bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐equivalent induced neurons from patients reveal neuronal fate loss and metabolic transformation underlying neurodegeneration in sporadic Alzheimer’s disease
Authors: Mertens Jerome
Published: December 2023

Background

Old age is the dominating risk factor for Alzheimer’s Disease (AD), which exclusively affects people at older ages. Sporadic AD represents the overwhelming majority of all cases, but most research on AD has been performed on genetic causes and their directly related pathways, also because we were in lack of models that can reflect complex human genetics and age in a neuronal context.

Method

Patient‐specific iPSC models represent an attractive solution, but iPSC reprogramming results in cellular rejuvenation and thus yields phenotypically young neurons mirroring fetal development. By contrast, direct conversion of old patient fibroblasts into induced neurons (iNs) preserves endogenous signatures of aging and produces neurons that resemble the adult human brain on an epigenome‐ and transcriptome‐wide scale. To control for the involvement of aging in AD, we generated age‐equivalent fibroblast‐derived iNs and rejuvenated iPSC‐derived neurons from a cohort of AD patients and controls.

Result

Patient‐derived AD iNs reflect a hypo‐mature neuronal identity characterized by markers of stress, cell cycle, glycolytic reprogramming, and de‐differentiation, which share similarities with malignant cancer transformation and age‐dependent epigenetic erosion. We identified an isoform switch of pyruvate kinase M (PKM) to the PKM2 isoform as a trigger of a Warburg effect‐like metabolic switch, and further as a key transcriptional regulator leading to cell fate instability. Metabolomics, glucose tracing, and acetylome analysis confirmed a hyper‐acetylated state of AD iNs. This affects several splicing factors, triggering an isoform switch to PKM that ultimately leads to a loss of neuronal fate and maturity. Inhibition of the resulting citrate shunt to acetylCoA modulates the isoform switch in favor of PKM1, and re‐instates a mature and more resilient neuronal state.

Conclusion

We conclude that age‐equivalent adult‐like iNs from patients are a useful model to study age‐dependent pathological signatures of AD. This iN model identifies AD‐related neuronal changes as part of an active cellular program that impairs neuronal cell identity and neuronal resilience by utilizing cancer‐related signaling cascades. We further reason that the AD‐specific metabolic switch and fate loss in neurons regulates, and is reinforced by, alternative splicing of PKM.
ASO‐mediated downregulation of Amyloid Precursor Protein: a new avenue for AD treatment?
Authors: Gabriele Rebcca M C , Arber Charles , Zetterberg Henrik , Abel Emily , Fox Nick C , Jolly Sarah , Whiting Paul , Zhao Hien , Wray Selina
Published: December 2023

Background

Mutations in the APP, PSEN1 and PSEN2 genes are causative of familial AD (fAD) and lead to accelerated cerebral amyloid beta (Aβ) accumulation. This finding led to the development of the amyloid cascade hypothesis which proposed that the aberrant production of Aβ peptides triggers a cascade of events that ultimately leads to neurodegeneration and clinical Alzheimer’s disease. Synthetic antisense oligonucleotides (ASOs) are small molecules that modify gene expression at the RNA level. We investigated the effect of ASO‐mediated APP downregulation in induced pluripotent stem cell derived neurons from individuals with fAD mutations in APP and PSEN1 to determine whether this approach can rescue disease‐associated phenotypes or Aβ processing defects.

Method

iPSC with PSEN1 Int4del and R278I mutations, and APP duplication were differentiated into cortical neurons before treatment with ASOs targeting APP or non‐targeting controls. APP downregulation was assessed at the RNA level using qPCR and protein level by western blot. The impact of APP downregulation was assessed utilising a triplex ELISA to measure Ab38/40/42 and immunocytochemistry with antibodies against Rab5 and LAMP1 to assess the endolysosomal system.

Result

ASO treatment led to a dose‐dependent downregulation of APP, both at the RNA and protein levels. Downregulation was stable over 3 weeks following ASO administration. This resulted in a significant reduction in the absolute levels of each Aβ species measured, although the Ab42/40 ratio was unchanged.

Conclusion

Considering the central role of Aβ in AD pathology, it is reasonable to believe that the downregulation of APP could be a successful therapeutic approach. ASO‐mediated APP downregulation was efficient and stable, highlighting the potential of this approach. Although the Aβ ratio was unchanged following APP downregulation, the absolute value of each Aβ species was significantly reduced, and so we hypothesise that lower levels of total Ab may reduce its harmful effects. Future work will determine the impact of reducing Ab levels on downstream cellular dysfunction, including endosome/lysosome defects.
Association between Anemia and Dementia in Korea older adults: A national cohort study
Authors: Cho Yong Hyuk , Roh Hyun Woong , Hong Chang Hyung , Son Sang Joon , Nam You Jin , Hong Sunhwa , Park Sunghong , Back Joung Hwan
Published: December 2023

Background

As the global elderly population increases, the prevalence of dementia is also increasing. Korea is one of the rapidly aging countries in the world, and 10.33% of elderly people aged 65 and older are receiving treatment for dementia as reported in 2021. Since disease modifying drugs have not yet been developed for dementia, the importance of modifiable risk factors that can lower the risk of dementia is being emphasized, and one of them is anemia in the elderly. We analyze national cohort data of approximately 20 years to disclose the relationship between anemia and dementia in Korean elderly, and suggest that anemia is a modifiable risk factor for dementia needed active intervention.

