed by cognitive testing with the Mini Mental State Assessment (MMSE) and Montreal Cognitive Assessment (MOCA). A MOCA cut‐off of <27 was used to diagnose MCI. Logistic regressions evaluated the associations of clinical risk factors with presence of MCI, corrected for age and education as confounders.

Result

Forty‐six participants were recruited and completed cognitive testing. Twenty‐three participants (50.0%) had subjective cognitive complaints. Cognitive assessment revealed that 16 participants (34.8%) had MCI. Among epilepsy factors, multivariate logistic regression found that a seizure frequency of once a month or more was strongly associated with increased risk of MCI (OR 109, p = 0.004). Epilepsy subtype, duration and use of multiple anti‐seizure medications were not significantly associated with MCI.

Conclusion

This pilot cross‐sectional study showed that MCI is a significant problem among PWE, and that suboptimal seizure control was associated with increased risk of MCI. Prospective studies are need to determine effective interventions to mitigate MCI among PWE.
Utility of two computerized assessments for predicting clinical progression in individuals with early Alzheimer’s Disease
Authors: Schoemaker Dorothee , Atkins Alexandra , Abraham Chelsea , Welch Matthew , Plassman Brenda L , Sickel Nancy , Madsen Corrine , Klein Hans , DiGregorio Danielle T , Welsh‐Bohmer Kathleen A. , Keefe Richard SE
Published: January 2025

Background

Interventional trials in Alzheimer’s Disease (AD) are increasingly targeting early disease stages. To optimize the likelihood of successful outcomes for these trials, there is an important need for tools capable of identifying individuals prone to exhibit clinical progression throughout the course of the trial. The Expanded Brief Assessment of Cognition (Expanded‐BAC) and the Virtual Reality Functional Capacity Assessment Tool – Short List (VRFCAT‐SLx) are two computerized tests assessing cognitive and functional abilities, respectively. They offer automated instructions and scoring, which significantly improves standardization and reduces administration errors. Importantly, they minimize reliance on caregiver availability, which can be a significant barrier to trial participation. The goal of this project was to evaluate the value of the Expanded‐BAC and VRFCAT‐SLx in predicting clinical progression in individuals with early AD.

Method

A total of 51 participants with clinical diagnoses of MCI or early AD (NIA‐AA clinical criteria) completed both a baseline and follow‐up visit including the CDR, Expanded‐BAC, and VRFCAT‐SLx. The mean follow‐up interval was of 9.5 months (SD = 4.7 months). Clinical progression was operationalized as a change of 0.5 or more on the CDR Sum of Boxes score (CDR SoB) over the follow‐up interval. Baseline performance on the Expanded‐BAC and the VRFCAT‐SLx was contrasted between clinical progressors and non‐progressors using ANCOVAs adjusting for follow‐up duration. Linear regression models were computed to assess the predictive value of baseline performance on the Expanded‐BAC and the VRFCAT‐SLx on CDR SoB changes over time, also adjusting for follow‐up duration.

Result

At follow‐up, there were 18 clinical progressors and 33 non‐progressors. The Expanded‐BAC composite score and the VRFCAT‐SLx total adjusted time at baseline significantly differed between progressors and non‐progressors, with progressors showing poorer performance on both measures (Figure 1). In linear regression models, performance at baseline on the Expanded‐BAC (r2 = 0.24, p<0.01) and the VRFCAT‐SLx (r2 = 0.16, p<0.05) significantly predicted changes in CDR SoB over the follow‐up interval.

Conclusion

These preliminary results suggest that performance on the Expanded‐BAC and the VRFCAT‐SLx can predict clinical progression in individuals with early AD. These two computerized tests might thus be useful tools to identify individuals likely to exhibit clinical progression in the course of a trial.
Longitudinal differences in language in middle‐aged and older people with normal cognition, subjective cognitive impairment, and mild cognitive impairment. Results of the Compostela Aging Study
Authors: Facal David , Campos‐Magdaleno Maria , Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Mallo Sabela Carme , Arora Sonali , Fernández‐Feijoo Fátima
Published: January 2025

Background

Language performance has been considered a potential screening tool in the continuum from healthy cognitive aging to cognitive impairment and dementia. Language impairment and most notably impairment in semantic verbal fluency has been shown to increase with the progress in this continuum (Liampas et al., 2023).

