bluuebunny/crossref_metadata_2025 huggingface dataset:
500nm blue‐green light therapy for cognitive function in Alzheimer’s continuum and factors affecting efficacy
Authors: Wang Ziqi , Yang Junlan , Feng Qiansen , Li Linlin , Chen Lei , Wang Jiayu , Wu Jiajing
Published: January 2025

Background

Light therapy has emerged as an effective method for Alzheimer’s disease (AD). However, the efficacy on cognitive function in Alzheimer’s continuum and factors affecting efficacy have not been established. The study aimed to evaluate the efficacy of 500 nm blue‐green light therapy on cognitive function for Alzheimer’s continuum, and the main factors affecting light therapy efficacy were analyzed.

Method

Forty‐two participants were enrolled in this studies, including 13 healthy control [HC, equal to 0 standard deviation, (SD)], 9 subtle cognitive impairment (SCI, ≥0.5 SD), 8 early mild cognitive impairment (eMCI, ≥1.0 SD), 6 late MCI (lMCI, ≥1.5 SD), 6 dementia of AD (dAD, ≥2.0 SD). All the participants treated with 500 nm blue‐green light for 50 minutes with 4 weeks in the morning. A reduction of 4 or more points in the Alzheimer’s Disease Assessment Scale‐cognitive subscale (ADAS‐cog) scores was considered valid for cognitive improvement.

Result

The total efficacy after light therapy was 16.7%. The efficacy in HC, SCI, eMCI, lMCI and dAD after light therapy were 15.4%, 11.1%, 12.5%, 16.7% and 33.3%, respectively. Light therapy efficacy was not significantly correlated with the participant’s sex, age, diagnostic type, education, apolipoprotein E epsilon 4, the Mini‐mental State Examination scores; the Montreal Cognitive Assessment‐Basic scores, Hamilton Anxiety Scale scores, Hamilton Depression Scale scores, or the Pittsburgh Sleep Quotient Index. In multivariate analysis, the ADAS‐cog scores before light therapy (OR 1.279, 95% CI 1.021∼1.602, p = 0.033) was an independent predictor, while the Everyday Cognition (ECog) scores and the Mild Behavioral Impairment Checklist (MBI‐C) scores before light therapy didn’t influence the efficacy.

Conclusion

Four weeks of 500 nm blue‐green light therapy had different efficacy on cognitive function for Alzheimer’s continuum. Baseline cognitive status may influence light therapy efficacy.
Developing Novel Small Molecule Proteostasis Enhancers for Alzheimer’s Disease (AD)
Authors: Ariyath Ajish , Fernando Warnakulasuriya Mary Ann Dipika Binosha , Martins Ralph N , Bharadwaj Prashant
Published: January 2025

Background

The autophagy lysosomal pathway (ALP) and the ubiquitin‐proteasome system (UPS) are key proteostasis mechanisms in cells, which are dysfunctional in AD and linked to protein aggregation and neuronal death. Autophagy is over activated in Alzheimer’s disease brain whereas UPS is severely impaired. Activating autophagy has received most attention, however recent evidence suggests that UPS can clear aggregate proteins and a potential therapeutic target for AD and protein misfolding diseases.

Method

We previously developed an assay using the MC65 AD cell model and demonstrated that Amyloid Precursor Protein (APP) derived carboxy terminal peptides (APP‐C99) and amyloid‐β protein (Aβ) is rapidly cleared in this model. Using this model we screened a library of small molecule proteostasis modulators and identified IU1, a USP14 inhibitor that improved cell survival and promoted Aβ clearance. Our study investigated whether new analogues of IU1 could provide better neuroprotection in AD. Screening of 71 novel small molecule proteostasis inhibitors using this cell model, discovered two novel lead compounds C10 and C51. These compounds effect on autophagy, proteasome activity, and APP‐C99/Aβ clearance were further analyzed using techniques involving immunofluorescence staining, toxicity analysis, western blot, DUB, proteasome and luminescence assays.

Result

Initial study used an in‐silico artificial intelligence screening platform from Atomwise to design and develop novel small molecule USP14 binding ligands. Cell studies have shown promising results with compounds C10 and C51 from the screened library of proteostasis modulators in alleviating AD proteostasis dysfunction, protein aggregation and regulating autophagy clearance. Cell survival by IU1 was 40% which was improved to 55% using C10 and C51, where it reduced accumulation of APP‐C99 and Aβ. Also, reduced levels of autophagy markers LC3 and p62, restored proteasomal activity in the AD cell model.

Conclusion

In conclusion, ours is the first novel report of using IU1 in an AD model as a USP14 inhibitor. The novel IU1 analogues C10 and C51 looks more promising and hold potential as candidates for pre‐clinical validation in AD. The next steps involve testing therapeutic efficacy, target engagement, and brain bioavailability in AD animal models, with completed cell model assessments and upcoming focus on confirming deubiquitinating enzyme (DUB) specificity.
Dementia friends unite! Exploring the effectiveness of a dementia education initiative co‐produced with and for multicultural communities
Authors: Caballero Gabriela E , Tsouros Emy , Tran Mai , Jasim Nibras , Chan Sonia , Dinh Angie , Dinh Vivian , Chan Eliza , Richardson Kylie , Sartawy Sanna , Kaapro Sharyn , Hulm Zac , Siette Joyce , Dadich Ann , DiGiacomo Michelle , Steiner‐Lim Genevieve Z , Karamacoska Diana
Published: January 2025

Background

People living with dementia and their carers, particularly those from culturally and linguistically diverse backgrounds, consistently demonstrate limited knowledge about and negative attitudes towards dementia. This can limit access to preventive and post‐diagnostic care. Culturally sensitive dementia education is an inclusive and practical intervention that can be used in multicultural contexts to increase awareness and destigmatise the condition. Our study aimed to explore the reach and effectiveness of a multilingual dementia education initiative, co‐produced by multicultural service providers and people with lived and caring experiences of dementia.

