bluuebunny/crossref_metadata_2025 huggingface dataset:
TDP‐43 proteinopathy induced transcriptional alterations in Alzheimer’s disease
Authors: Pevey Ryan S
Published: January 2025

Background

TDP‐43 is an RNA binding protein that is a pathological hallmark of multiple neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). The frequency of observed TDP‐43 pathology is estimated at 97% in ALS, 45% in FTD and 40‐57% in AD and is characterized by a mislocalization of TDP‐43 from the nucleus to the cytoplasm. Indeed, TDP‐43 is the third most common proteinopathy in AD, behind only Amyloid beta and Tau. The normal function of TDP‐43 has been linked to multiple steps in RNA processing including transcription, splicing, RNA transport, stability, localization, and translation. Most studies aimed at understanding TDP‐43 pathology have been performed in the context of ALS and FTD, while little is known about the molecular mechanisms and consequences of TDP‐43 pathology in AD. We hypothesize that TDP‐43 dependent alterations in gene expression in neurons with TDP‐43 pathology are contributing to neuronal dysfunction and degeneration in AD and related dementias.

Methods

To test this hypothesis, we sorted neuronal nuclei with normal and depleted TDP‐43 levels from human post‐mortem AD and Mild Cognitive Impairment (MCI) patients as well as Non‐neurological Disease (ND) Controls.

Results

RNA sequencing results from these sorted nuclear isolates show substantial genome wide transcriptional alterations in gene expression as well as alternative splicing, and TDP‐43‐associated cryptic exon inclusion.

Conclusions

These results support the significant role of TDP‐43 pathology on the transcriptome of up to half of AD patients and the need for further exploration of a common but overlooked aspect of the most common progressive dementia in patients today.
Brief health literacy assessment as an enhancement to existing cognitive screening tests: an exploratory investigation
Authors: Vogeley Abigail , Curtis Laura M , Opsasnick Lauren , Batio Stephanie , Russell Andrea , Light Sophia W. , Yeh Fangyu , Yoshino‐Benavente Julia , Bonham Morgan , Lovett Rebecca , Wolf Michael S
Published: January 2025

Background

Most cognitive screening tests used in primary care to identify adults with cognitive impairment, including Alzheimer’s disease and related dementias, have been limited in their diagnostic accuracy, especially in mild cases. Resultant false positives or false negatives (e.g., delayed diagnoses) have respective harms. While expressed concern of an individual’s real‐world self‐care abilities from a caregiver can improve confidence in a screening result, as many as half of patients with cognitive complaints may lack this informant. We explored whether the addition of an objective, brief, health literacy assessment could improve the accuracy of a longstanding, common cognitive screening tool.

Method

Data came from a longitudinal aging study of older adults from Chicago, IL. Cognitive function was assessed using Z‐scores generated from a comprehensive neurocognitive battery of 13 measured across 5 domains. Participants were determined to have an impairment if they scored ←1 on ≥2 tests within at least one domain. The Mini Mental Status Exam (MMSE) and the Newest Vital Sign (NVS), a common 3‐minute, 6‐item measure of health literacy, were administered. Receiver operating characteristic (ROC) curves assessed the specificity and sensitivity of adjusted MMSE models (cut‐off score ≤26) with and without the NVS to detect cognitive impairment. Areas under the curve (AUCs) were compared using the DeLong test.

Result

Participants (N = 389) were on average 71 years old (SD 5.2); most participants were female (72%) and non‐Hispanic White (56%). Most (86%) had 2+ chronic conditions (M 3.4 (SD 1.8)), and 28% had at least a mild cognitive impairment based on our comprehensive neurocognitive battery. ROC analyses indicated that cognitive impairment detection by the MMSE alone (AUC = 0.79, 95% CI [0.73‐0.84]) was significantly improved (Z = ‐3.68, 95% CI [0.03,0.11], p‐value = <0.001) with inclusion of the NVS (AUC = 0.86, 95% CI [0.82‐0.90]).

Conclusion

Our findings demonstrate the potential benefit of integrating a brief assessment of real‐world self‐care task performance and health literacy, such as the NVS, with routine cognitive screening tests to improve accurate identification of cognitive impairment in primary care. Improving the accuracy of common screening tools may help facilitate earlier detection, diagnosis, and subsequent care.
Elevated brain miR298 is associated with a reduced risk of Alzheimer’s disease
Authors: Lahiri Debomoy K. , Wang Ruizhi , Maloney Bryan , Ghetti Bernardino , Saykin Andrew J. , Kumar Subodh , White Fletcher A , Greig Nigel H , Sambamurti Kumar , Counts Scott E.
Published: January 2025

Background

Non‐coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA‐induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule‐associated protein tau and amyloid‐β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus. We report that miR298 plays a vital role in maintaining APP and tau homeostasis and that miR298 imbalances may impact AD progression.

Method

Levels of miR298 from non‐cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources were measured by qRT‐PCR and assessed for associations with AD risk and potential covariates such as age and APOE genotype. Other biomarkers were assessed in cortical samples from the same subjects, as we previously described. Further, APP, tau, and cytokines were profiled in miR298 mimic‐ or its antagomiR‐expressing human neuronal and astrocyte cultures.