Method

The study sample was drawn from the participants of the Compostela Aging Study who completed baseline and two follow‐up assessment, each of them about 18 months after the previous cognitive and neuropsychological evaluation (Pereiro et al., 2021). Sample included 22 persons with uni‐domain mild cognitive impairment (MCI), 20 with multi‐domain MCI, 46 with subjective cognitive decline and 73 cognitively unimpaired participants. Language performance was assessed via Boston naming test, semantic, phonemic and ideational fluency. GLM repeated measures were implemented comparing performance in the three assessments for each of the language measures as a dependent variable, and the diagnostic group as a factor. Age and years of formal education were included as covariates.

Result

A significant interaction between time of assessment and group was only found for the Boston naming test (F = 1.75, p<0.05, η2 = 0,03, B‐1 = 0,53). Age, but not education, was a significant covariate for all the language measures.

Conclusion

Even though language measures could be relevant to detect early changes in cognitive status, these measures has scarcely been studied in recent literature. According to these preliminary analyses of the longitudinal results of our study, the Boston naming test could be a linguistic marker of cognitive changes in late adulthood.

References:

Lampas, I., Folia, V., Morfakidou, R., Siokas, V., Yannakoulia, M., Sakka, P., Scarmeas, N., Hadjigeorgiou, G., Dardiotis, E., Kosmidis, M.H. (2023). Language differences among individuals with normal cognition, amnestic and non‐amnestic MCI, and Alzheimer’s disease. Archives of Clinical Neuropsychology 38, 525. https://doi.org/10.1093/arclin/acac080

Pereiro, A.X., Valladares‐Rodríguez, S., Felpete, A. Lojo‐Seoane, C., Campos‐Magdaleno, M., Mallo, S.C., Facal, D., Anido‐Rifón, L., Belleville, S., Juncos‐Rabadán, O. (2021). Relevance of complaint severity in predicting the progression of subjective cognitive decline and mild cognitive impairment: A machine learning approach. Journal of Alzheimers Disease 82, 3, 1229‐1242. https://doi.org/10.3233/JAD‐210334.
Cholinergic white matter pathways in Alzheimer’s disease, dementia with Lewy bodies, and other neurodegenerative diseases: a post‐mortem MRI study
Authors: López‐González Francisco J. , Nemy Milan , Rabano Alberto , Grothe Michel J. , Sanchez‐Juan Pascual , Ferreira Daniel
Published: January 2025

Background

In‐vivo magnetic resonance imaging (MRI) has recently shown that patients with clinically diagnosed Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) exhibit degeneration of the cholinergic nucleus basalis of Meynert and its white matter (WM) projections through the cingulum and external capsule pathways1. Here, we propose an imaging‐pathologic validation study aimed at investigating cholinergic WM pathways using post‐mortem MRI of autopsy‐confirmed AD, Lewy body dementia (LBD), and other neurodegenerative diseases (OTH).

Method

We included 53 brain donors (34 AD, 10 LBD, and 9 OTH, mainly including frontotemporal lobe degeneration and vascular disease, Table 1). All donors underwent post‐mortem MRI in situ within 5 hours after death and were later subjected to neuropathological examination performed according to published consensus criteria. Post‐mortem MRI examination included 3D T1 structural imaging and diffusion‐weighted imaging acquired using a 3T scanner. Previously established masks of cholinergic WM pathways (i.e., cingulum and external capsule pathways) were transformed from standard MNI space to each individual’s b0 image in native space using the nonlinear SyN registration algorithm. Native space mean diffusivity (MD) maps were estimated for each donor using the FMRIB Diffusion Toolbox from FSL. Microstructural properties of each participant’s cholinergic WM pathway were then estimated by averaging the MD values within the back‐transformed masks in native space. Differences in age‐adjusted MD values between diagnostic groups were analysed using the Mann‐Whitney U‐test.

Result

AD donors were older than LBD donors (p = 0.007), and both groups were older than the OTH group. After adjusting for age, AD showed significantly higher MD values in cholinergic WM pathways when compared with OTH (Cohen’s d = 1.45, p<0.001) and LBD (Cohen’s d = 0.91, p<0.01) (Figure 1). Elevated MD values in LBD compared to OTH did not reach statistical significance in this small sample (Cohen’s d = 0.85, p = 0.11).