Method

We conducted a quasi‐experimental education intervention targeting English, Arabic, Vietnamese, Cantonese, Mandarin, and Greek‐speaking people in Sydney, Australia. The intervention involved three two‐hour information sessions delivered in‐language by trained bilingual co‐facilitators over three months. The RE‐AIM framework was used to analyse the intervention’s reach and effectiveness. Reach was assessed by the number of attendees at each session. Effectiveness was measured pre‐ and post‐intervention using an adapted survey incorporating 10‐items from the dementia knowledge assessment scale (DKAS) and 14‐items from the dementia attitudes scale (DAS). Mann‐Whitney U tests compared mean rank differences pre‐ and post‐intervention for each scale item.

Results

We reached over 220 people across six languages. There were statistically significant improvements from pre‐ to post‐intervention on five DKAS items regarding causes, risk factors, and symptom management (all p ≤ 0.050), and eight DAS items regarding perceptions and stigma (all p ≤ 0.019).

Discussion/Conclusion

The education initiative was effective in this multicultural context, but ongoing education is needed to address persistent dementia knowledge gaps and negative attitudes. Co‐production with multicultural stakeholders likely enhanced understanding of community needs, resulting in greater information access and acceptability. To measure longer‐term effectiveness, the adapted survey will be re‐administered to capture changes in dementia knowledge and attitudes, 12‐months post‐intervention. While culturally tailored education might overcome nuanced learning and support needs, a culturally sensitive approach is likely to be more effective to enact dementia‐friendly community principles in multicultural contexts.
Plasma NfL and GFAP for predicting VCID brain changes in the population
Authors: Raghavan Sheelakumari , Hofrenning Ekaterina I. , Fought Angela J. , Algeciras‐Schimnich Alicia , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Lowe Val J. , Graff‐Radford Jonathan , Vemuri Prashanthi
Published: January 2025

Background

Vascular contributions to cognitive impairment and dementia (VCID) are often comorbid with Alzheimer’s disease and increase the risk of dementia. Blood‐based biomarkers may be promising for identifying individuals at high risk for VCID due to small vessel disease (SVD).

Method

We included 1709 participants from the Mayo Clinic Study of Aging who had concurrent MRI, plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) measured on the HD‐X Simoa Quanterix platform, and clinical dementia rating scale (CDR). We categorized participants into SVD vs. not using WMH/TIV≥1.3% which corresponds to Fazekas>=2 cutoff and cognitively impaired (CI) vs. not using CDR≥0.5. We obtained four groups using SVD and cognitively normal and impaired classifications: cognitively unimpaired without SVD (CU), CU with SVD (Vas‐CU), CI with SVD (VCI), and CI without SVD (Non‐vas‐CI). Univariate and multivariable logistic regression models were used to obtain odds ratios, confidence intervals and ROC curves to evaluate the association between plasma markers and each disease group compared to CU. We also evaluated these analyses in amyloid positive and negative participants.

Result

There was a high proportion of CU (Vas‐CU/(CU+Vas‐CU)=18%) and CI (VCI/(VCI+ Non‐vas‐CI)=47%) participants with SVD in the population‐based sample. Higher plasma levels were associated with greater vascular burden and differed by amyloid status (Figure 1). ROC analyses showed that both NfL and GFAP provided discrimination between Vas‐CU and CU groups (AUC=0.83) as well as VCI and CU groups (AUC=0.88) (Figure 2, Table 1). Though GFAP and NfL are non‐specific and may also reflect non‐vascular damage, we found that these plasma markers did not clearly separate NonVas‐CI from the CU group in the overall cohort (AUC=0.69). When amyloid status was available, the discriminative power of NfL and GFAP in separating the 4 groups was very low in amyloid positive participants. On the other hand, NfL and GFAP separated Vas‐CU and VCI groups from CI reasonably well in the amyloid negative group.

Conclusion

Plasma biomarkers associated with SVD‐burden provided reliable discriminative power in predicting VCID, particularly in the absence of amyloid, suggesting their utility in the prognosis and stratification for clinical trials.
The Effect of a Combined Intervention Program Combining Cognitive Training and Physical Activity in Community‐Dwelling Elderly Without Cognitive Impairment
Authors: Shin Ye‐Eun , Han Myeong‐Il , Park Kyung‐Hwan , Choi Mal‐Rye , Sung Nam‐Ju , Kim Sol‐Yi
Published: January 2025

Background

Combined cognitive training and physical activity has been known to improve brain function. The purpose of this study is to investigate whether combined intervention affects the improvement of cognitive function in the community‐dwelling elderly, and to determine if it improves physical function, such as motor speed and balance.