Result

Levels of miR298 varied in postmortem temporal lobe between AD patients and age‐matched NCI controls. Higher brain miR298 levels were associated with a reduced risk of AD. Subject age and APOE genotype altered this association; specifically, greater age and dose of the APOEε4 allele were associated with an increased risk of AD. However, APOEε4 dose‐associated risk reduced as age increased. We identified putative binding sites for miR298 on APP, BACE1, MAPT, IL1α, and IL6 mRNAs to form RISC. We showed that treatment by miR298 reduced tau, APP, and BACE1 proteins and mRNA levels in cell cultures.

Conclusion

These studies suggest that miR298 regulates a coordinated network of AD‐related proteins APP, BACE1, and tau. Hence, such network regulation may represent a rational therapeutic target for reducing AD risk and disease modification. In addition to late‐onset cases, we will profile miR298 in brain tissue samples from early‐onset AD cases. Future work involves testing miR298 in AD animal models, such as in human tau‐overexpressing transgenic mice. We sincerely thank grant support from NIA/NIH.
Subjective memory complaints and neuropathologic changes at age 90 and older: The 90+ Study
Authors: Melikyan Zarui A. , Kawas Claudia H. , Paganini‐Hill Annlia , Al‐Darsani Zeinah , Jiang Luohua , Bukhari Syed A. , Montine Thomas J. , Corrada María M. M.
Published: January 2025

Background

Subjective Memory Complaints (SMC) are defined as the perception of one’s own memory. In several studies SMC are associated with Alzheimer’s disease (AD) neuropathologic changes, and only one study has analyzed and found an association of SMC with other neurodegenerative, but not vascular, neuropathologic changes. Yet, the evidence on the association of SMC with non‐AD neuropathologic changes is insufficient. We aim to examine the association of SMC with neurodegenerative and vascular neuropathologic changes in individuals age 90 and older (oldest‐old) without dementia at death.

Method

The participants of The 90+ Study, a longitudinal study of aging and cognition, who had neuropathologic examination, SMC evaluation, and had no dementia at consensus case conference were included in the analysis. SMC was evaluated with a question from the Geriatric Depression Questionnaire (GDS) “Do you feel you have more problems with memory than most?”, consensus case conference diagnosis was normal cognition or Cognitive Impairment No Dementia (CIND). SMC was dichotomized as reported ever vs. never during the study follow‐up, and neuropathologic changes were dichotomized as present (see Table 2) vs. absent. We estimated odds ratio [OR] and 95% confidence interval [CI] for presence of each neuropathologic change in those with normal cognition and CIND using logistic regression adjusted for demographics, GDS minus the SMC item averaged across all visits, and MMSE averaged across all visits.

Result

In 238 participants mean age at autopsy was 98 years, 121 (51%) had normal cognition, 67 (28%) have ever reported SMC (Table 1). Those with normal cognition and SMC had higher odds of AD neuropathologic change (OR = 2.9; CI: 1.5‐7.9; p = 0.04), Lewy Body Disease (LBD) (OR = 3.6; CI: 1.8‐11.8; p = 0.04), and atherosclerosis (OR = 3.1; CI: 1.2‐8.1; p = 0.02). There were no significant findings in those with CIND (Figure, Table 2).

Conclusion

In the oldest‐old with normal cognition SMC are associated with higher odds of neurodegenerative (AD and LBD) and vascular (atherosclerosis) neuropathologic changes. It is possible that those with normal cognition complain more selectively with respect to neuropathologic changes, compared to those with CIND.
Relationship between disturbed sleep and longitudinal changes in cerebral beta‐amyloid accumulation in cognitively normal elderly adults
Authors: Lee Min Ji , Keum Musung , Kim Jee Wook , Suh Guk‐Hee , Choe Young Min ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

In our previous study, using cross‐sectional data, we noted that poor sleep quality during midlife increases pathological beta‐amyloid protein (Aβ) deposition. This study aimed to investigate the relationship of disturbed sleep and longitudinal changes in cerebral Aβ accumulation in elderly individuals with normal cognition.

Method

Three‐hundred and two cognitively normal old adults from the Alzheimer’s Disease Neuroimaging Initiative received (18F)‐florbetapir positron emission tomography (PET) scans. Sleep disturbance and depression were measured using the baseline Neuropsychiatric Inventory (NPI) or NPI‐Questionnaire sleep and depression items. Multiple linear regression analysis was performed to examine the relationship between poor sleep and baseline Aβ deposition and rate of change in Aβ accumulation after adjusting for age, gender, education, and depression.

Result

In cognitively normal elderly individuals, poorer sleep was significantly associated with higher rates of Aβ accumulation after controlling for age, gender, education and depression. In contrast, we could not find any significant relationship between sleep disturbance and baseline Aβ deposition.

Conclusion

Our results suggest that disturbed sleep accelerates longitudinal Aβ accumulation in cognitively healthy old adults. On the other hand, the present results do not support the hypothesis of opposite direction that Aβ deposition influences sleep disturbance.
Initial solvent conditions impact the reproducibility and aggregation trajectory of monomeric Amyloid Aβ
Authors: Najarzadeh Zahra , Glabe Charles G
Published: January 2025

Background

Our goal is to identify conditions to produce structurally homogeneous and reproducible preparations of different polymorphic structures. Here we investigate the effect of several widely used methods for solubilizing Abeta on the subsequent aggregation process.