Conclusion

We expanded previous in‐vivo MRI findings to post‐mortem MRI and confirmed the degeneration of cholinergic WM pathways in AD. Additionally, we highlighted the difference between AD and LBD donors, with a more severe cholinergic pathway degeneration in AD donors.

References:

1. Schumacher J, et al. Cholinergic WM pathways in dementia with Lewy bodies and AD. Brain. 2022 Jun 3;145(5):1773‐1784.
Neuroinflammation and synapse loss determines the cognitive fate in Alzheimer Disease
Authors: Kumar Sunny , Diez Ibai , Amaral Ana Claudia , Aguero Cinthya , Klein Charles Zachary , Scapellato Margaret , Sinha Riddhimaa , Gomez‐Isla Teresa
Published: January 2025

Background

Some individuals can tolerate the presence of Alzheimer disease neuropathologic changes (ADNC) (e.g., plaques and tangles) without developing dementia. A better understanding of the mechanisms underlying this brain resilience to ADNC may inform the development of novel disease biomarkers and therapies. We investigated the differences in brain changes and gene expression profiles associated with opposite cognitive outcomes (dementia vs. no dementia) in the presence of ADNC.

Methods

We studied postmortem brain samples from 103 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). They all had undergone longitudinal antemortem cognitive assessments. At autopsy, 51 fulfilled neuropathologic criteria for high likelihood of AD (25 demented and 26 cognitively normal ‘resilient’), and 52 fulfilled criteria for low likelihood of AD (26 demented ‘frail’ and 26 cognitively normal ‘controls’). Cases were matched for age, gender, level of education, and co‐pathologies (vascular lesions, Lewy bodies, and TDP‐43 aggregates). Detailed quantitative neuropathological and biochemical assessments and bulk RNA‐seq‐based transcriptomic analyses were conducted in superior temporal and dorsolateral prefrontal cortices.

Results

Demented AD had a similar number of tau tangles compared to resilient but a significantly higher tau neuropil thread burden and soluble hyperphosphorylated tau oligomer levels in synapse‐enriched fractions. The burden of CD68+ microglia was significantly higher in demented AD and frail but not in resilient compared with control brains. Demented AD and frail had a higher loss of synapses than resilient compared with control brains. These differential brain changes paralleled a significant reduction in resilient compared to demented AD in the expression of genes associated with apoptotic, neuroinflammation/response to cytokines, and protein phosphorylation processes. Levels of soluble hyperphosphorylated tau oligomers in synapses and CD68+ microglia burden emerged as the strongest correlates with synaptic densities and antemortem measures of cognition.

Conclusions

These findings suggest that enhanced tau pathology in neurites and synapses may instigate glial inflammatory responses and synapse elimination, determining the cognitive fate of individuals who harbor ADNC.
Domain Specific Age at Onset of Decline in Down Syndrome
Authors: Kennedy James Tyler , Handen Benjamin L , Head Elizabeth , Mapstone Mark , Christian Bradley T. , Ances Beau
Published: January 2025

Background

Individuals with Down syndrome (DS) typically develop Alzheimer’s disease (AD) at an early age. Estimates of the age of decline vary, but typically place it in the early‐mid 50s. As AD onset can be difficult to identify in intellectually impaired cohorts, understanding the expected timing of decline may help individuals and caregivers prepare. It is unclear how timing in changes in different domains relates to the onset of AD dementia.

Method

Data was obtained for individuals with DS (188 total, 53% male), ages 25 to 61, from the Alzheimer’s Biomarker Consortium–Down Syndrome and used in cross‐sectional analyses based on the baseline session. Decline was determined by performance on direct measures of cognition with participants and interviews of caregivers. Diagnosis of AD related decline was arrived at by group consensus. Domain‐specific decline was dichotomized as a stable vs decline binary for Adaptive, Behavioral/Emotional, Cognitive, Interpersonal, Memory, and Psychomotor changes. Consensus and domain‐specific data (Consensus n = 175, 18 declining, Domain n = 186‐187, 21‐60 declining) was available. The association between age and decline was analyzed in logistic generalized additive models (GAM), controlling for sex. Ages where individuals were equally likely to be stable or declining were extracted from GAM models. The relationship between domains/consensus was also examined using tetrachoric correlations. Results were considered significant at a p < .05 following multiple comparison correction.

