bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer’s disease multiomic signatures mediated by Cholesterol Ester Transfer Protein
Authors: Abel Tamar R , Pandey Ravi S , Spruce Catrina , Poliakova Tetiana , Wellington Cheryl L , Carter Gregory W
Published: January 2025

Background

Altered lipid profiles and lipid processing genes are associated with Alzheimer’s disease (AD). There is a reported genetic interaction between the AD risk gene APOE and cholesterol ester transfer protein (CETP). Mice lack functional CETP which is critical to the balance of circulating lipoproteins; this imparts cardioprotective effects and may make mice resistant to AD. Additionally, previous studies in transgenic humanized CETP (hCETP) mice have demonstrated that CETP addition in mice increases expression of AD risk genes and markers of AD pathogenicity. Together, this suggests that CETP may modify AD risk in an APOE4‐dependent manner. This project aims to determine molecular pathways and signatures in AD mediated by CETP with an emphasis on molecular pathways shared with APOE as a potential disease‐altering mechanism.

Methods

To identify pathways shared by CETP and APOE we created molecular networks using publicly available online tools including the AD Atlas and STRING (v12.0). The Heart and Diabetes Institute Metabolomics Laboratory Portal was leveraged to perform Genome Wide Association Study (GWAS) analysis to establish changes in lipid species abundance shared by CETP and APOE genetic variants. Transcriptional signatures in several mouse models were compared to human AD gene modules to determine pathological relevance of hCETP and APOE4 mouse models.

Results

Molecular networks implicated several genes as being co‐expressed suggesting they may co‐function with CETP and APOE. These co‐expression edges included C4A/B compliment genes, PSMB8, APOJ/CLU, and APP. GWAS analysis resulted in several notable findings including that CETP variants have a strong effect on the relative abundance of phosphatidylcholine (PC) lipid species. Additionally, while APOE4 is positively associated with total PC, the common loss‐of‐function variant CETP I405V (rs5882) is associated with reduced PC levels. Transcriptional changes in lipid‐related transgenic and MODEL‐AD knock‐in mouse models exhibited significant associations with immune processes.

Conclusions

These findings indicate that both CETP and APOE influence total PC and are associated with molecular pathways of immune activation and amyloid biology. Overall this evidence suggests that CETP and APOE act on shared pathways, likely mediated by lipid metabolism and peripheral immunity, that contribute to AD susceptibility.
The Quick Dementia Rating System and the Clinical Dementia Rating Scale: Investigation of agreement and related features in a predominantly unimpaired sample
Authors: Huang Qi , Bolt Daniel M. , Jonaitis Erin M. , Hermann Bruce P , Studer Rachel L , Ryther Brenda , Sparks Lia J. , Galvin James E , Johnson Sterling C. , Langhough Rebecca E.
Published: January 2025

Background

The Clinical Dementia Rating Scale (CDR) is a gold standard metric for staging the nature and severity of global cognitive and functional impairment in Alzheimer’s disease (AD) and other dementias. Prior evidence from older and/or smaller samples suggests that The Quick Dementia Rating System (QDRS) informant questionnaire provides results comparable to the CDR and can be completed in just 3‐5 minutes, sans a trained clinician or rater. This study aimed to: 1) investigate concordance between the QDRS‐derived global CDR (“QDRS‐global”; Galvin, 2015) and CDR‐global scores; 2) examine item‐level QDRS/CDR agreement; and (3) evaluate QDRS‐global/CDR‐global concordant/discordant groups against concurrent Preclinical Alzheimer’s Cognitive Composite (PACC3) performance.

Method

The study included 351 QDRS/CDR pairs (n = 297 participants) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Analyses include descriptive indices of QDRS/CDR agreement (e.g., QDRS‐global false negative [FN], false positive [FP] rates relative to CDR‐global scores (each collapsed to 0 = unimpaired;.5 = impaired due to few values>.5), Lasso logistic regression identifying QDRS items associated with discordance, tetrachoric correlations evaluating psychometric functioning of CDR and QDRS items, and linear mixed models examining associations between QDRS/CDR concordant/discordant groups and PACC3 performance.

Result

The QDRS‐global/CDR‐global scores concordance rate was 70.66% (see also Table 1). Relative to CDR‐global, the QDRS‐global FP and FN rates were 39.2% and 11.3%, respectively. Item‐level results were consistent with this pattern for all item pairs, except for FuncHome/HomeHob showing a greater tendency for QDRS FNs. Logistic regression and psychometric analyses highlighted the QDRS Memory item as primarily responsible for FPs and FNs (Figure 1). After adjusting for covariates, QDRS‐concurrent PACC3 scores differed significantly for two pairs of QDRS‐global/CDR‐global concordance/discordance groups — True Negative (TN) vs. True Positive (TP), FP vs. TP (Table 2; Tukey‐adjusted pairwise comparisons). The latter suggests that QDRS‐global classification of impairment is more likely to be a FP‐misclassification for participants with high PACC3 scores than for those with low PACC3 scores.