Method

Aliquots of HPLC‐purified synthetic Aβ40 in originally lyophilized from acetonitrile/water (AcN) 50% v/v were dissolved in hexafluoroisopropanol (HFIP) 100%, AcN 50% v/v, NH4OH 2%, or 50 mM Phosphate buffer (PB), re‐aliquoted and lyophilized. These aliquots were dissolved in 2% NH4OH, HFIP, AcN 50%, DMSO or 50 mM NaOH to make a stock solution (4mM) or directly dissolved in PB to a final concentration of 50µM. Fibrillation kinetics assays were conducted in triplicate after dilution of the stock solutions 50 uM in PB and fibrillization monitored by thioflavin‐T (ThT).

Result

We observed large differences in the aggregation behavior of Aβ depending on initial solvent conditions, impacting lag phase, ThT kinetics, fluorescence end point, fibrilization rate, and overall reproducibility. Solubilization in 50 mM NaOH significantly enhances the reproducibility of fibrillation compared to other methods confirming previously published work. Initial solubilization HFIP and NH4OH for stock preparation yields less reproducible aggregation behavior. Dissolving peptide in NH4OH leads to a longer lag phase (almost 10 h longer) compared to using other solvents. Directly dissolving the peptide in PB demonstrates better reproducibility compared to preparing stock in solvents like HFIP, NH4OH, AcN50%, and DMSO. Additionally, we demonstrate that sonication and centrifugation of the stock before dilution contribute to achieving an aggregate‐free monomeric solution. Even after monomerization in 50 mM NaOH, prior treatment with other solvents results in reproducible differences in aggregation behavior, suggesting that the monomeric peptide may retain local structure imprinted by prior solvent exposure.

Conclusion

Our analysis indicates that solubilization with NaOH (50mM) offers a dependable method for solubilizing Aβ monomer. This results in monomeric and homogeneous peptide stock solutions, exhibiting exceptionally reproducible assembly kinetics when returned to near‐neutral pH. Prior solubilization and monomerization of Aβ in HFIP, DMSO, AcN and NH4OH results in variable kinetics and extent of fibrillation. Prior exposure to these other solvents produces reproducible differences in aggregation even after monomerization in NaOH.
DeepHoloBrain: From Geometric Deep Model to Computational Neuroscience
Authors: Dan Tingting , Wu Guorong
Published: January 2025

Background

The human brain is a complex inter‐wired system that emerges spontaneous functional fluctuations. In spite of tremendous success in the experimental neuroscience field, a system‐level understanding of how brain anatomy supports various neural activities remains elusive.

Method

Capitalizing on the unprecedented amount of neuroimaging data, we present a physics‐informed deep model to uncover the coupling mechanism between brain structure and function through the lens of data geometry that is rooted in the widespread wiring topology of connections between distant brain regions. Since deciphering the puzzle of self‐organized patterns in functional fluctuations is the gateway to understanding the emergence of cognition and behavior, we devise a geometric deep model to uncover manifold mapping functions that characterize the intrinsic feature representations of evolving functional fluctuations on the Riemannian manifold. In lieu of learning unconstrained mapping functions, we introduce a set of graph‐harmonic scattering transforms to impose the brain‐wide geometry on top of manifold mapping functions, which allows us to cast the manifold‐based deep learning into a reminiscent of MLP‐Mixer architecture (in computer vision) for Riemannian manifold.

Result

As a proof‐of‐concept approach, we explore a neural‐manifold perspective to understand the relationship between (static) brain structure and (dynamic) function, challenging the prevailing notion in cognitive neuroscience by proposing that neural activities are essentially excited by brain‐wide oscillation waves living on the geometry of human connectomes, instead of being confined to focal areas.

Conclusion

In practice, we evaluate the clinical value of our mixer model in (1) disease early diagnosis and (2) generality of adapting the pre‐trained model to a new dataset. Our extensive experimental results affirm the model’s effectiveness and practicality, marking a significant advancement in the field of neuroscience.
Serological inflammation markers and their association with cognition in the oldest old; The 90+ Study
Authors: Leiby Anne‐Marie C , Farahmand Ghasem , Ramanathan Aanan , Woodworth Davis C. , Jiang Luohua , Yu Jiaxin , Qian Tianchen , Corrada María M. M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: January 2025

Background

Recent studies in the younger old have identified associations between cognitive performance and markers of inflammation, including interleukin‐6 (IL‐6) and erythrocyte sedimentation rate (ESR). These associations remain unexplored in the oldest old (age 90+), an age group most vulnerable to dementia. In addition, no studies have examined if amyloid burden impacts these associations. This study aims to: (1) examine the associations between inflammatory markers (IL‐6, ESR) and cognitive performance in individuals age 90+ and (2) to examine if amyloid burden impacts these associations.

Method

Participants with at least one plasma measure of inflammation and amyloid burden measured by positron emission tomography (PET) were selected from The 90+ Study (n = 112 for IL‐6, n = 123 for ESR). Cognitive measures included (1) global cognitive score defined as the average of the standardized scores of Mini‐Mental State Examination (MMSE) and Modified MMSE (3MS), and (2) memory score, that was the average of the standardized scores of California Verbal Learning Test (CVLT) and memory items of 3MS. PET amyloid burden was measured by standardized uptake value ratio (SUVR). We examined the associations between IL‐6 and ESR (independent variables) with cognitive measures (dependent variable) using linear regression models. Two models were implemented: first, without adjustment and second, with adjustment for amyloid. Both models were also adjusted for age at blood draw, sex, and education (college/no college). We additionally adjusted for amyloid burden and years between blood draw and PET scan in the second model.