Result

Age was significantly associated with decline for all measures except the Behavioral/Emotional domain. AD related decline began at age 54, domain‐specific estimates varied: earliest in Memory (49.7) and Cognitive (49.8) and latest in Behavioral/Emotional (64.7). The relationship between age and decline probability was linear except for AD consensus where slope slows at age 44 and the Cognitive measure where slope increases at age 37. Age at decline did not differ between sexes. Correlations ranged from 0.96 (Memory with Consensus) to 0.47 (Consensus with Behavioral/Emotional).

Conclusion

AD decline occurs at the age of 54 and is preceded by a change in cognition and memory ∼4 years earlier. Sex does not affect decline onset. Change in memory and cognition are closely related while behavioral/emotional changes are not strongly associated with AD‐related decline or other domains.
Uncovering the role of cerebrovascular phenotypes in AD through deep multi‐omic molecular profiling of human brains
Authors: D'Oliveira Albanus Ricardo , Aladyeva Ekaterina , Bertucci Taylor , Brase Logan ,   Dominantly Inherited Alzheimer Network (DIAN), Benitez Bruno A. , Sutherland Greg T , Karch Celeste M. , Temple Sally , Harari Oscar
Published: January 2025

Background

The cerebrovasculature is an essential component of brain homeostasis. Cerebrovascular disorders are associated with an increased risk for neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration are poorly understood.

Method

We optimized nuclei isolation from human brains to increase the representation of cerebrovascular cells (CVC) and performed single‐nucleus transcriptomic profiles (snRNA‐seq) of parietal cortex from healthy and AD donors from the Australian Brain Bank Network (ABBN; n = 72 brains), which are richly annotated for cerebrovascular phenotypes, including cerebral amyloid angiopathy (CAA). In parallel, we generated spatially resolved transcriptomic profiles for a subset of these samples. We integrated our new data with seven public snRNA‐seq datasets to create a comprehensive cerebrovascular atlas. Simultaneously, we reprocessed public snATAC‐seq data from cases and controls to identify regulatory elements in CVC likely mediating AD gene risk.

Result

Our cerebrovascular atlas encompassed ∼133K CVC across five major cell types (endothelial, smooth muscle, pericytes, fibroblasts, ependymal). This high resolution allowed the identification of perturbed CVC transcriptional programs between cases and controls, including pronounced disruptions in cellular homeostasis via heat shock proteins and smooth‐muscle‐specific downregulation of ANKRD36 in early‐onset AD patients. Rare variants in ANKRD36 were recently implicated in AD in a whole‐exome sequencing study. We also identified transcriptional signatures associated with CAA in vascular and glial cells. We validated these results using spatial transcriptomics and data from the Seattle AD cohort. Lastly, we prioritized eight independent AD risk loci, including APP and APOE, where at least one fine‐mapped risk variant (95% credible set) overlapped a regulatory element active in vascular cells. At the APH1B locus, we identified a vascular enhancer likely regulating TPM1 and USP3. All loci putatively acting through vascular cells were shared with at least one other cell type (e.g., CASS4 with microglia), supporting reports of shared genetic risk between AD and cerebrovascular disease but suggesting the shared risk is mediated in a cell type‐specific manner (Figure 1).

Conclusion

Our work provides novel insights into the role of cerebrovascular dysfunction in AD and identifies genes and regulatory elements mediating AD genetic risk through CVC.
Reduction of neurogranin protein correlates with increases of inflammasome proteins in post mortem cases of intermediate Alzheimer’s disease
Authors: Vontell Regina T , Barreda Ayled , Blennow Kaj , Zetterberg Henrik , Vaccari Juan Pablo de Rivero , Bramlett Helen M , Dietrich W Dalton , Keane Robert W , Davis David A. , Rundek Tatjana , Sun Xiaoyan
Published: January 2025

Background

Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer’s disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.

Method

We investigated the protein expression, morphological differences of Ng and correlated Ng to hyperphosphorylated tau in the postmortem brains of 17 AD cases and 17 age and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC).

Result

We show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ ASC positive microglia, in AD.