Conclusion

In this late‐middle‐aged, predominantly unimpaired sample, the QDRS appears well‐suited for screening for impairment. Future analyses will examine whether more nuanced scoring of the QDRS Memory item may reduce FP and FN rates and will investigate relations to biomarkers for AD and other dementias.
Linkage and Haplotype Association of Cognitive SuperAging to Chromosome 14 in the Midwestern Amish
Authors: Dorfsman Daniel A. , Prough Michael B. , Gulyayev Alex V. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Adams Larry D. , Laux Renee A. , Song Yeunjoo E. , Lynn Audrey , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy L. , Main Leighanne R. , Wang Ping , Liu Yining , Moore Noel C. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A , Scott William K.
Published: January 2025

Background

While Alzheimer’s disease and dementia prevalence increase with age, some older adults retain cognitive performance equal to those in mid‐life. One group, referred to as SuperAgers (SA), are ≥ 80 years old and demonstrate episodic memory function at or above the level expected for a middle‐aged adult. Genetic studies of SA may reveal heritable factors that promote superior cognition in older adults. This study utilizes an Amish sample to identify genetic factors underlying SA using both pedigree‐based and pedigree‐free analytical methods.

Method

Adult Amish participants underwent a comprehensive neuropsychological examination. Those aged ≥ 80 with episodic memory ≥ the mean for ages 35‐44 and performance in non‐episodic memory tasks (e.g., language, executive function tests) within one standard deviation or better for their own age were considered SA (N = 83). Using family records, SA subjects were grouped into 16 pedigrees for parametric and non‐parametric linkage analysis in MERLIN. To assess the evidence of a shared haplotype across pedigrees, pairwise identical‐by‐descent segments were generated in the overall sample using iLASH and then assembled into multi‐sample IBD haplotype clusters using DASH. IBD haplotype frequencies were compared between SA and a comparison group comprised of age‐matched cognitively unimpaired non‐SA, as well as individuals exhibiting cognitive impairment (N = 304). Genetic variants within haplotypes of interest were tested for association with SA in GENESIS.

Result

In the parametric analysis, HLOD scores > 3 were detected on chromosomes 1 (peak at 44 Mb), 2 (203 Mb), 7 (30 Mb), 14 (100 Mb), and 20 (17 Mb). IBD haplotypes within a 5Mb region centered around the peak linkage signals were further assessed. The strongest haplotype‐based association was observed on a ∼660 Kb segment on chromosome 14 (αBonferroni‐adjusted = 1.4e‐4, p = 3.16e‐5). Single‐variant association testing within the boundaries of the chromosome 14 haplotype identified 6 strongly correlated intronic/intergenic variants enriched in SA (MAF = 0.01, αBonferroni‐adjusted = 1.8e‐5, p = 5.22e‐8).

Conclusion

This investigation found evidence of linkage and association of SA to a region on chromosome 14. Multiple genes in the region including DLK1, implicated in hippocampal neurogenesis, represent candidate targets for further study.
A Pilot Study to evaluate feasibility of a teleneuropsychological protocol in older adults in Panama and Florida
Authors: Santos Luis Guillermo , Perez‐Lao Ambar R , Oviedo Diana C , Britton Gabrielle B , Smith Glenn E.
Published: January 2025

Background

The use of videoconference platforms for neuropsychological assessment was not as common among mental health practitioners before the COVID‐19 pandemic. However, due to lockdowns and quarantines worldwide, mental health professionals had to find a feasible alternative and shift to virtual evaluations. This increased the use of teleneuropsychology in both at a clinical and research level. Studies conducted during the pandemic provided evidence of the feasibility of virtual assessments, but data from low‐and middle‐income countries is scarce and conclusions from studies in other regions cannot be generalized. The objective of this study is to develop and apply a teleneuropsychological assessment battery on a group of elderly adults in Panama and Hispanics living in the United States.

Method

This is a multicenter study that will gather data from a Panamanian Cohort parallel to the current Florida‐based study Development and Validation of TeleNeuropsychology Normative Data for Older Adults (FLOAT). So far 80 participants over 50 years old have been assessed in Panama and Florida. Inclusion criteria includes passing a screening with TICS‐M for low risk of developing dementia and having basic knowledge and accessibility of electronic devices. Researchers contact potential participants through calls and WhatsApp chats to explain the study and obtain informed consent. Participants are then screened to see if they are eligible to be assessed through the video conference platform. Participants must complete the teleneuropsychological assessment battery from the National Alzheimer’s Coordinating Center (NACC), and different questionnaires to provide socio‐demographic and functional data. All information is gathered with the REDCap platform.

Result

One hundred participants will be assessed with a teleneuropsychology protocol in each cohort. Once all data is collected, it will be analyzed with multivariate statistics methods. We expect to describe the protocol’s feasibility assessing older adults in both locations.

Conclusion

To our knowledge this is the first study of its kind in Panama and one of the only ones in the region. The study seeks to generate data that could be shared and applied for future research or clinical practice regarding teleneuropsychological assessments with older adults with similar cohorts.
Acute communication between microglia and other immune cells in the anti‐Aβ antibody injected cortex
Authors: Foley Kate E. , Krick Katelynn E. , Weekman Erica M. , Wilcock Donna M.
Published: January 2025

Background

Anti‐Aβ immunotherapy use to treat Alzheimer’s disease is on the rise. While anti‐Aβ antibodies provide hope in targeting Aβ plaques in the brain, a major side effect of amyloid‐related imaging abnormalities (ARIA) persists with no known cause. As severe ARIA is typically seen within the first few infusions in human clinical trials, we sought to identify acute effects of anti‐Aβ antibody on brain.