Result

Mean age at blood draw was 94.7±2.8 and most participants were female (63.4%) and white (92.7%) (Table 1). In model 1, for both IL‐6 and ESR, higher levels were significantly associated with lower global cognitive scores (Table 2). Only IL‐6 was significantly associated with memory score (Table 2). Amyloid adjustment in model 2 had little effect on our results (Table 2).

Conclusion

This study suggests that systemic inflammation could contribute to cognitive performance in individuals aged 90 and older. Additionally, this influence may be linked to a process not attributed to amyloid. Further research is warranted to explore the role of inflammation in non‐Alzheimer’s disease dementias.
Short tandem repeat expansions are a novel genetic risk factor for Alzheimer’s disease
Authors: Guo Michael H , Lee Wan‐Ping , Vardarajan Badri N , Schellenberg Gerard D. , Phillips‐Cremins Jennifer E
Published: January 2025

Background

Studies of the genetics of Alzheimer’s disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, much of the disease heritability has yet to be uncovered, suggesting that other forms of genetic variation promote substantial portions of genetic risk. Uncovering the genetic basis of AD can lead to new disease biomarkers and delineate disease mechanisms. As there are over one million short tandem repeats (STRs) in the genome and pathogenic expansions of STR cause over 30 neurologic diseases, it is important to ascertain whether STRs may also be implicated in AD risk.

Method

Here, we utilize PCR‐free whole genome sequencing data from 2,981 individuals (1,489 AD case and 1,492 control individuals) to study the role of STRs in AD. We applied two cutting‐edge algorithms, ExpansionHunter and gangSTR, to genotype 321,742 STR tracts across the genome using the whole genome sequencing data. For each STR, we identified individuals carrying an expansion defined as having an STR tract length that is an outlier from the population. We then calculated the number of STR expansions in each individual and tested for differences in aggregate burden of STR expansions in AD case versus control individuals.

Result

Individuals with AD had a 1.19‐fold increase burden of STR expansions compared to controls (p = 8.27 × 10‐3, two‐sided Mann Whitney test). Individuals carrying > 30 STR expansions had 3.62‐fold higher odds of having AD and had more advanced spread of tau neuropathology as measured by Braak staging. AD STR expansions were highly enriched within gene regulatory elements active in the hippocampus.

Conclusion

These results demonstrate that harboring a high burden of STR expansions in the genome increases risk of AD and that STR expansions may serve as a novel genomic biomarker of AD risk and neuropathologic progression. Our findings suggest that STRs may disrupt gene expression and underscore the pivotal role of genomic instability in the onset and progression of AD.
The Digital Clock and Recall is More Equitable and Less Biased than the Mini‐Mental State Examination in Terms of Ethnicity
Authors: Toro‐Serey Claudio , Jannati Ali , Banks Russell , Showalter John , Bates David , Tobyne Sean , Pascual‐Leone Alvaro
Published: January 2025

Background

Early detection of cognitive impairment is crucial for maximizing the benefits of disease‐modifying treatments for Alzheimer’s disease (AD). Brief, automatically‐scored digital cognitive assessments such as the Digital Clock and Recall (DCR) show promise in streamlining this early detection. However, wide adoption of such assessments in diverse populations requires evaluation of their demographic biases. Here, we compared the biases due to ethnicity, race, and education level between the DCR and the Mini‐Mental State Examination (MMSE).

Method

We studied 706 primarily English‐speaking participants from Bio‐Hermes‐001 study (age mean±SD = 71.5±6.7; 58.9% female; years of education mean±SD = 15.4±2.7; 85.1% White; 9.3% Hispanic), classified a priori as cognitively unimpaired (CU; n = 360), mild cognitive impairment (MCI; n = 234), or probable Alzheimer’s dementia (pAD; n = 111) based on expert consensus and neuropsychological evaluation. We also studied 770 participants in a prescreening study for AD‐related clinical trials (age mean±SD = 68.8±13.2; 64% female; education = 15±2.6; 78% White; 20% Hispanic) including CU (n = 338), MCI (n = 178), and pAD (N = 254). For each dataset, bias was compared by bootstrapping two multiple linear regressions predicting either Z‐scaled DCR or MMSE scores using race, ethnicity, sex, education, and age as predictors. The bootstrapped demographic coefficients (i.e. mean differences) were compared between tests and significance was determined via 95% confidence intervals on these differences.

Result

A larger ethnicity bias was observed for the MMSE than for the DCR, which was significant in the Bio‐Hermes (bias difference = 0.44 larger for MMSE, 95% CI = 0.12–0.75) but not the pre‐screener study (bias difference = 0.20 larger for MMSE, 95% CI = ‐0.32–0.74). We found significant differences between Hispanic and non‐Hispanic individuals only for MMSE in both datasets (Mann‐Whitney test, p<0.01). Bias for race and education was not significantly different between tests.