Conclusion

The finding of a negative correlation between Ng and ASC speck protein expression in postmortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD.
Lemborexant, a Dual Orexin Receptor Antagonist, ameliorates Tau‐mediated Sleep Loss and Neurodegeneration
Authors: Parhizkar Samira , Chen Wei , Bao Xin , Gent Grace , Rensing Nicholas , Tycksen Eric , Franke Emily , Manis Melissa , Bosch Megan E. , Lee Choonghee , Serrano Javier R. , Landsness Eric , Wong Michael , Holtzman David M.
Published: January 2025

Background

Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD) and primary tauopathies. We have previously shown that APOE4, the strongest genetic risk factor for AD, directly influences the severity of key pathological hallmarks of neurodegeneration including tau deposition, microglial reactivity and brain atrophy. Sleep loss influences tau accumulation and microglial reactivity in both mice and humans, suggesting that sleep loss may contribute to neurodegeneration not only by influencing protein aggregation, but also through an immune mechanism. Therefore, we aimed to investigate whether promoting sleep as a therapeutic strategy could mitigate the damaging effects of chronic microglial reactivity that contribute to tau‐mediated neurodegeneration.

Method

We used lemborexant, a dual orexin receptor antagonist that promotes sleep in both mice and humans. We orally gavaged P301S/APOE4 mice, a model of tauopathy with brain atrophy, and non‐tau depositing APOE4 knock‐in mice daily with 30mg/kg lemborexant or vehicle (n = 16‐20/genotype and treatment group) at one‐hour post‐dark onset. Mice were treated from 7.5 months (M), when tau‐mediated neuroinflammation is observed without overt neuronal loss in P301S/APOE4 mice, until 9.5M.

Result

In P301S/APOE4 mice, lemborexant not only improved tau‐associated sleep loss, specifically non‐rapid eye movement sleep, but also dramatically reduced pathological tau deposition. Antagonizing orexin receptor signaling improved tau‐mediated neurodegeneration noted by a decrease in plasma neurofilament light chain levels, as well as brain atrophy compared to vehicle‐treated P301S/APOE4 controls. In support of these findings, lemborexant‐treated P301S/APOE4 mice displayed reduced microglial reactivity of disease‐associated microglia including immunostaining for CD68 and Clec7a compared to controls. Both astroglial and microglial APOE co‐localization were significantly reduced in lemborexant‐treated P301S/APOE4 mice, the latter of which is more commonly observed during elevated inflammatory and damaging conditions. Unbiased transcriptome profiling provided potential mechanistic insights into functional pathways influenced by lemborexant in P301S/APOE4 mice, including those regulating synaptic activity such as Slc17a7, Shank1, Shank2, which was further accompanied by reduced pre‐ and post‐synaptic loss.

Conclusion

Our study provides novel therapeutic evidence that antagonizing the orexin signaling pathway using lemborexant is neuroprotective by restoring sleep deficits as well as limiting tau‐mediated neuronal and synaptic damage, potentially by suppressing chronic neuroinflammation.
The impact of knowledge of β‐amyloid PET scan result on cognitive test performance: results of the REVEAL‐SCAN study
Authors: Karlawish Jason , Harkins Kristin , Pal Subhamoy , Welsh‐Bohmer Kathleen A. , Roberts J. Scott , Gregoire Allyson , Reader Jonathan M , Bakulski Kelly M. , Green Robert C.
Published: January 2025

Background

The impact of knowledge of β‐amyloid status on cognitively unimpaired persons' cognitive test performance is unknown.

Method

Cognitively unimpaired adults aged 65‐80 with a first‐degree relative with AD received a dementia risk estimate and were randomly assigned to disclosure (D+) or non‐disclosure (D‐) of their β‐amyloid PET scan result. At 6 weeks and 6 months post‐disclosure, participants completed the ADCS‐PACC, a composite of Free and Cued Selective Reminding (free portion), Logical Memory IIa test, Digit‐Symbol Substitution, and MMSE. Scores from each test are standardized to a Z‐score metric and a composite score calculated by summing the standardized Z‐scores.