Method

To determine cellular changes due to anti‐Aβ antibody exposure, we intracranially injected 14mo APP male and female mice with anti‐Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24hrs or 3days, we harvested the cortex and performed a glial cell enriched preparation for single cell sequencing. Cell types, proportions, and cell‐to‐cell signaling was evaluated between the two injection conditions and two acute timepoints.

Result

We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti‐Aβ antibody injected cortices revealed more ligand‐receptor communications between cell types, as well as stronger communications at 24hrs. At 3days, while there were more L‐R communications for the anti‐Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. Specific pathways such as CD48 and PD‐L1 were enriched in the anti‐Aβ antibody condition, but not the control IgG condition in microglia‐to‐microglia communication. We also found evidence of an initial and strong communication emphasis in microglia‐to‐peripheral immune cells at 24hrs, specifically in the TGFβ signaling pathway. Additionally, we found that peripheral immune cells that were exposed to anti‐Aβ antibody failed to signal via the TNF pathway, which was strongly enriched in the control IgG condition at both timepoints.

Conclusion

We identify several pathways that differ between anti‐Aβ antibody and control IgG injections at acute timepoints. These data lay the groundwork for understanding the brain’s unique response to anti‐Aβ antibody and its predisposition to ARIA.
Characterizing Tau Neuropathology Across Brain Regions in Patients Carrying PSEN1 Jalisco Mutation
Authors: Breningstall Bayla M , Abdollahi Evan , Hiniker Anne , Hawes Debra , Ringman John M , Bienkowski Michael S
Published: January 2025

Background

Mutations in the presenilin 1 (PSEN1) gene cause early onset autosomal dominant Alzheimer’s Disease (AD), and the Jalisco mutation (A431E) is a subset found in people of Mexican descent (Yescas P, 2006). The Jalisco A431E mutation has been shown to produce distinct AD neuropathology such as cotton‐wool amyloid plaques as well as motor dysfunction like spastic paraparesis (Orozco‐Barajas, 2022). High levels of tau neuropathology have been observed with other PSEN1 mutations, but tau neuropathology in Jalisco patients has not been examined. Therefore, we sought to quantify the distribution of tau across a variety of brain regions in patients with A431E mutation and compare to patients with other PSEN1 mutations (A260V and T245P) or high stage sporadic AD.

Method

Ten coronal brain sections from 9 PSEN1 (n = 5 A431E; n = 2 A260V, n = 2 T245P) and 9 high stage AD subjects immunohistochemically labelled with AT8 were obtained from the USC Alzheimer’s Disease Research Center (ADRC). Regions analyzed included cerebral cortex (prefrontal, parietal, temporal, and occipital areas), hippocampus, striatum, midbrain, cerebellum, pons, and medulla. Ilastik, a machine‐learning based software, was trained on positive AT8 staining versus background pixels and applied this training to the whole slide image. This binary output was then overlaid with a manually drawn ROI atlas in the Quantitative Imaging Toolkit (QIT), and positive pixels per pixels of the region was used to calculate density of AT8 pathology.

Result

AT8 density was significantly higher across the brain in patients with PSEN1 mutations compared to sporadic AD. Although small sample size is limited for these patient groups, we found that A431E patients had lower AT8 density in the hippocampus compared to other PSEN1 patients, most notably in dentate gyrus, as well as Brodmann Areas 35 and 36.

Conclusion

These data show a high burden of tau fibrils as measured by AT8 across brain regions in people with PSEN1 mutations as compared to other high AD patients. Notably, A431E patients had different distributions than other PSEN1 patients. These findings help further characterize early onset autosomal dominant AD within patients of Mexican heritage and how tau neuropathology might contribute to its unique symptoms.
Association between pulmonary function and cognition in urban Indian adults – A cross sectional analysis
Authors: Mallikarjun Divya N , S Monisha , Lingegodwa Abhishek Mensegere , Stezin Albert , Partha Ajith , M Amitha C , Narayanasamy Rajitha , R Meghana , Menon Meenakshi , Velavarajan Goutham , Vishwanath Vindhya , Malo Palash K , HS Sunitha , HS Deva Kumar , Agrawal Deepashri , Hameed Shafeeq K Shahul , Arvind Prathima , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Pulmonary Function Tests (PFTs) are the non‐invasive tests to measure the lung function. Relationship between pulmonary function and cognition is an emerging area of research, understanding this is crucial for prevention and management of dementia. Hence this study aims to investigate the association between pulmonary function and cognition.

Method

This cross sectional analysis includes the participants aged 45 years and above (N = 924) from an ongoing longitudinal study, the Tata Longitudinal Study of Aging (TLSA), conducted in urban Bangalore, India. The pulmonary function was assessed through spirometry, Z scores were calculated for Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second (FEV1), and Peak Expiratory Flow (PEF), then categorized into equal quartiles. Cognition was assessed using Addenbrooke’s Cognitive Examination III (ACE III). The association between pulmonary function and cognition was examined using multiple linear regression with three models: Model 1 – unadjusted, model 2‐adjusted for age and gender, model 3 – adjusted for age, gender, education, smoking status, depression, anxiety, hypertension, diabetes, cardiac illness and respiratory disease.