Conclusion

Unlike the MMSE, the DCR is not influenced by ethnicity. Given the higher prevalence of cognitive impairment and greater risk of dementia in ethnic minorities (with Hispanics forming the largest minority group), the deployment of less biased assessments such as the DCR is important for more equitable cognitive screening.
Cognitive performance assessment in healthy older adults: Results from an 18‐month multicomponent cognitive stimulation randomized clinical trial
Authors: Silva Thais Bento Lima , Ordonez Tiago Nascimento , dos Santos Gabriela , Moreira Ana Paula Bagli , Costa Laydiane Alves , Perpétuo Bárbara , Lessa Patrícia Prata , Moraes Luiz Carlos , Cardoso Neide Pereira , Brucki Sonia Maria Dozzi , Yassuda Monica Sanches
Published: January 2025

Background

This study investigated the effects of cognitive stimulation on older adults over 18 months through a randomized clinical trial with 190 participants divided into Training Group (TG), Active Control Group (ACG), and Passive Control Group (PCG). Initial sociodemographic characterization (Table 1) ensured homogeneity among the groups. The clinical trial design aimed to assess the long‐term impacts of multicompartment cognitive stimulation on the cognitive function of older adults in the TG.

Method

Participants were randomly assigned to TG, ACG, or PCG, with an assessment of initial sociodemographic characteristics to ensure homogeneity. The analysis of cognitive performance (Table 2) and the development of the composite score (Table 3) were conducted. Using standardized z scores and specific formulas, the composite score incorporated assessments of memory, attention, executive functions, and logical reasoning, providing a comprehensive and balanced measure of cognitive function.

Result

The evaluation of cognitive performance (Table 2) using individual instruments did not identify significant variations between the groups. However, composite scores (Table 3) indicated notable improvements in overall cognition for the TG compared to the other groups. Repeated measures ANOVA revealed significant differences in the composite cognition score for TG participants over time (T0 versus T3).

Conclusion

The results highlight the effectiveness of long‐term cognitive stimulation, especially in the TG, suggesting measurable benefits in the cognition of healthy older adults. This study contributes to the development of a composite score for analyzing cognition in healthy older adults, utilizing nationally and internationally validated instruments. Additionally, it provides insights into the effects of long‐term multicompartment cognitive stimulation, guiding future interventions to promote cognitive health in older adults.
Genetic correlation and causality assessment between Alzheimer’s disease and asthma
Authors: Bamidele Olasunkanmi David , Adewuyi Emmanuel O , Porter Tenielle , Armstrong Ayeisha Milligan , Verdile Giuseppe , Laws Simon M. ,   Neurological Conditions Group
Published: January 2025

Background

Observational studies have suggested a co‐occurring relationship between Alzheimer’s disease (AD) and asthma. However, the aetiology and biological mechanisms underlying AD and its potential association with asthma, an autoimmune condition, remain unclear.

Method

We examine the genetic relationship between AD and asthma by analysing large‐scale genome‐wide association study (GWAS) summary data from international research consortia and groups. We conducted a linkage disequilibrium score regression (LDSC) analysis to assess AD’s genome‐wide (global) genetic correlation with asthma. We also performed a two‐sample Mendelian randomization (MR) analysis to investigate the potential bi‐directional causal relationships between AD and asthma. We performed additional analyses for possible (partial) replication of our genetic correlation and causality findings on the side of both AD and asthma.

Result

Our LDSC‐based genetic correlation estimates revealed a positive and significant global genetic correlation (rG) of AD with asthma (rG = 0.19, SE = 0.04, P = 5.57 × 10‐6). We used additional asthma GWAS data for replication testing, with consistent, significant results across all data. We observed a similar pattern of correlation estimate direction in our (partial) replication testing for AD (clinically diagnosed cases), although only one of the asthma GWAS data’s results was significant (likely due to a smaller sample size). Based on the inverse‐variance weighted (IVW) model, our MR analysis found no evidence for a significant causal association between AD and asthma. This MR result was consistent with AD or asthma as an exposure or outcome variable, respectively. Sensitivity testing using other MR approaches produced results similar to our IVW model, supporting no evidence of a causal association between AD and asthma.

Conclusion

Our study reveals a significant genetic correlation but non‐causal association between AD and asthma, implicating the presence of shared genetic mechanisms and biological pathways in both conditions.
Alzheimer’s disease‐associated gene ranking using PhenoGeneRanker
Authors: Rahman Most Tahmina , Saeed Fahad , Bozdag Serdar ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurogenerative disease that affect millions worldwide with no effective treatment. Several studies have been conducted to decipher to genomic underpinnings of AD. Due to its complex nature, many genes have been found to be associated with AD. Despite these findings, the pathophysiology of the disease is still elusive. In this study, we integrated multimodal gene and phenotype datasets of AD using network biology methods to prioritize potential AD‐related genes.

Method

We collected phenotypic and genotypic datasets of AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and protein‐protein interaction (PPI) dataset from STRING database. We constructed a multiplex heterogeneous network composed of patient and gene similarity networks. We built three phenotypic network layers utilizing the patient’s demographic, cognitive and neuroimaging data, and two gene similarity network layers using gene expression and PPI data (Table 1). Starting from AD‐associated gene APP, we applied PhenoGeneRanker to traverse this network to discover potential AD‐associated genes. To assess the impact of each network layer and seed gene, we also run PhenoGeneRanker on different variants of the network and seed genes. We performed Gene Ontology (GO) enrichment to assess the results.