Result

315 participants were randomized (84 elevated (41 A+D+/43 A+D‐)) and 231 not elevated (118 A‐D+, 113 A‐D‐)). After adjusting for baseline PACC scores, analyses compared PACC scores between (1.) A+D+ and A+D‐ and (2.) A‐D+ and A‐D‐ and stratified by race. A+ participants who learned their result (D+) had lower mean follow‐up PACC scores than participants who did not learn their β‐amyloid PET scan result (D‐) at 6 weeks (β = ‐0.89, 95% CI: ‐1.65, ‐0.13, p = 0.023) but not at 6 months post‐disclosure (β = ‐0.50, 95% CI ‐1.28, 0.27, p = .21). Mean follow‐up PACC scores did not differ between A‐ who did or did not learn their result at both 6 weeks (β ‐0.02, 95% CI: ‐0.42, 0.37, p = 0.91) and 6 months post‐disclosure (β ‐0.15, 95% CI ‐0.54, 0.25, p = .47). Analyses stratified by race showed Black/African American A+D+ had lower scores than A+D‐ at 6 weeks (β ‐2.01, 95% CI: ‐3.57, ‐0.45, p = 0.01) and 6 months post‐disclosure (β ‐1.63, 95% CI ‐3.19, ‐0.06, p = .04). Disclosure had no impact on scores of nonblack participants with elevated amyloid and the scores of any of not elevated participant groups.

Conclusion

Knowledge of an elevated amyloid result reduced cognitively unimpaired persons PACC scores. A greater impact was observed in Black/African American participants’ test performance compared to non‐Black participants. In contrast, knowledge of not‐elevated amyloid showed no impact on test performance in any of the groups. Clinical trials should consider the potential impact of AD biomarker knowledge on cognitive outcomes.
Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response
Authors: Puangmalai Nicha , Bhatt Nemil , Bittar Alice , Jerez Cynthia , Shchankin Nikita , Kayed Rakez
Published: January 2025

Background

The misfolding and aggregation of the tau protein into neurofibrillary tangles constitute a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain‐derived tau polymorphs (TBI‐BDTPs) remain elusive.

Method

We explored whether TBI‐BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild‐type mice were exposed to TBI‐BDTPs from sham, single‐blast (SB), or repeated‐blast (RB) conditions, and their memory function was assessed through behavioral assays at 2‐ and 8‐month post‐injection.

Result

Our findings revealed that RB‐BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB‐BDTP‐exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers.

Conclusion

Collectively, our results shed light on the intricate mechanisms underlying TBI‐BDTP‐induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.
Evaluating the repurposing potential of the anti‐depressant Agomelatine for Alzheimer’s Disease
Authors: Terry Grace A , Merav Michelle , Rockwell Patricia , Serrano Peter , Xie Lei , Figueiredo‐Pereira Maria
Published: January 2025

Background

The limited treatment options for Alzheimer’s emphasizes the need to explore novel drug targets and bring new therapeutics to market. Drug repurposing is an efficient route to bring a safe and effective treatment to the clinic. Agomelatine (AGO) was identified by a high‐throughput drug screening algorithm as having mechanistic potential to treat Alzheimer’s. AGO is used as an atypical antidepressant and works as an MT1/MT2 receptor agonist and a 5HT2C serotonin receptor antagonist.

Method

The TgF344‐AD rat model was used to test AGO’s potential to reduce cognitive deficits and neuropathology. The TgF344‐AD rat model expresses human mutant “Swedish” amyloid‐precursor protein (APPsw) and a Δ exon 9 presenilin 1 (PS1ΔE9). As it presents with age‐dependent progressive Alzheimer’s pathology and cognitive decline it is an ideal model for investigating AGO’s effect on the robust presentation of Alzheimer’s. Treatment with AGO at ∼10 mg/kg body weight/day began at 5 months of age (pre‐pathology) and continued until 11 months of age when cognitive testing (active place avoidance task) and tissue collection occurred. Immunohistochemistry was used to evaluate amyloid beta plaque burden. Bulk RNAsequencing was conducted to investigate AGO’s effect on gene expression.

Result

AGO treated female TgF344‐AD rats showed reduced cognitive deficits with an increased latency to first entrance in aPAT testing compared to non‐treated transgenic littermates. There were no differences between the cognitive performance of AGO treated and untreated male TgF344‐AD rats. Interestingly, this reduced cognitive deficit did not correlate with decreased amyloid beta pathology. RNA sequencing analysis showed that DDIT3 (CHOP) mRNA levels were downregulated in the AGO treated compared to untreated TgF344‐AD females. DDIT3 is a pro‐apoptotic transcription factor.