Result

Regression analysis revealed an association between pulmonary function and cognition across all the models. In the fully adjusted model, compared to the lowest quartile (quartile 4), participants in highest quartiles of FVC performed better in ACE [quartile 1 (β = 2.36, 95% CI, 0.56‐4.15, p = 0.01), quartile 2 (β = 2.62, 95% CI, 1.08‐4.15, p = 0.001), quartile 3 (β = 1.87, 95% CI, 0.53‐3.22, p = 0.006)], similarly for PEF, participants in highest quartiles exhibited better ACE score [quartile 1 (β = 3.42, 95% CI, 2.02‐4.82, p <0.001), quartile 2 (β = 3.49, 95% CI, 2.16‐4.81, p <0.001), quartile 3 (β = 3.72, 95% CI, 2.41‐5.03, p ≤0.001)], there was no significant association found between FEV1 and ACE score.

Conclusion

These findings indicate the link between pulmonary function and cognitive performance, highlighting the importance of respiratory well‐being in preserving the cognitive function.
A Study on Refractive Errors and Cognitive functions in the Aging Population
Authors: Velavarajan Goutham , M Amitha C , Partha Ajith , M Divya N , R Meghana , Menon Meenakshi , Lingegodwa Abhishek Mensegere , Stezin Albert , S Monisha , HS Dev Kumar , Narayanasamy Rajitha , Vishwanath Vindhya , Malo Palash K , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Singh Sadhana , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Refractive errors are common visual comorbidities among the elderly. Cognitive dysfunction also occurs in this population. A study by Ong et al (2013) demonstrated an association of refractive errors with poor cognitive performance. In this study, we explored the potential association between refractive errors (RE) and cognitive functions (CF) in an elderly population from South India.

Method

This cross‐sectional analysis, based on the Tata Longitudinal Study on Aging (CBR‐TLSA) cohort (Sundarakumar et al., 2020), included participants with a minimum visual acuity of ≤ 0.52 LogMar using the LogMAR chart (Aurolab, India). Those meeting the criteria underwent objective refraction with a retinoscope (Welch Allyn, Dublin, USA) to classify RE (Emmetropia, Myopia, Hypermetropia). CF was assessed using Addenbrooke’s Cognitive Examination III (ACE III) and various cognitive tests, including Digit Forward/Backward, Trail Making Test A/B, Modified Taylor Complex Figure Immediate/Delayed Recall, Digit Simple Substitution Test (DSST), and COGNITO (Computerized assessment of adult information processing) battery domain‐specific tests. Cognitive tasks were performed post‐acuity correction with prescription glasses.

Result

The demographic characteristics of the study sample are mentioned in Table 1. Among 856 participants, 149 (17%) were Emmetropes, 224 (26%) were Myopes, and 483 (56%) were Hypermetropes. The Myopes performed poorly in TMT‐B (β = 14.9 (CI: 1.16, 28.68), p = 0.03), MTCF IR (β = ‐2.15 (CI: ‐3.8, ‐0.49), p = 0.01), MTCF DR (β = ‐2.2 (CI: ‐3.9, ‐0.48), p = 0.011), and reading and sentence comprehension (β = ‐0.37 (CI: ‐0.63, ‐0.11), p = 0.004) compared to emmetropes. Hypermetropic showed poor performance in Ace visuo‐spatial (β = ‐0.43 (CI: ‐0.79, ‐0.06), p = 0.02), MTCF DR (β = ‐1.5 (CI: ‐3.08, ‐0.03), p = 0.045), and showed better performance in Digit Forward Total Correct (β = 0.96 (CI:0.03,1.89), p = 0.04) & span (β = 0.53 (CI:0.07,1.004), p = 0.02).

Conclusion

Our study found that individuals with myopia and hypermetropia performed worse on certain cognitive tests compared to those with normal vision. Myopic individuals struggled with tasks involving complex figure recall and comprehension, while hypermetropic individuals had difficulties with visuospatial tasks and they did better in attention tasks. These findings suggest that corrected RE in older adults could contribute to cognitive challenges and needs to be further researched.
Influence of menopause on cognitive performance in aging Indian women: A cross‐sectional study
Authors: Pradhan Hitesh , Sundarakumar Jonas S.
Published: January 2025

Background

Studies have reported the neuroprotective role of estrogen, and that the post‐menopausal state could be a risk factor for cognitive decline. However, the relationship between menopausal age and cognitive functions has not been adequately studied in the Indian population.

Method

Srinivaspura Neuro Senescence and Cognition (SANSCOG) is an ongoing rural community‐based longitudinal study on aging in India. We analyzed baseline data (January 2018 – April 2023) of 1,473 post‐menopausal women with clinical and neurocognitive assessments. Age at menopause was categorized into premature (<41 years), early (41‐44 years), and normal (45‐54 years). Participants were excluded if they had undergone hormone replacement therapy and attained late menopause (≥55 years). Cognitive performance was assessed using Hindi‐Mental State Examination (HMSE). A linear regression model was used to examine the association between age at menopause and cognitive functions while adjusting for education, marital status, reproductive history, hypertension, diabetes, smoking, physical inactivity, and BMI. We also checked for the interaction between age and menopause.

Result

Premature (β = ‐0.76, 95% CI = ‐1.47, ‐0.07) menopause was significantly associated with poorer cognitive performance. Additionally, older age (≥65 years), education, BMI, physical inactivity, and number of children were also significantly associated with cognitive performance. Women aged 65 years and above who attained premature menopause had significantly poorer cognitive performance compared to women aged less than 65 years who attained normal menopause (β = ‐4.64, 95% CI = ‐6.50, ‐2.79).