Method

The study was conducted among community‐dwelling elderly aged 65 years. Participants had no evident cognitive impairment on the Cognitive Impairment Screening Test (CIST), and be physically active. Demographic data was collected, and cognitive function was assessed using a neuropsychological test battery which consists of the Word List Test, Organization Skills, TMT, Word Recall, Boston Naming Test, and orientation. Physical functioning was assessed using the Brief Physical Performance Battery (SPPB), which consists of balance, gait speed, and chair rise assessments. The intervention was a group‐based, combines cognitive training and physical activity and allows to perform simultaneously, with a total of eight sessions, each lasting 60 minutes. Differences were tested between pre‐intervention and post‐intervention scores.

Result

A total of 73 participants completed the intervention and were eligible for analysis. After the intervention training, the total score of the neurocognitive test battery increased by 7.32 (±4.20) points (p<0.001) and the SPPB increased by 1.59 (±1.22) points (p<0.001), respectively. In the detailed items of the neurocognitive test battery, word memory was higher in men 3.71 than in women 2.05 (p = .013), and word recall was higher in women 1.44 than in men 0.36 (p = .013), which both reveal significant difference. According to age, orientation was significantly different with a score of 1.45 for those aged 85 years and older than 0.46 for those aged 75‐79 years (p = .044). There were no significant differences in BMI and living arrangements. Multiple regression analysis showed that education (secondary or higher) (p = .008), living arrangement (children) (p = .042), hypertension medication (p = .014), and diabetes medication (p = .015) had a significant effect on neurocognitive performance of this intervention.

Conclusion

The results demonstrated that combined intervention improved overall cognitive function and physical performance in community‐dwelling elderly with no apparent cognitive impairment.
Reversal of C9orf72 mutation‐induced transcriptional dysregulation and pathology in cultured human neurons by allele‐specific excision
Authors: Sachdev Aradhana , Gil Kamaljot , Sckaff Maria , Birk Alisha M , Arogundade Olubankole Aladesuyi , Brown Katherine A , Chouhan Runvir S , Lewin Patrick Issagholian , Patel Esha , Keough Kathleen , Conklin Bruce , Smith Alec ST , Clelland Claire
Published: January 2025

Background

Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus.

Method

We generated five different genomic excisions at the C9orf72 locus in a patient‐derived iPSC line and a WT line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 FTD/ALS in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes. A coding SNP in the patient cell line allowed us to distinguish transcripts from the normal vs. mutant allele.

Results

Using ddPCR, we determined that transcription from the mutant allele is upregulated at least ten‐fold, and that sense transcription is independently regulated from each allele whereas antisense transcription is regulated by the opposite allele. Surprisingly, excision of the WT allele increased pathologic dipeptide repeat expression from the mutant allele. Importantly, a single allele was sufficient to supply a normal amount of protein, suggesting that the C9orf72 gene is haplo‐sufficient in induced motor neurons. Excision of the mutant repeat expansion reverted all pathology (RNA abnormalities, dipeptide repeat production and TDP‐43 pathology) and improved electrophysiological function, whereas silencing sense expression did not eliminate all DPRs, presumably because of the antisense expression.

Conclusion

These data increase our understanding of C9orf72 gene regulation and inform gene therapy approaches, including ASOs and CRISPR gene editing, and provide a therapeutic CRISPR gene editing approach to treat C9 FTD/ALS.
Natural amyloid deposition and neuroinflammation in both brain and eyeball of the old 5xFAD transgenic mouse using Integrated evaluation platform system combining amyloid PET/CT and Macro‐laser light sheet microscopy imaging with tissue clearing
Authors: Son Hye Joo
Published: January 2025

Background

Macro laser light‐sheet illuminating microscopy (Macro‐LSFM), allied with tissue clearing technologies, herald a transformative paradigm in biomedical imaging, allowing 3D visualization of neuropathologic networks in a transparent intact mouse brain. Moreover, although traditional focus of AD diagnostic has been on CNS pathology, emerging research points to peripheral amyloid‐beta deposition, specifically in the eyeball, as an avenue for investigation. Coupled with conventional [18F]flutemetamol PET/CT imaging, this study leverages the innovative imaging capabilities of Macro‐LSFM with hydrophilic tissue‐clearing technique to elucidate the 3D spatial distribution of AD‐associated neuroinflammation and neuropathologic change both in the brain and eyeball of old transgenic AD mouse.

Method

For thirteen 5xFAD (43 weeks) and seven control mice, we applied a hydrophilic tissue clearing pipelines to extracted brain and eyeball samples, encompassing fixation, clearing, permeabilization, and volume immunostaining using fluorochrome‐conjugated Thioflavin S for β‐amyloid (488 nm), anti‐CD11b for microglia (561 nm), and anti‐ACSA‐2 for astrocytes (647 nm). Macro‐LSFM imaging was performed using a Lightsheet Z.1 microscope (Objective 5x NA 0.16, Zoom 0.75x, single‐mode illumination). 3D volumetric surface models for amyloid, astrocytes, and microglia mapping were generated using Imaris v9.6 software with a minimum surface grain size of 4.0 μm.

Result

In Macro‐LSFM, AD showed significantly higher total surface volumes of amyloid accumulation than control (AD, 898634368 µm³ [383355488‐1324986752]; Control, 33320178 µm³ [11156785‐65390988], p=0.0006). Eyeballs of AD also showed higher amyloid deposits than control (AD, 51091002 µm³ [1002006‐97460784]; Control, 229293 µm³ [8466‐3501462], p=0.0066), showing strong positive correlation of amyloid accumulation between brain and eyeball (R=0.8, p=0.001). AD showed higher anti‐ACSA‐2 specific astrocyte (AD, 59064360 µm³ [27815500‐222619280]; Control 20272722 µm³ [9317288‐27223352], p=0.0047) and anti‐CD11b specific microglial expression (AD, 51210100 µm³ [15309118‐135532144]; Control, 23461593 µm³ [14499170‐27924110], p=0.0162) than control.