Result

We performed GO enrichment for the top 200 ranked genes. As a negative control, we repeated the same for the bottom 200 ranked genes. The top genes were enriched in terms such as amyloid precursor protein metabolic process, lipid metabolic process, and programmed cell death (Table 2), whereas bottom‐ranked genes had no GO enrichment. We also found some genes in the top 200 such as PSEN2, CLU, SORL1, PICALM, and APOE, which were identified as AD‐related genes in literature. Our top 2000 gene list captured over 50% of genes that were reported as AD‐associated (Figure 1). Ablation studies were performed to assess the impact of each network layer and seed genes. We observed that impact of PPI layer and APP seed gene were high.

Conclusion

We identified candidate genes for AD that were enriched in disease‐related GO terms and captured previously reported genes, which suggest that other top‐ranked genes could be novel AD‐associated genes.
Methods and initial characteristics of aged participants in a randomized clinical trial on cognitive stimulation
Authors: Silva Thais Bento Lima , Ordonez Tiago Nascimento , dos Santos Gabriela , Moreira Ana Paula Bagli , Costa Laydiane Alves , Perpétuo Bárbara , Lessa Patrícia Prata , Moraes Luiz Carlos , Cardoso Neide Pereira , Brucki Sonia , Yassuda Monica Sanches
Published: January 2025

Background

Scientific investigations underscore the cognitive, psychological, and social benefits of cognitive stimulation for aged individuals, yet rigorous long‐term studies remain limited.

Method

This abstract outlines the methods and initial participant characteristics of a controlled, randomized clinical trial on cognitive stimulation. A total of 578 aged individuals responded to the study call, with 362 meeting eligibility criteria. Subsequently, 255 participants were selected and randomized into Training Group (TG), Active Control Group (ACG), and Passive Control Group (PCG). During the baseline phase (T0), 48 participants withdrew, resulting in a T0 sample of 207 participants.

Result

The three groups exhibited homogeneity in cognitive performance, sociodemographic, and psychosocial variables, with only depressive symptoms showing a significant difference, where TG scored higher. Despite this difference, other variables indicated equivalence among the research groups.

Conclusion

The outlined methods serve as inspiration for future research on cognitive stimulation in the aged.
On the Risk of Alzheimer’s Disease in Survivors of Myocardial Infarction: A Mendelian Randomization Study
Authors: Ashebir Yibeltal Arega , Zhang Yian , Shao Yongzhao
Published: January 2025

Background

Myocardial infarction (MI) is a leading cause of death while those surviving MI are still at risk of developing dementias. Alzheimer’s disease (AD) is the leading cause of dementia currently without a cure or an effective prevention even in vulnerable subpopulations. Both AD and MI are common causes of disabilities and deaths in aging populations. It is of interest to investigate AD risk and possible preventive measures for AD among vulnerable aging populations including those surviving MI (survMI).

Method

Employing a two‐sample Mendelian randomization (2SMR) analysis, we assessed the causal relationship between survMI and the risk of AD, utilizing independent AD and MI genome‐wide association study (GWAS) summary datasets. Sensitivity tests, including MR‐Egger intercept test, Cochran Q‐test, and leave‐one‐out analysis, were performed to ensure robustness.

Result

The 2SMR study, utilizing 62 independent single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), revealed a decreased risk of AD associated with survMI (OR = 0.897, p = 6.03E‐11). The MR‐Egger intercept test (p = 0.405) indicated the absence of horizontal pleiotropy, and no evidence of heterogeneity was observed based on the Cochran Q‐test (p = 0.429). Some of the instrumental genetic variants, rs765549, rs11652894, rs12693302, and rs10455872 are linked to LPL, SREBF1, PDE1A, and SLC22A3 genes—targets of medicines and dietary supplements like calcium channel blockers and Omega‐3/fish oil commonly used to enhance MI survival chances.

Conclusion

The 2SMR analysis indicated a significant causal association between survMI and a reduced risk of AD. This suggests that commonly‐used medications, including calcium channel blockers, and supplements like Omega‐3 products, may contribute to lowering the risk of AD. Further studies are essential to validate these findings and explore potential preventive measures for AD using combinations of medications and dietary supplements commonly employed to enhance the probability of surviving MI.
Somatic Loss of the Y Chromosome and Alzheimer’s Disease Risk
Authors: Cukier Holly N. , Palmer Ellen L. , Benchek Penelope , Wheeler Nicholas R. , Smeisek Sandra , Naj Adam C. , Haines Jonathan L. , Pericak‐Vance Margaret A , Forsberg Lars , Song Yeunjoo E. , Bush William S.
Published: January 2025

Background

Mosaic loss of the Y chromosome (LOY) is a somatic, age‐related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer’s Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting a potential functional role in AD pathogenesis.

Method

In this study, we further validate the association between LOY in blood and AD via prospective analyses of 1,447 males. We defined a continuous estimate of LOY mosaicism by computing the median of the log R ratio (mLRRY) from raw intensity genotyping data. We also perform Mendelian Randomization analysis on 10,013 males across 26 US cohorts from the Alzheimer’s Disease Genetics Consortium (ADGC) dataset.