Conclusion

Our study shows that menopausal age is associated with cognitive performance. Among older women (≥65 years), premature menopause is adversely associated with cognitive performance, suggesting that the effects of reduced estrogen are likely to be evident in later life. Future work should explore the association of menopausal age with performance across individual cognitive domains and brain MRI.
Extensive antagonistic genetic underpinnings of sex disparities in Alzheimer’s disease and hypertension
Authors: Kulminski Alexander M. , Feng Fan , Kulminskaya Irina , Nazarian Alireza , Loiko Elena , Loika Yury
Published: January 2025

Background

The Alzheimer’s Association reports that more than two‐thirds of the approximately 5 million Alzheimer’s disease (AD) cases in the USA are women. With studies suggesting a high genetic heritability for AD, gaining a better understanding of the genetic architecture underlying sex disparities in AD and its risk factors could enhance the understanding of their mechanisms.

Method

We conducted genome‐wide association studies (GWAS) and pleiotropic meta‐analysis of AD and its risk factor—hypertension—in men and women of European ancestry. The AD GWAS focused on 168,962 men (including 6,229 cases) and 199,668 women (including 7,628 cases) from 10 cohorts. The hypertension GWAS included 177,597 men (96,835 cases) and 205,482 women (88,861 cases) from eight of the 10 AD cohorts. Sex‐specific associations were characterized by the Wald chi‐square test and Fisher’s method, and their significance was assessed at a false discovery rate q‐value of 5% or less.

Result

GWAS of AD and hypertension identified 176 and 195 loci, respectively, on all chromosomes with the differences in the effects between sexes attaining q<0.05. Associations with AD were of the same directions in men and women only in one—the APOE gene—locus, with significantly larger adverse effect for the ε4‐encoding rs429358 polymorphism in women (β = 1.35, CI = 1.30‐1.41) than men (β = 1.16, CI = 1.10‐1.22). Associations with hypertension were of the same directions in each sex in 74 of 195 loci on all chromosomes, except chromosome 14. The ε4 allele showed no association with hypertension in either sex. No significant differences between sexes in the significant protective associations with AD and hypertension were identified for the ε2 allele. Our analyses revealed seven pleiotropic loci mapped to COL24A1, MGC4859‐PHF14, MFHAS1‐ERI1, SBF2, KICS2, BCL11B, and RPAP1 gene clusters characterized by the differences in the associations with AD and hypertension between sexes at q<0.05. In three underlined clusters, the associations with hypertension were of the same direction in men and women.

Conclusion

Although the APOE ε4 allele partly underlies AD‐related sex disparities, the most substantial contribution comes from antagonistic relationships between genes and AD in men and women. Sex‐specific pleiotropic loci suggest contribution of hypertension to these AD‐related sex disparities.
LOAD1 and LOAD2: Longitudinal characterization of mouse models carrying human‐relevant risk factors for late‐onset Alzheimer’s disease
Authors: Bernabe Cristian S , Kotredes Kevin P , Pandey Ravi S , Carter Gregory W , Sasner Michael , Oblak Adrian L , Howell Gareth R , Lamb Bruce T. , Territo Paul R ,   MODEL‐AD consortium
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common form of dementia, yet the effectiveness of disease‐modifying interventions is inconclusive. Although exceptional progress in our understanding of AD neuropathology has been made via transgenic mouse models bearing familial mutations, they often fail to recapitulate the disease progression of late‐onset AD (LOAD). To address this, MODEL‐AD has developed LOAD1 and LOAD2 mouse models which carry the most common human‐relevant risk factors for AD. In‐depth, longitudinal characterization through aging will reveal useful insights to develop novel treatments for LOAD.

Method

APOEε4 and Trem2*R47H, two risk factors for LOAD, were incorporated into C57BL/6J mice to produce the double homozygous LOAD1 model, whereas LOAD2 also contains humanized amyloid‐beta (Aβ) yielding a triple homozygous model. Cohorts of LOAD1 and LOAD2 mice were aged on multiple sites to 4‐, 12‐, 18‐, and 24‐month timepoints and both sexes were characterized using behavior, PET/CT, cytokines/Aβ40‐42 immunoassays, and astrocyte and microglia immunohistochemistry.

Result

Although aging LOAD1 and LOAD2 mice did not display significant cognitive deficits, there was a genotype‐dependent increase of plasma levels of Ab40‐Ab42. Both sexes across genotypes showed significant region‐dependent increases in brain glycolysis and tissue perfusion between 4 and 24 months. Consistent with the increased brain metabolism and perfusion neurovascular coupling phenotypes, immunopathology analyses revealed an age‐dependent increased number of astrocytes across genotypes that was restricted to cortical regions. Similarly, the total number of activated microglia was slightly elevated in cortical regions of aging mice, even though the results were only marginally significant. Lastly, aged LOAD1 mice displayed increased brain levels of the pro‐inflammatory cytokine IL‐12p70 when compared to LOAD2. Longitudinal analyses of brain and plasma cytokines are still in progress.