Conclusion

Our synergistic amyloid PET/LSFM approach revealed that active neuroinflammation persists in old AD brain, marked by substantial amyloid deposition, challenging the traditional sequence of early neuroinflammation leading to late‐stage neurodegeneration. Our novel observation of correlated ocular amyloid deposition introduces the eye as a promising, accessible site for the early diagnosis of AD pathology.
Gender Differences in Frontotemporal Dementia: Clinical, Brain Structural, White Matter Hyperintensity, and Brain Metabolic Features
Authors: Chu Min , Liu Li , Nie Binbin , Wu Liyong
Published: January 2025

Background

Gender is a factor influencing the clinical and radiological heterogeneity in dementia. However, gender differences in frontotemporal dementia (FTD) are still underexplored. This study aims to investigate the gender heterogeneity in FTD patients and its association with clinical and imaging features.

Method

FTD patients from two independent cohorts were included in this study, one from our center and the other from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). For clinical characteristics analysis, our center enrolled 64 male and 70 female FTD patients, while FTLDNI selected 91 male and 69 female patients. For brain structural analysis, both our center and FTLDNI included 40 males and 49 females. In the white matter hyperintensity analysis, our center enrolled 21 male patients and 26 female patients, while FTLDNI included 76 male and 61 female patients. In metabolic analysis, only 21 male and 31 female patients were included in our center.

Result

In the Chinese FTD cohort, females had a shorter education year than males, while males had more severe executive dysfunction and hallucinations and agitation symptoms. Males had a higher proportion in the behavioral subtype, while females higher in the language subtype in FTLDNI. Female patients had more significant gray matter atrophy, particularly in the frontal and cingulate regions, compared to male patients. As for white matter hyperintensities, there were no significant differences in quantity and volume between the two genders. Regarding gray matter metabolism, despite females showing more severe gray matter atrophy, they seemed to have better brain reserve function. The atrophy of the left frontal and basal ganglia in females is significantly correlated with cognitive decline, while males exhibit a link between anterior cingulate atrophy and executive dysfunction. Although a significant mediating model was not found, gender has a tendency mediating effect on visual‐vocabulary testing through the fronto‐temporal‐parietal brain region.

Conclusion

This study describes the clinical and imaging differences between genders in FTD, which might be attributed to gender influencing different neural circuits. Gender differences need to be considered in precision therapy and clinical trial design.
The effect of sleep apnoea related pathways on longitudinal changes in the brain
Authors: Weihs Antoine , Frenzel Stefan , Ewert Ralf , Stubbe Beate , Penzel Thomas , Fietze Ingo , Bülow Robin , Voelzke Henry , Grabe Hans J.
Published: January 2025

Background

Sleep apnoea is gaining attention as a modifiable risk factor for neurodegenerative disorders, with recent cross‐sectional studies observing associations with advanced brain ageing and increased white matter hyperintensity (WMH) burden. Building upon these findings, we investigate the effects of sleep apnoea on longitudinal changes in brain structural measures using lab‐based polysomnography and 7‐year follow‐up MRI measurements from the general population‐based Study of Health in Pomerania (SHIP).

Method

Ordinary least square regression was used. Brain measures (brain age, total brain volume (TBV), mean cortical thickness and WMH at follow‐up) were chosen as outcomes and sleep apnoea metrics (apnoea hypopnea index (AHI), oxygen desaturation index (ODI), arousal index (ARI) and mean oxygen saturation (meanO2) during sleep) as exposures. All models were adjusted for the corresponding baseline MRI metric, follow‐up time, age*sex, intracranial volume and total sleep time (TST). The exposure and all numerical covariates were modelled non‐linearly using restricted cubic splines. AHI, ODI, TST and meanO2 were manually scored according to American Academy of Sleep Medicine standards. ARI was automatically assessed using Sleepware (Phillips, Amsterdam, Netherlands). Structural MRI measurements were segmented using T1‐weighted images in FreeSurfer v7.2. WMH were segmented with the lesion growth algorithm implemented in the LST toolbox v3.0.0 using T1‐weighted and FLAIR sequences. Additionally, brain age scores were generated to represent age‐related structural brain changes.

Result

N=387 subjects (47.3% female, baseline age 50.7±12.4 years) with baseline and follow‐up MRI (mean follow‐up time: 7.4±0.6 years) and baseline polysomnography measurements were included. No longitudinal effect was identified when investigating sleep apnoea severity (AHI). Looking at apnoea‐related oxygen desaturation subprocesses, only an inverse relationship was observed between meanO2 and TBV. Exploring sleep fragmentation, a positive effect was observed between ARI and brain age and an inverse effect between ARI and TBV and mean cortical thickness. These effects remained stable when additionally accounting for metabolic, socioeconomic or lifestyle factors.

Conclusion

Using longitudinal MRI and lab‐based polysomnography measurements, we found sleep fragmentation to be associated with brain atrophy after 7 years. While further studies are needed, this indicates that sleep fragmentation might be an interesting target to slow the onset of neurodegenerative disorders.
Sars‐Cov‐2 infection and dementia risk: a nationwide, nested case‐control study
Authors: Zur Nika , Stein Nili , Saliba Walid , Weinstein Galit
Published: January 2025

Background

Cognitive impairment following Sars‐Cov‐2 infection is common. We aimed to explore whether covid‐19 is associated with a higher risk of dementia in a nationwide sample of middle‐age and older Israeli adults.