Conclusion

Agomelatine showed a female only reduction in cognitive deficits, which did not correlate with a decrease in amyloid beta plaque deposition. This finding paired with the decrease of DDIT3 gene expression suggests that Agomelatine has a neuroprotective mechanism that is independent of amyloid burden. Future studies will analyze neuronal loss via NeuN staining to determine if AGO prevents neuronal loss, thus supporting its ability to mitigate cognitive deficits in the TgF344‐AD rat model.
Precision Phenotyping of Mild Behavioral Impairment and the Early Detection of Dementia
Authors: Vahia Ipsit V
Published: January 2025

There is growing recognition of the importance of changes in behavior as an early clinical marker of the onset of Alzheimer’s disease. Behavior symptoms may precede the onset of cognitive symptoms by as many as three years. However, these symptoms are often confused for primary psychiatric pathology and there is an urgent need for markers that can help quantify behaviors with the eventual goal of helping distinguish behavior changes related to psychiatric pathology from behavior changes related to the onset of dementia.

This talk will summarize the state of knowledge on mild behavioral impairment, and present data from three studies demonstrating how a range of sensor‐derived biomarkers can quantify subtle changes in behavior with precision. The talk will include case presentations around detection of apathy, agitation, pacing. It will also demonstrate how these markers can identify response to medications, which may be one way of distinguishing the presence of psychiatric versus neurodegenerative pathology.

Finally, the talk will present data from ongoing clinical trials around how these biomarkers may translate into research and eventually practice.
A human induced pluripotent stem cell model of Alzheimer’s Disease‐associated fractalkine receptor polymorphism to assess AD‐related microglial dysfunction
Authors: Tutrow Kaylee , Harkin Jade , Hernandez Melody , Huang Kang‐Chieh S , Bissel Stephanie J , Puntambekar Shweta S , Lamb Bruce T. , Meyer Jason S.
Published: January 2025

Background

Dysfunctional microglial activity has recently been identified as a potential mechanism leading to accumulation of amyloid beta and pTau and subsequent neurodegeneration in Alzheimer’s Disease. The CX3CR1/fractalkine axis serves as a mechanism for bi‐directional communication between microglia and neurons, respectively, to promote a resting, anti‐inflammatory state in microglia. Previous studies have demonstrated that deficiency in CX3CR1 signaling leads microglia to a more pro‐inflammatory phenotype, phagocytic deficits, and increased susceptibility of neurons to cell death. Additionally, the CX3CR1‐V249I polymorphism was recently identified as a potential risk allele for Alzheimer’s Disease with worsened Braak staging in post‐mortem Alzheimer’s patients. However, the role of fractalkine dysfunction in human cells and the mechanisms by which microglia with the CX3CR1‐V249I SNP contribute to neurodegeneration remain unclear.

Method

To address this shortcoming, we utilized human induced pluripotent stem cells and CRISPR/Cas9 gene editing technology to elucidate the effects of the CX3CR1‐V249I polymorphism on human microglia‐like cells (hMGLs) compared to an isogenic control cell line. Isogenic control cells alongside both heterozygous and homozygous CX3CR1 V249I cell lines were differentiated in parallel to yield enriched populations of hMGLs. Resulting hMGLs were then assessed for uptake of amyloid beta 1‐42 using flow cytometry, cell death in response to cytokine starvation, changes in proliferation, and finally alterations to migratory behavior using a microfluidic chamber.

Result

We demonstrate the effective differentiation of hMGLS from both isogenic control and CX3CR1‐V249I backgrounds, which express characteristic microglial markers and are functionally phagocytic. Microglia bearing the homozygous CX3CR1‐V249I allele, but not heterozygous cells, demonstrated decreased uptake of amyloid beta in vitro compared to isogenic controls. Additionally, homozygous V249I microglia demonstrated increased stress‐induced cell death, as well as altered proliferation and decreased migratory capability.

Conclusion

These findings suggest that the CX3CR1‐V249I polymorphism may cause a dysfunctional microglia phenotype that may contribute to neuronal dysfunction and death. Ongoing work will expand upon the transcriptome and secretome profile of CX3CR1‐V249I microglia and elucidate how this gene variant contributes to Alzheimer’s Disease‐related neurodegeneration.
The role of clusterin and the variant rs11136000_T throughout the spectrum of Alzheimer’s disease
Authors: Dauar Marina Tedeschi , Picard Cynthia , Labonte Anne , Villeneuve Sylvia , Poirier Judes , Group PREVENT‐AD Research
Published: January 2025

Background

Clusterin is a major cholesterol transporter in the central nervous system (CNS) and different SNPs in the CLU gene have been associated with Alzheimer’s disease (AD) risk. The rs11136000_T variant in the CLU gene has been shown to decrease the risk of AD. In this work, we investigate the role of the CLU rs11136000_T protective variant and of the clusterin protein throughout different phases of the AD spectrum.