Result

Age at blood draw was stratified into four bins consistent with prior literature (≤65, 66‐75, 76‐85, ≥86), and Wilcoxan rank sum tests were performed to examine the distribution of LOY by age at blood sampling. This trend of LOY increasing with age was highly significant over all samples and between all age groups. Within males with an available clinical diagnosis (n = 3117), there are significant differences between males ≤65 and all other age groups (66‐75 p = 0.00061, 76‐85 p = 7.9e‐12, ≥86 p = 5.5e‐13).

To evaluate the association between LOY and risk of developing AD in follow‐up, we fit a Cox proportional hazards model associating binary LOY to years of disease‐free follow‐up within 1,447 individuals for whom blood was sampled prior to any AD diagnosis. Of these, there were 42 subsequent AD events with all others remaining controls. Overall, we find a significantly increased hazard (1.98 [1.17–6.91], p = 0.0021) in men with LOY versus those without. To account for potential biases in sample ascertainment with respect to age and case/control status, we performed Mendelian Randomization analyses of LOY. Using the Wright‐based instrument, we had a significant two‐sample Mendelian randomization effect using the Inverse Variance Weighted approach (p = 0.008).

Conclusion

Significant results from these analyses provide further evidence for a role of LOY in the development of Alzheimer’s Disease.
Protein degradation impairment and synapse elimination by microglia in BSN P3866A knock‐in mouse model of tauopathy
Authors: Patel Henika , Martinez Pablo , Lopes Daniella , Jury Nur , Vanderbosch Katie , You Yanwen , Kouri Naomi , Rothberg Darren M. , Yaguchi Hiroaki , Tanaka Shinya , Wakabayashi Koichi , Yabe Ichiro , Murray Melissa E. , Reeves Cristian A Lasagna
Published: January 2025

Background

Tau aggregation is the major cause of several neurodegenerative tauopathies. Tau interaction with other proteins affects the formation of tau aggregates with seeding activity but less is known about its effects on tau‐seed properties. Our previous study revealed that Bassoon (BSN), a presynaptic protein, interacts with tau‐seed, exacerbating its toxicity in vivo. Bsndownregulation reduced tau spreading and overall pathology. Intriguingly, a parallel study associated missense mutations in BSN with tau aggregation in patients, prompting an investigation into the influence of genetic mutations in BSN on tau pathology for potential therapeutic insights.

Method

We generated a knock‐in mouse model (BSNKI) harboring the disease‐associated p.Pro3866Ala mutation in endogenous Bsn. Cognitive and motor abilities were assessed in aged heterozygous and homozygous BSNKI mice, followed by analyses of BSN and tau patterns, gliosis, and gene expression changes in their brains. Additionally, we validated our findings in a human BSN mutation carrier.

Result

At 10 months, BSNKI mice displayed motor impairments on the rotarod, and grip strength assays compared to WT mice. Their brains displayed somatic BSN and pathological tau accumulation, with the gene expression changes indicating alterations in microglia activation, protein degradation pathways, complement activation, and synapse pruning. We also observed an accumulation of pathological tau at the synapses and synapse engulfment by microglia. Histopathological analyses revealed robust microglia activation and co‐deposition of proteasomal subunits with BSN. The human BSN mutation carrier displayed inclusions of BSN and tau pathology similar to observations in the BSNKI model.

Conclusion

Our BSNKI mouse model, reflecting a disease‐associated BSN mutation, revealed motor impairments and pathological tau and BSN deposits, mirroring observations in BSN mutation carriers. Notably, BSN seems to play a dual role, promoting tau aggregation and sequestering protein degradation molecules, leading to tau and protein accumulation at the soma and synapse, triggering microgliosis and neuroinflammation. These findings propose BSN as a promising therapeutic target for tauopathies, underscoring the need for further exploration to elucidate underlying mechanisms and therapeutic implications.
Late‐life hemoglobin A1C is associated with postmortem neuropathology in older adults with and without diabetes
Authors: Biswas Roshni , Capuano Ana W. , Mehta Rupal I. , Bennett David A. , Arvanitakis Zoe
Published: January 2025

Background

Hemoglobin A1C (A1C) is a measure of long‐term glycemic control. In a previous study using a single measure of A1C, we showed that it is related to postmortem cerebrovascular pathology. Here, we use annually collected A1C data to study the relationship of A1C average and variability over time with neuropathology in a large number of older adults with and without diabetes.

Method

Our study included annually collected longitudinal data on 820 older women and men (mean years of follow‐up 4.0 years, SD = 4.5) who had at least two measures of A1C and two neuropsychological evaluations, and who agreed to autopsy. We excluded those with dementia at the time of their first A1C measurements. Systematic postmortem neuropathologic evaluations documented the presence and size (macroscopic and microscopic) of brain infarcts. Modified silver stain‐based Alzheimer’s disease (AD) measures included global scores. We evaluated the association of A1C mean and variability (measured as the coefficient of variation of A1C measurements) during the study, with neuropathology, using a series of models (e.g., linear models, logistic regression, and extensions) adjusting for age at death, sex, and education.