Method

This nested case‐control study was based on electronic health care data from the largest healthcare provider in Israel. From a cohort of 1,145,322 dementia‐free individuals aged ≥50y at baseline (March 2020), we matched subjects with incident dementia to controls without dementia using a density sampling by age, sex, and date of entry to the study, with a ratio of 1 to 10. The follow‐up ended in May 2022. SARS‐CoV‐2 infection was defined based on positive PCR or institutional antigen tests. Conditional logistic regression was used, adjusting for potential confounders including ethnicity, socioeconomic status, comorbidity and smoking. Interaction of covid‐19 with sociodemographic factors and comorbidities were additionally tested. Lastly, the association between covid‐19 severity and dementia were examined, with severity defined as mild without hospitalization, and hospitalization with mild, moderate and severe disease based on hospitalization discharge records.

Result

Sample mean age was 77.5±9.0 years and 173,668 (57.9%) were females. Overall, 27,280 had incident dementia during the follow up, matched to 272,800 healthy controls. A positive test for covid‐19 was detected among 2,072 (7.6%) cases and 6,722(2.5%) controls. Overall, SARS‐CoV‐2 infection was associated with increased dementia risk (OR = 1.15; 95% CI 1.06‐1.25; P<0.001). There was no increased risk of dementia in those with prior mild covid‐19 who were not hospitalized compared to those without covid‐19 history (OR = 1.003; 95% CI 0.914‐1.101; P = 0.905). However, compared to no covid‐19 history, hospitalization with mild, moderate and severe disease was associated with 83%, 93% and 75% increased risk for subsequent dementia, respectively (OR = 1.833; 95% CI 1.410‐2.382; P<0.001; OR = 1.928; 95% CI 1.366‐2.722; P<0.001; OR = 1.745; 95% CI 1.316‐2.313; P<0.001). Finally, no interactions were observed.

Conclusion

In this nation‐based sample, a history of SARS‐CoV‐2 infection was associated with a 15% increased risk for dementia during a 27‐months follow‐up. Increased dementia risk was observed only among covid‐19 patients who were hospitalized. Future investigations with longer follow‐ups are needed to clarify the implications of covid‐19 on brain health.
Proteomics‐Based Prediction of Hippocampal Atrophy in the General Population
Authors: Chen Meilin , Wang Zhibo , Ning Yuye , Jia Jianping
Published: January 2025

Background

Hippocampal atrophy is being characterized as a key biomarker in neurodegenerative disease, especially for dementia. Nevertheless, detecting hippocampus relied on magnetic resonance imaging (MRI), it's very costly and time‐consuming. Our objective is to develop a predictive score to detect MRI‐related hippocampal volume based on large‐scale blood proteomics.

Method

This prospective cohort study utilized data from the UK Biobank, encompassing baseline assessments from 2006 to 2010 and follow‐up data up to September 2023. We focused on 5,680 participants with available Olink blood proteomics data (approximately 3000 proteins) and MRI‐related hippocampal volume. Feature selection and developing predictive score were used a least absolute shrinkage and selection operator (LASSO) regression. Moreover, we tested the prognostic value of the predictive model in the prediction of dementia outcomes in participants without known dementia with over 10‐years follow‐up period.

Result

Our predictive score, incorporating 74 distinct proteins, was trained in a cohort of 4,544 individuals and validated in the additional cohort of 1,136 individuals. The predictive score accurately predicted MRI‐related hippocampal volume in the validation cohorts (Figure 1). Based on the predictive scores, we created four groups: high risk, medium risk, low risk, and minimal risk, according to selected cutoff values (10%, 50%, and 90%). The score was effective in identifying individuals at risk of dementia risk, thereby allowing stratification to different risk groups for dementia incidence. The hazard ratio for dementia incidence in the minimal risk group was 0.04 [95%CI: 0.02‐0.06] compared with the high‐risk group (Figure 2). Moreover, the predictive score was still effective in identifying individuals at risk of dementia risk in the independently cohort of 45,000 participants.

Conclusion

The predictive scores, based on simple blood proteins, accurately predicts hippocampal volume and assesses the risk of dementia incidence. The score may enhance early screening for hippocampal atrophy and provide guidance for preventive care in early dementia.
Spatial Similarity of Person‐Specific Resting State Topography in Cognitive SuperAgers
Authors: Diamond Bram R , Martersteck Adam , Rogalski Emily J
Published: January 2025

Background

Memory decline in late life is a common hallmark of aging, yet SuperAgers are individuals age 80+ with episodic memory performances at least as good as cognitively average 50‐to‐60‐year‐olds. Recent work, combining anatomical and functional MRI, has shown the precise boundaries of large‐scale resting state networks vary at the individual level. Further, the use of person‐specific rather than standard parcellations has led to more behaviorally meaningful associations, and has not been explored in SuperAgers. The current project examines whether the topography of person‐specific resting state networks differ between SuperAgers and older‐aged controls (OACs).