Conclusion

LOAD1 and LOAD2 PET/CT analyses revealed phenotypes which are in line with imaging profiles of patients at prodromal stages of AD. Combined with the astrogliosis, these strains are promising venues that can be used to test early disease‐modifying therapeutic targets and can also serve as platform to incorporate additional human‐relevant AD risk factors.
Exploring the neuroprotective effects of fenchone against ICV‐STZ‐induced Sporadic Alzheimer’s disease in rats: Investigating neuroinflammation, oxidative stress and mitochondrial dysfunction as potential mechanisms
Authors: Mini Mini
Published: January 2025

Background

Sporadic Alzheimer’s disease (sAD) is the most prevalent type of dementia, characterized by progressive neurodegeneration. Intracerebroventricular (ICV) administration of streptozotocin (STZ) serves as a model for sAD, inducing neurodegeneration through oxidative stress, apoptotic damage, mitochondrial dysfunction, and neuroinflammation. Fenchone, a monoterpenoid, has been reported to possess neuroprotective properties by attenuating oxidative stress, acetylcholinesterase activity, mitochondrial dysfunction and neuroinflammation. This study aimed to explore the neuroprotective potential of fenchone in ICV‐STZ‐induced sAD and its associated pathology in wistar rats.

Method

To assess the neuroprotective potential of fenchone (20, 40, and 80 mg/kg) and galantamine (2 mg/kg) were given orally in ICV‐STZ‐induced wistar rats for 21 days. Behavioral assessments, including locomotor activity, Morris water maze, and novel object recognition, were conducted. Subsequently, rats were sacrificed on the 21st day, hippocampus and pre‐frontal cortex were prepared for the quantification of oxidative stress, apoptotic markers, mitochondrial complex activity, acetylcholinesterase activity, and neuroinflammatory markers.

Result

In‐vivo, studies revealed that fenchone treatment ameliorated ICV‐STZ‐induced cognitive deficits in the Morris water maze and novel object recognition tests. Furthermore, fenchone arrested oxidative stress (glutathione (GSH), catalase, superoxide dismutase (SOD), and lipid peroxidation (LPO)), decreased apoptotic damage (caspase 3) and neuroinflammation (TNF‐α and IL‐6) in the cortex and hippocampus regions of the brain. Additionally, normalization of mitochondrial enzyme complexes and acetylcholinesterase activities was observed.

Conclusion

This study demonstrates the neuroprotective effects of fenchone in the ICV‐STZ rat model, alleviating oxidative stress, apoptotic damage, reversing mitochondrial dysfunction, acetylcholinesterase activity, and neuroinflammation in brain.
A new pipeline for converting neuroimaging data into computational models of ISF/CSF processes
Authors: Elbert Donald L.
Published: January 2025

Background

A multitude of high‐quality imaging modalities exist that provide structural data at unprecedented levels of detail. Tissue ultrastructure greatly influences the rate of transport of proteins and other molecules that contribute to neurodegeneration. However, our ability to model flow and diffusion processes in the brain lags behind the quality of the neuroimaging data. Here, a new framework will be presented for converting neuroimaging data into computational fluid dynamics (CFD) models in a scalable manner suitable for high performance computing. TEM data from the Allen Institute will illustrate its capabilities.

Methods

Segmented TEM images were downloaded from the MicronsExplorer public storage cache. Segmented image stack volumes (4 × 4 × 4 µm) were converted into surface meshes using the Lewiner Marching Cubes algorithm. Convection and diffusion along the surface of individual cells was modeled. After each timestep mass was allowed to exchange between neighboring cells, implemented on a high performance computing cluster using the MPI protocol on 40 or more computing cores. Multiple volumes were analyzed simultaneously, with updates of the flux between cells in different volumes occurring at each time step. These steps were performed with new custom CFD code written in C and Julia.

Results

Segmented z‐stacks of TEM data from the MICrONS Explorer website were downloaded in 4 × 4 × 4 µm blocks, which typically contain ≈500 distinct cells (Fig. 1A&B). The meshing algorithm leads to perfect matching between adjacent cells (Fig. 1C). The convection‐diffusion equations are solved, modeling flow/diffusion of solutes between cells (Fig. 1D&E). Equations are solved for all ≈500 distinct cells in parallel, with concentrations at matching faces re‐balanced at each time step (Fig. 2A&B). A manager‐worker MPI model allows for solution on an arbitrary number of cores (Fig. 2C). The interfaces between cell surfaces across volumes are also perfectly matched, allowing for adjustment of the flux of mass between volumes at each timestep (Fig. 2D).

Conclusions

A new modeling framework is described for solution of transport equations on high performance computing clusters for any imaging modality that produces segmented z‐stacked images.
Older African Americans with Type 2 Diabetes have Lower Frontal and Medial Temporal Lobe Cognitive Function
Authors: Napoleon Darian A. , Fausto Bernadette A. , Piaszczynska Wiktoria , Tawe Fanyu Hercules , Budak Miray , Malin Steven K. , Fitzgerald‐Bocarsly Patricia , Gluck Mark A.
Published: January 2025

Background

Alzheimer’s disease (AD) is sometimes characterized as “type 3 diabetes” because hyperglycemia impairs cognitive function, particularly in the medial temporal lobe (MTL) and prefrontal regions1,2. Further, both AD and type 2 diabetes (T2D) disproportionately impact African Americans. Although people with T2D are generally suggested to have lower episodic memory and executive function, limited data exist in older African Americans. Thus, we examined the effect of T2D on frontal and MTL cognitive functions in older African Americans.