Result

Participants (mean age‐at‐death = 90.9 [SD = 6.5] years; education = 15.8 [SD = 3.3] years;75% women) had an average of 5.7 (SD = 2.8) annually collected A1C measurements. The average person‐specific mean and coefficient of variation of A1C during the study were 6.0 (SD = 0.64) and 0.04 (SD = 0.03), respectively. Analyses showed that the mean A1C was associated with an increased odds of macroinfarcts (OR = 1.27; 95%CI:1.01‐1.59), but not microinfarcts. Notably, mean A1C was inversely associated with global AD pathology (β = ‐0.08, p‐value = 0.01). Variability in A1C was not associated with neuropathology.

Conclusion

Using longitudinal A1C measures, we confirmed that A1C level is associated with cerebrovascular pathology and identified an inverse association with AD pathology. However, A1C variability over time showed no associations. Further studies are needed to understand the relationship of A1C to neuropathologies.
Behavioral studies in a new mouse model of hemochromatosis mutations and Alzheimer’s amyloidosis
Authors: Acquah Elvis , Johnstone Daniel ,   Adrienne (Lz) Milward
Published: January 2025

Background

Brain iron dyshomeostasis has been observed in behavioral deficits relevant to neurodegenerative diseases such as Alzheimer’s disease (AD), but it remains unclear whether it is a primary cause or an epiphenomenon of disease.

Method

We assessed the effects of brain iron dyshomeostasis on spatial cognition and cognitive flexibility using the IntelliCage system, recognition memory using novel object recognition tasks and anxiety‐like behavior using the open field and elevated plus maze tests. We investigated these phenotypes in a Hfe‐/‐xTfr2mut mouse model of brain iron dyshomeostasis alone (Irondys) or combined with an APPswe/PS1∆E9 model of Alzheimer’s Aβ amyloidosis (Aβ+Irondys), compared with APPswe/PS1∆E9 mice with Aβ amyloidosis alone (Aβ) or wildtype controls.

Result

Brain iron levels in the Irondys models were ∼1.5x higher than wildtype control levels at 3 months of age, increasing to ∼1.8x or more at older ages. Brain iron dyshomeostasis alone had no effect on spatial cognition, cognitive flexibility or recognition memory. It moderately accelerated AD‐related anxiety‐like behavior in males when combined with Aβ, with Aβ+Irondys males spending less time in exposed areas of the open field arena than Aβ males at age 6 months (n = 7‐13 mice/group/sex, p˂0.05). At this age, irrespective of Aβ status, both male and female mice with brain iron dyshomeostasis also covered less distance in the elevated plus maze (n = 6‐10 mice/group/sex, p˂0.0001), while males of this group demonstrated this phenotype in the open field (n = 7‐13 mice/group/sex, p˂0.01). This iron‐related effect on locomotor activity was diminished by 9 months of age in the open field, with only the male Irondys groups covering less distance than the Aβ groups (n = 7‐13 mice/group/sex, p = 0.02). Interestingly, at 9 months of age, there was a dramatic reduction in locomotor activity of both Aβ mice and wildtype controls in the elevated plus maze, suggesting brain iron dyshomeostasis drives a natural age‐related decline in locomotor activity.

Conclusion

While there was generally no strong effect of brain iron dyshomeostasis on most of the AD‐related behavioral phenotypes investigated, there was striking impairment of locomotion, independent of AD‐related mutations and amyloidosis. This suggests movement impairment may be an earlier feature of brain iron dyshomeostasis than cognitive decline.
Specific expression of APOE in astrocytes reduces Aβ accumulation and plaque‐related pathology in a mouse model of amyloidosis
Authors: WANG NA , Doss Sydney V. , Chang Yuzhou , Tauer William , Ren Yingxue , Qi Fangfang , Bu Guojun , Liu Chia‐Chen , Wu Long‐Jun
Published: January 2025

Background

Accumulation of the amyloid‐β (Aβ) peptide into amyloid plaque is one of the key pathological markers of Alzheimer’s disease (AD). Apolipoprotein E (APOE) is known to modify AD risk and has been reported to influence Aβ accumulation in the brain in an isoform‐dependent manner. ApoE can be produced by various cell types in the brain, with astrocytes being the main producer. Increasing studies show that altering apoE levels can influence Aβ plaque pathology. However, it is not fully understood how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology.

Method

We utilized mouse models expressing APOE isoforms in astrocytes and crossed them with 5xFAD mouse models of amyloidosis. We analyzed the changes to amyloid plaques and assessed the impact on cellular responses to amyloid plaques in condition of astrocytic APOE expression.

Result

Specific expression of APOE3 in astrocytes resulted in compact amyloid plaques and a large increase in plaque deposition, while the total plaque burden was reduced. Astrocytic APOE2 expression led to similar changes to amyloid plaques, but the fold change is lower comparing to that in astrocytic APOE3 models. Intriguingly, the total microglial response increased dramatically in condition of astrocytic APOE3 expression but not in condition of astrocytic APOE2 expression. Further, the ratio of plaque associated Lgals3/Iba1 is higher in condition of astrocytic APOE3 expression, indicating increased microglial activation. Additionally, astrocyte GFAP levels only increased in astrocytic APOE3 models, but not in astrocytic APOE2 models. Finally, APOE isoform effect on dystrophic neurites amount was also observed.

Conclusion

Together, our study reveals an important role of astrocytic APOE on the deposition and accumulation of Aβ plaques as well as on Aβ‐associated downstream effects.