Methods

Twenty‐four SuperAgers and 16 OACs were included in the study. SuperAger/OAC phenotype was determined based on measures of episodic memory, executive functioning, verbal fluency, and picture naming across two visits, separated by at least 18 months. Person‐specific network parcellations were derived for each participant using their first visit resting state fMRI connectivity, constrained by anatomical priors, with a Multi‐Session Hierarchical Bayesian Model (MS‐HBM; Kong et al., 2021). Sørensen‐Dice spatial similarity coefficients (Dice) were calculated to determine the within‐group spatial similarity of each network. Dice was defined as the number of overlapping vertices between two participants’ network segmentation, multiplied by two, and divided by the sum of vertices in both network segmentations. Dice was calculated for each participant compared to all other within‐group participants and averaged to create a Dice score per participant per network. Dice scores for each of the 17 person‐specific networks were compared between SuperAgers and OACs using Mann‐Whitney tests, Bonferroni‐corrected.

Results

Demographics did not differ significantly between groups. Person‐specific network topography varied between participants (Figure 1). SuperAgers had significantly lower Dice scores than OACs in six of 17 networks (Figure 2; p‐value ≤ 0.0029).

Conclusion

Compared to OACs, SuperAgers demonstrated greater within‐group variability in resting state network topography. Greater spatial variability may reflect unique patterns of functional or structural topography that support SuperAgers’ exceptional memory abilities. Future investigations will include further examination of the functional connectome of SuperAgers, leveraging the precision approach employed here.
Unsupervised Learning‐based Drug Repositioning for Alzheimer’s Disease Targeting Brain Cell Type Specific Genetic Subtypes
Authors: Mishra Ankit Kumar , Sahelijo Nathan J , Priyadarshi Dhawal , Jun Gyungah R
Published: January 2025

Background

Alzheimer’s disease (AD) presents challenges with its complex neurodegenerative mechanisms, leading to a high failure rate in clinical trials. While drug repositioning offers a cost‐effective solution, the lack of a subtype‐driven strategy hinders success. Previously, we defined genetic subtypes and their prioritized genes for each genetic subtype (Sahelijo et al., 2022). This study evaluated unsupervised learning algorithms to characterize existing compounds targeting prioritized genes for the genetic subtypes.

Method

Compounds in at least Phase 2 clinical trials were gathered from PubChem. Active compounds against subtype‐specific genes were selected, and their structural data were transformed into pharmacophore fingerprints using ChemmineR. Unsupervised algorithms (Agglomerative Clustering, Ensemble Clustering, Gaussian Mixture Models, Bayesian Gaussian Mixture Models) were optimized using evaluation metrics (Calinski‐Harabasz, Davies‐Bouldin, Silhouette) to cluster compounds within each subtype with the optimal cluster number and optimal algorithm. The finalized clusters of compounds were evaluated using significance values and mean within‐cluster Jaccard similarity scores and were characterized with target genes and mechanisms of action.

Result

Four of the nine genetic subtypes generated compound clusters, including 3 clusters using Agglomerative Clustering for Ast‐M2 with 11 targets and 180 compounds, 2 clusters using BGMM for Ast‐M9 with 14 targets and 341 compounds, and 4 clusters using Ensemble Clustering for Oli‐M45 with 11 targets and 66 compounds and for Oli‐M50 with 18 genes and 431 compounds. We observed common structural signatures between Ast‐M2, Ast‐M9, and Oli‐M50 clusters, while Oli‐M45 clusters did not share any signatures with other clusters. The most significant cluster was found for the Oli‐M45 subtype, with a cluster significance value of 8.49 and the highest mean compound similarity score of 0.96. The top‐ranked cluster primarily contained Vinblastine formulations—microtubule and tubulin polymerization inhibitors—targeting TUBA1A and TUBA1B.

Conclusion

We demonstrated a novel drug repositioning framework for AD using unsupervised learning algorithms, enabling precision medicine and subtype‐driven repositioning. This framework will be implemented in our future software tools.
The Psychosocial Analyzation of Alzheimer’s Disease and other Dementia among Black Ohioans
Authors: Harris Camren J
Published: January 2025

Background

Older Black Americans are twice as likely to have Alzheimer’s Disease or another dementia, and 65% of Black Americans say that they know somebody with Alzheimer’s or dementia. More locally, according to Ohio county level estimates, 11.3% of Ohioans aged 65 are currently living with Alzheimer’s Disease. Higher than the national average 10.7%

Method

A small sample size of Black Ohioans from different counties took a questionnaire pertaining to information as it relates to Alzheimer’s Disease and other dementia in the Black Communities in Ohio.

Result

82% of Black Ohioans surveyed know someone who has been diagnosed with Alzheimer’s Disease or related dementia. 64% of Black Ohioans do not believe cognitive decline issues are a part of normal aging. Only 35% of Black Ohioans surveyed say they are very knowledgeable about dementia. 87% of Black Ohioans surveyed are concerned about developing Alzheimer’s. 94% of Black Ohioans surveyed believe that the lack of access to resources is a reason why Black Americans are more likely to be diagnosed with Alzheimer’s Disease. 62% of Black Ohioans surveyed say they would consider participating in clinical trial concerning Alzheimer’s and/or related dementias if provided more information. 94% recorded that they have not (in the last 6 months) become aware of any elected officials creating or advocating for any legislation concerning cognitive care or dementia support and treatment. 52% believe dementia care, support and treatment should be a priority for elected officials.