Method

Levels of clusterin, Tau, phospho(181) Tau (p‐tau), and Aß were measured using ELISA and synaptic proteins were measured using immunoprecipitation followed by mass spectroscopy in the CSF of cognitively unimpaired individuals. Flortaucipir PET was used to measure tau deposition and 18F‐NAV4694 PET was used to measure amyloid burden in the same subjects. ELISA was used to measure clusterin levels and RT‐PCR was used to measure mRNA levels in cortical areas of autopsied‐confirmed controls and AD subjects. Genotype was performed using Illumina Infinium Omni2.5M‐8 microarray.

Result

There was no effect of the protective genotype on the levels of PET biomarkers, CSF biomarkers or synaptic proteins in cognitively unimpaired individuals. CSF clusterin levels were positively associated with Aß (p = 0.021), total‐tau (p<0.001), p‐tau (p<0.001), synaptotagmin (p<0.001), SNAP 25 (p = 00006), GAP 43 (p = 0.00055) and neurogranin (p = 0.0086) in the CSF and with amyloid deposition in the hippocampus (p = 0.018) and tau retention in the entorhinal cortex (p = 0.0082) and temporal pole (p = 0.0124) in cognitively unimpaired individuals at high risk for AD. Clusterin is increased in the brain of individuals who are homozygous for the CLU_T variant (p = 0.04) and in AD patients compared to age‐matched controls (p = 0.024). mRNA levels are increased in individuals homozygous for the CLU_T variant (p = 0.003), but there are no significant differences in AD patients compared to controls (p = 0.07).

Conclusion

Our work shows significant correlation between CSF clusterin and the main AD biomarkers (PET and CSF) and synaptic proteins before disease onset, in subjects at high risk for the disease. In the later stage of the disease, clusterin protein and CLU mRNA levels are increased as a function of genotype and disease status, suggesting that CLU may play a protective role by increases in gene expression in the CNS.
Examining the Association Between Differences in Post Turning Driving Behavior on a Driving Simulator and Amyloid Status in Cognitively Normal Older Adults
Authors: Rose Savannah G. , Flynn Emma , Carmichael Douglas , Murphy Yi Lu , Koeppe Robert A. , Persad Carol C. , Maher Amanda Cook , Giordani Bruno
Published: January 2025

Background

Older adults diagnosed with Mild Cognitive Impairment (MCI) and dementia are at increased risk of driving impairment. As the prevalence of dementia, particularly Alzheimer’s dementia, increases, researching the link between driving behaviors and cognitive decline may aid early identification of at‐risk cognitively normal older adults. This study assesses differences in driving behavior following a left hand turn between amyloid positive and negative cognitively normal older adults.

Method

Seventy‐three cognitive normal adults aged 65+ were categorized as either amyloid positive or amyloid negative based on PiB PET imaging and a centiloid scale (≥20 = positive, ≤10 = negative). Forty‐three participants were amyloid negative (CN‐) and 27 were positive (CN+). All participants completed a 20‐minute simulator drive programmed with realistic driving scenarios, including a 90 degree left turn from a stop sign at two intersecting rural two lane roads. Assessed turning behavior in the 120 meters after the left turn included the average absolute value of lane deviation, number of off‐road errors and oncoming traffic errors, number of over‐corrections, and number of total errors. Group differences were analyzed using independent samples t‐tests.

Result

There were no demographic differences between the groups. The CN‐ group had faster speed after the turn, faster average speed in the 120m post‐turn, and greater average absolute value lane offset compared to the CN+ group. The CN‐ group also made more errors, including both off‐road and oncoming‐traffic error types, compared to the CN+ group. There was no significant difference between the number of over corrections or total errors by group.

Conclusion

Overall, cognitively normal older adults with elevated brain amyloid displayed potentially more cautious driving behavior than their peers without elevated amyloid. It remains to be seen whether these more cautious behaviors are potentially due to decreased confidence or subconscious recognition of cognitive changes. Nonetheless, they may signal early, subtle signs of AD‐related processes differentiating individuals at‐risk for AD‐related cognitive decline.