Method

Eighty‐four older cognitively unimpaired African Americans (70.88±6.31y; 74% female) were recruited from the Pathways to Healthy Aging in African Americans study at Rutgers University–Newark. Individuals were categorized as having T2D using HbA1c (≥6.5%; n = 48) or non‐T2D (≤6.4%; n = 36). Participants completed a cognitive battery of frontal and MTL cognitive tasks: motor speed of processing (Trail Making Test–Part A); set‐shifting (Trail Making Test–Part B); and generalization of prior learning (Concurrent Discrimination and Transfer Task). ANCOVAs were used to examine differences between groups on cognitive performance with age, sex, and education as covariates.

Result

Participants with T2D demonstrated poorer motor speed of processing (p = 0.046, η2p = 0.05) and set‐shifting performance (p = 0.05; η2p = 0.047) than those without T2D. Moreover, participants with T2D demonstrated lower generalization of prior learning accuracy (p = 0.05; η2p = 0.047).

Conclusion

T2D lowers frontal and MTL function in cognitively unimpaired older African Americans with when compared to those without diabetes. Further investigation into the overlapping pathologies of AD and T2D are warranted to optimize interventions aimed at prevention of AD in older adults.
β‐amyloid impaired mitochondrial proteostasis through the impact on LONP1
Authors: Wang Wenzhang
Published: January 2025

Background

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD.

Method

An unbiased screening of intraneuronal Aβ42 protein‐interactome was perfumed in AD cell culture. Mitochondrial protease activity and mitochondria functions were investigated in AD models in vitro and in vivo, while cognitive behaviors of AD transgenic mice were analyzed by memory capacity tests.

Result

We identified LONP1, an ATP‐dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3‐m6A signaling contributed at least in part to Aβ42‐induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ‐induced mitochondrial deficits and cognitive deficits.

Conclusion

These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a novel mechanism underlying intracellular Aβ42‐induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.
Distinct Methylomic Signatures Emerge in the Prefrontal Cortex Following Amyloid‐Beta Immunisation, with Altered Expression Patterns in Astrocytes
Authors: MacBean Lachlan Ford , Smith Adam , Boche Delphine , Lunnon Katie
Published: January 2025

Background

Post‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.

Method

DNA and RNA was isolated from post‐mortem prefrontal cortex tissue of immunised cases (n = 14) who received varying doses (ug) and number of doses during the trial period. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included cell enrichment analysis of the top most differentially expressed genes.

Result

After correcting for common known variables (age, sex, cell type composition) and batch effects, a DMP located within CUGBP Elav‐like family member 2 (CUGBP2) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with nine regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. In addition, a similar model performed on the RNA‐sequencing data showed no overlap with the aforementioned DMRs, but did exhibit significant gene expression alterations associated with astrocytes.

Conclusion

Indicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing genotyping data to identify potential methylation quantitative trait loci and further our understanding of the relationship between single nucleotide polymorphisms and methylation changes.
Neuropathological Mapping of Synaptic Vesicle Protein 2A in Human Brains: Ground Truth for PET Interpretation in Neurodegenerative Diseases
Authors: Bavarsad Mahsa Shanaki , Spina Salvatore , Seeley William , Rabinovici Gil D. , Grinberg Lea T.
Published: January 2025

Background

Synaptic loss, a key indicator of cognitive decline in neurodegenerative diseases, lacks a clinical biomarker, but emerging PET‐scan tracers targeting synaptic vesicle protein 2A (SV2A) show promise. The current understanding of regional changes in neurodegenerative disorders and the distribution of SV2A in the human brain is quite limited. This knowledge gap presents challenges when assessing the feasibility of using SV2A tracers in therapeutic applications. To assess the potential of SV2A tracers in diagnosis and therapy monitoring and enhance SV2A PET data interpretation, we quantified SV2A and synaptophysin (SYP) density in postmortem human brain tissue. We included subjects with different neurodegenerative conditions and healthy controls (CT) and mapped five susceptible regions.

Method

Histological slides (8µm) of 28 cases (Table 1) underwent immunohistochemistry SV2A and synaptophysin. Slides were scanned using a calibrated Zeiss Axioscan. Synaptic density was quantified using the Zen software in 40 cortical ROIs (20 white & 20 gray matter) per area/case. Values were normalized by white matter intensity. Moreover, we used frozen tissue from a subset of the same cases and areas to perform Western blot (WB) using the same antibodies against SV2A and (SYP), plus Beta‐actin. Intensity values were measured by using Image J software.

Result

The immunohistochemical analysis revealed decreased SV2A density across all diseases, exhibiting distinctive regional and disease‐specific patterns (Fig. 1). However, the correlation between SV2A and synaptophysin density was weak (Fig. 1). Western blot analysis similarity showed a distinctive reduction of SV2A with regional and disease‐specific patterns. The correlation with synaptophysin was moderate (Fig. 2).