Conclusion

Black Ohioans are concerned about the rising prevalence of Alzheimer’s Disease, however social barriers that prevent equitable access to care, support and treatment is of overwhelming concern. Additionally, Black Ohioans are interested in participating in clinical trials but due to the lack of resourceful information presented and/or provided concerning clinical trials to Black communities, further creates reluctance to participate. Lastly, more than half of the Black Ohioans surveyed are simply unaware of the public policy issues and priorities concerning cognitive decline, but would like for elected officials (federal, state and local) to be more intentional about utilizing public policy to build a better dementia infrastructure for those affected by Alzheimer’s Disease and other dementias.
Early Alterations of White Matter Neuroinflammation in Autosomal Dominant Alzheimer's Disease
Authors: Wang Qing , Jiang Meng , Cohen Kayle , Flores Shaney , Keefe Sarah J. , Patel Aakash , Chen Gengsheng , Millar Peter R , Schindler Suzanne E. , Cruchaga Carlos , Gordon Brian A. , Morris John C. , Bateman Randall J. , McDade Eric , Wang Yong , Benzinger Tammie L.S. ,   Dominantly Inherited Alzheimer Network
Published: January 2025

Background

Autosomal Dominant Alzheimer's Disease (ADAD) is a rare and early‐onset form of Alzheimer's disease with a familial pattern of inheritance. While the pathological features of ADAD, such as amyloid plaques and neurofibrillary tangles, have been extensively studied, the involvement of white matter (WM) neuroinflammation is not well‐explored. In sporadic AD, the hindered ratio (HR) derived from diffusion basis spectrum imaging (DBSI) has been used to study neuroinflammation in WM. This study aims to investigate the potential role of WM neuroinflammation as an early driver in the progression of ADAD using DBSI.

Method

This study included 104 participants from the Dominantly Inherited Alzheimer Network (DIAN) Observational Study. 60 participants were identified as mutation carriers of pathologic variants in PSEN1, PSEN2, or APP. Estimated years until symptom onset (EYO) were calculated for each participant based on previous methods (1). Participants’ demographics are summarized in Table 1. Diffusion MRI was acquired using a multi‐b value scheme (bmax =2000 s/mm2 and 28 directions) (2). The DBSI‐HR was quantified and obtained from the JHU white matter tracts. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed to compare demographic variables. The DBSI‐HR on each WM tract as a function of EYO was explored using generalized additive mixed models. All statistical tests were conducted in R4.2.2 (R Core Team). Age, sex, education, and APOE ε4 carrier status were adjusted as covariates.

Result

Demographic data are summarized in Table 1. Mutation carriers had an elevated averaged DBSI‐HR for total WM tracts compared to non‐carriers (Figure 1). Mutation carriers displayed divergent trends from non‐carriers prior to the expected symptom onset for the posterior thalamic radiation (‐5.87 EYO, Figure 2), tapetum (‐2.9 EYO), and sagittal stratum (‐1.20 EYO).

Conclusion

DBSI‐HR measurements indicate increased WM neuroinflammation in the posterior thalamic radiation, tapetum, and sagittal stratum prior to symptom onset in ADAD. We have recently identified these three WM tracts as having the earliest change in DBSI‐HR in sporadic AD. Together, these findings suggest that WM neuroinflammation occurs prior to onset of AD symptoms.
Associations between imaging biomarkers and sleep quality in the U.S. POINTER study baseline cohort
Authors: Winer Joseph R. , Ward Tyler J. , Scales Margaret , Taggett Jacinda , Howard Marjorie , Stone Katie L , Lockhart Samuel N. , Baker Laura D , Hayden Kathleen M. , Landau Susan M. , Harrison Theresa M. ,   The U.S. POINTER Study Group
Published: January 2025

Background

Worse sleep is associated with a greater risk of Alzheimer’s disease (AD). However, few studies have linked objective sleep with neuroimaging outcomes, limiting our understanding of how poor sleep impacts the brain. The U.S. POINTER trial, which has enrolled a heterogeneous cohort of older adults at elevated risk for cognitive decline, is a unique sample differing from prior investigations of sleep, aging, and brain health. Here we investigate how actigraphy‐assessed sleep duration and efficiency are cross‐sectionally associated with baseline neuroimaging measures of brain structure and AD pathology.

Method

Participants underwent neuroimaging (MRI, 18F‐florbetaben amyloid PET, and 18F‐MK6240 tau PET), cognitive testing, and wristwatch actigraphy, which assessed sleep duration and sleep efficiency averaged across six nights. Imaging analyses focused on bilateral entorhinal tau PET, cortical amyloid PET, hippocampal volume, white matter hyperintensity (WMH) volume, and diffusion free water. Based on prior literature suggesting short and long sleep duration are disadvantageous, quadratic models were fit for sleep duration predicting neuroimaging and cognitive measures, with age, sex, years of education, body mass index, and self‐identified racial ethnic category as covariates. Linear models were fit for sleep efficiency with the same covariates.

Result

Across 454 participants (Table 1), sleep measures were not related to cognition. Hippocampal volume, WMH volume, and free water showed U‐shaped relationships with sleep duration such that average sleep durations shorter and longer than approximately 6‐7 hours were associated with worse brain health outcomes (Figure 1). There were no associations between tau or amyloid PET and sleep duration. When stratified by amyloid status, associations between sleep duration and brain structure were significant in only the amyloid negative group. Unexpectedly, there were no associations between neuroimaging measures and sleep efficiency except for a significant positive relationship with entorhinal tau PET uptake.

Conclusion

In the largest and most heterogeneous sample to date of older adults with actigraphy and neuroimaging measures, sleep duration was associated with multiple measures of brain structure but not AD pathology. These relationships may reflect heterogeneity and selection characteristics of the at‐risk POINTER cohort, which differ from previous studies of sleep and AD biomarkers.
Blood‐based biomarkers of Alzheimer’s disease and 15‐year rate of olfactory decline in an elderly population
Authors: Ekström Ingrid , Vetrano Davide Liborio , Ruane Robert , Grande Giulia , Valletta Martina , Larsson Maria , Fredolini Claudia , Winblad Bengt , Fratiglioni Laura , Laukka Erika J
Published: January 2025

Background

Olfactory impairment has been observed as an early sensory marker of cognitive decline and dementia, but its association with biomarkers of Alzheimer’s disease (AD) pathology remains understudied, particularly in the context of blood‐based biomarkers.

Method

Here, we examine six common biomarkers of AD, tau phosphorylated at threonine 181 (P‐tau181), total tau (T‐tau), amyloid‐β ratio (Aβ42/Aβ40), P‐tau181/Aβ42 ratio, neurofilament light (Nfl), and glial fibrillary acidic protein (GFAP), derived from serum at the baseline assessment of the population‐based Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K; n = 1933, mean age at baseline = 71 years). Participants were free from dementia and neurodegenerative disorders at baseline. Linear mixed modeling examined the association between blood‐biomarker levels and Sniffin’ Sticks odor identification performance at baseline, and changes in performance over 15 years. Missing olfactory values during follow‐up were imputed by the maximum likelihood method.

Result

In multi‐adjusted models, controlling for demographic (age, sex, education), health (cerebrovascular disease, cardiovascular disease, chronic kidney disease, anemia, obesity) and cognitive (vocabulary) factors, higher levels of P‐tau181 (β = ‐0.087, 95% CI: ‐0.121 to ‐0.053), P‐tau181/Aβ42 ratio (β = ‐0.030, 95% CI: ‐0.054 to ‐0.006), Nfl (β = ‐0.055, 95% CI: ‐0.082 to ‐0.028), and GFAP (β = ‐0.026, 95% CI: ‐0.048 to ‐0.005) were associated with steeper olfactory decline over follow‐up. No significant associations with olfactory decline were observed for T‐tau or Aβ42/Aβ40. However, higher T‐tau levels were associated with lower olfactory baseline ability (β = ‐0.118, 95% CI: ‐0.234 to ‐0.007). Follow‐up analyses explored interactions for age, sex, and Apolipoprotein (APOE) ԑ4‐carrier‐status.

Conclusion

In sum, this study shows higher concentrations of blood‐based biomarkers of AD to be associated with faster rates of olfactory decline in community‐dwelling older adults. Our results support the validity of olfactory identification performance as a marker sensitive to underlying AD‐pathology. As such olfactory assessment could be of particular utility in settings where physiological biomarkers of pathology are unavailable, and olfactory performance may aid in determining which patients likely to benefit from further assessments.
Synergistic effects of GFAP and Aβ42 on clinical outcomes: Implications for white matter microstructure and verbal memory
Authors: Bettcher Brianne M , Paniagua Dan Lopez , Wang Yue , McConnell Brice , Coughlan Christina M , Carlisle Tara C , Thaker Ashesh A , Lippitt William , Filley Christopher M. , Pelak Victoria S , Potter Huntington , Solano D. Adriana , Boyd Jada , Carlson Nichole E
Published: January 2025

Background

Plasma GFAP, a biomarker of astrogliosis, has previously been linked with Alzheimer’s disease clinical status, amyloid levels, and memory performance in older adults. The neuroanatomical pathways by which GFAP might impact cognitive outcomes remains unclear. We evaluated whether fornix structure, which is critically involved in AD‐associated cholinergic pathways, is associated with interactive effects of plasma GFAP and amyloid levels. We also appraised whether fornix structure mediates associations between GFAP and verbal memory.

Method

In a cohort of both asymptomatic and symptomatic older adults (total n=90), we assessed GFAP, AD‐related proteins, and vascular markers in plasma, and we conducted comprehensive memory testing. Tractography‐based methods were used to assess structure of the fornix, and whole brain diffusion metrics were also ascertained to control for diffuse alterations in white matter.

Result

In individuals whose blood levels of Aβ42 were in the lowest tertile, higher GFAP levels were associated with lower fractional anisotropy (FA; p=0.007), higher mean diffusivity (MD; p<0.001), higher radial diffusivity (RD; p <0.001), and higher axial diffusivity (AD; p=0.001) in the left fornix. These associations were independent of APOE gene status, plasma levels of total tau and neurofilament light, plasma vascular biomarkers, and whole brain diffusion metrics. Fornix structure partially mediated the association between higher GFAP levels and lower verbal memory performance in participants with lower plasma Aβ42.

Conclusion

Results suggest that in the setting of greater amyloid deposition, higher levels of blood GFAP are associated with altered fornix microstructure. We also expanded on our prior GFAP‐verbal memory findings, demonstrating that in the subset of participants with lower blood Aβ42 levels, left fornix integrity may be a primary white matter pathway for the negative associations between GFAP and verbal memory performance. Overall, these findings suggest that GFAP may play an early, pivotal role in AD pathogenesis, and further demonstrate that the combination of blood GFAP and Aβ42 may have a particularly negative role in forniceal‐memory pathways.