Conclusion

In conclusion, our findings demonstrate reduced SV2A density and protein levels in disease categories corresponding to specific regional vulnerabilities, corroborating SV2A as a reliable marker of brain tissue integrity. Nevertheless, the observed correlation between SV2A and synaptophysin changes was less robust than anticipated, prompting questioning into whether SV2A changes accurately reflect synaptophysin alterations. Additional studies comparing the utility of both markers in predicting clinical decline, metabolic shifts, and the progression of neurodegeneration are warranted.
Temporal dynamics of microglial neuroprotection during chronic Aß ‐treatment in human iPSC‐derived 3D neurospheres
Authors: Wendt Stefan , Lin Ada J. , Ebert Sarah , Brennan Declan , Cai Wenji , Macvicar Brian , Nygaard Haakon B.
Published: January 2025

Background

Murine models of Alzheimer’s Disease (AD) have resulted in numerous discoveries leading to a better understanding of AD pathogenesis but results poorly translated to novel treatment options. Over the past years, iPSC‐derived human neuronal cultures have been developed to better model AD in vitro. One key hallmark of AD is the presence of insoluble Aß plaques in the brain. To model this microenvironment a 3D tissue culture is needed to successfully study the complex neuron‐glia‐Aß interaction. Here we present human iPSC‐derived 3D neurospheres for modelling severe amyloidosis through chronic Aß application.

Method

Neurospheres were formed from iPSC‐derived neuronal progenitor cells and expanded, differentiated and maintained for 60 days. Microglia were added to readily populate the tissue for the last 10 days of culture. Oligomeric Aß42 (∼35 nM) was added to the media chronically for 3 or 5 weeks. Neuronal activity was measured using GCAmP6f live imaging. Aß induced oxidative stress was quantified by using roGFP. Single nuclei RNA sequencing (NucSeq) was performed to obtain transcriptional data.

Result

Neurospheres, consisting of neurons and astrocytes, display robust synchronized neuronal activity. Aß treatment induces the formation of plaque‐like aggregates in the tissue within days. We found dysregulated neuronal activity and oxidative stress after 2‐3 weeks while severe neuronal loss can be observed after 4‐5 weeks. Infiltrating microglia display high phagocytic activity towards Aß and successfully reduced extracellular Aß deposits, loss of neuronal activity and oxidative stress when added early during the Aß treatment. Microglia transferred late during Ab exposure ameliorated neuronal death but fail to recover neuronal function or reduce oxidative stress at this time point. NucSeq allows identifying the transcriptional profile of each cell type and will be used to study cell type specific changes after Aß exposure with or without microglia.

Conclusion

We here present a human 3D cell culture model allowing the formation of neurospheres and a chronic Aß stimulation protocol to mimic amyloidosis as a novel human AD in vitro model. Transplanting microglia at different time points during culture allows to study the temporal dynamics of neuroprotective properties of microglia presenting a unique novel approach to reveal new potential therapeutic pathways.
Higher Gene Expression Of Dynein Heavy Chains In The Dorsolateral Prefrontal Cortex Predict Lower Neuropathology Burden And Better Cognitive Outcomes In Individuals With Alzheimer’s Disease
Authors: Lucero Esteban M , Brunetti Tonya , Chial Heidi J , Potter Huntington , Gignoux Chris
Published: January 2025

Background

Motor proteins play a key role in neuronal functions and morphology that are important for learning and memory. We have previously reported that increased expression KIF11/Kinesin‐5 overrides Aß‐mediated effects on dendritic spine density and long‐term potentiation in a mouse model of Alzheimer’s disease (AD), effectively maintaining cognitive function in the face of Aß pathology. Here, we evaluated the association of key AD phenotypes with mRNA expression levels of a select set of Dynein motor proteins

Method

We utilized measurements of gene expression, AD neuropathology burden, and cognition provided by the ROS/MAP study to determine whether an association exists between AD phenotypes and expression of genes for cytoplasmic and axonemal dynein heavy chains. Neuropathology burden was determined through immunohistochemistry. Z‐scores from the raw scores of 19 cognitive tests were used to determine global cognition. Neuropathology burden and global cognition measurements were provided by Rush Alzheimer’s Disease Center. Measurements of gene expression in the dorsolateral prefrontal cortex (DLPFC) (n = 634) were determined through an established RNAseq analysis pipeline (Logsdon et al., 2019, syn8456638;syn8456629) and made available to us through the Accelerating Medicines Partnership in Alzheimer’s Disease Target Discovery and Preclinical Validation knowledge portal (syn3219045). Associations of gene expression with neuropathology and cognition were determined through multiple linear regression and mixed effects models covarying for age, sex, education, and post‐mortem interval

Result

In participants with AD (CERAD score > 2), higher gene expression levels of DYNC1H1 and DNAH1 in the DLPFC predicted better cognitive performance longitudinally (p = 0.03 and p = 0.00197, respectively) and at the last visit prior to death (p = 8.701e‐05 and p = 3.571e‐05, respectively). Higher expression of DYNC1H1 and DNAH1 were also associated with lower amyloid pathology (p = 0.0001257 and p = 2.356e‐07, respectively) and tau tangles (p = 2.356e‐07 and p = 2.659e‐09, respectively)

Conclusion

Our finding that AD participants with higher expression levels of DYC1H1 and DNAH1 show reduced cognitive decline and decreased AD pathology suggest a potential beneficial effect of these motor proteins on AD progression. Based on the functions of these motor proteins, these findings warrant further studies to identify potential mechanisms underlying this association. Potential mechanisms include facilitation of higher rates of phagocytosis or neuronal lysosomal degradation of Aß