Method

We analyzed a large population‐based cohort study of aged ³65 years who participated in the national health screening program including blood tests and cognitive function tests from 2007 to 2008 in Korean National Health Insurance Service database 2006‐2020. The risk of AD according to the presence and severity of anemia was evaluated using a multivariable Cox regression model, after adjustments for sex, BMI, HTN, DM, LDL, TG, SCr, GFR and past medical history (depression, HTN, DM, cardiovascular disease, cerebrovascular disease).

Result

As a result of the analysis, dementia occurred in 27.9% of the total subjects (316,881 persons) during the follow‐up period until 2020. Also, dementia occurred in 27.5% of the normal group, but 30.1% of the anemia group. As a result of survival analysis, even after adjusting for sex, there was a statistically significant difference between the presence of anemia and the prevalence of dementia (HR 1.07, 95% CI 1.05‐1.09). In addition, even after adjusting for sex, BMI, HTN, DM, LDL, SCr, GFR, and past medical history, there was a statistically significant association between anemia and dementia (HR 1.05, 95% CI 1.03‐1.07).

Conclusion

We reported that the presence of anemia statue and the severity of anemia in the elderly were related to the occurrence of dementia through a national date of Korea. We suggest that anemia is a modifiable risk factor for dementia and requires intensive intervention in the elderly.
Visual Cognitive Assessment Test (VCAT): Utility in detecting early dementia in diverse language cohorts
Authors: Ng Kok Pin , Ong Gwen Cui Fann , Yeoh Odelia Huai‐En , Raghu Rema , Rosa‐Neto Pedro , Gauthier Serge , Liu Yidan , Li Xiaofeng , Baek Min Jae , Kim SangYun , Kandiah Nagaendran
Published: December 2023

Background

Cognitive tests play a crucial role in evaluating mild cognitive impairment (MCI) and dementia. As most tests are originally developed in English‐speaking cohorts, their application in multilingual populations will need to be translated and may affect the test psychometrics. Therefore, the VCAT was developed as a language‐neutral visual‐based assessment to mitigate this issue. Although the VCAT has been validated in Southeast Asian countries, its performance in wider language cohorts remains unclear. Here, we aim to compare the utility of VCAT with established screening tests, Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination (MMSE), in distinguishing MCI and dementia from cognitively normal (CN) individuals in a multinational study.

Method

This collaboration between Canada, China, India, Korea and Singapore recruited 614 participants (306 CN, 212 MCI, 94 Dementia). The administration of the cognitive tests were standardized across all study sites. Participants underwent the MMSE, MoCA, and VCAT on the same day, with their scores and demographic data (age, gender, years of education, ethnicity, primary written and spoken language) collected in the centers respectively. The performance of VCAT in distinguishing MCI and dementia from CN were assessed within each sites using the area under the curve (AUC).

Result

Baseline demographics of the participants in each site were summarized in Table 1. The mean (SD) MMSE, MoCA and VCAT scores in each diagnostic group across all countries were summarized in Table 2. The mean (SD) VCAT scores across all countries for CN, MCI and dementia were 25.91 (3.14); 21.00 (5.36) and 11.91 (4.79) respectively. Corresponding scores for MoCA were 26.09 (2.76); 22.62 (4.43); 14.02 (5.17) and corresponding scores for MMSE were 28.34 (1.79); 26.55 (2.90); 18.91 (4.81). The AUC of VCAT in detecting cognitive impairment (MCI+Dementia) was found to be 0.83 (95%CI 0.80 to 0.86), which is comparable to the MoCA 0.82 (95%CI 0.78 to 0.85) and the MMSE 0.78 (95%CI 0.74 to 0.81).

Conclusion

VCAT was comparable to the MoCA and MMSE in distinguishing cognitive impairment from CN in a multinational, multilingual population. Further studies with wider language populations are needed to further validate the utility of VCAT globally.
Physically demanding work and cognitive impairment in late life
Authors: Barbosa Matheus Ghossain , Rabelo Wendell Lima , Bertola Laiss , Lima‐Costa Maria Fernanda , Ferri Cleusa P
Published: December 2023

Background

Cognitive decline is increasing in prevalence worldwide and poses a heavy burden on society. Sociodemographic factors and health behaviors associated with cognitive decline have been described. While physical exercise has been reported as a protective factor, less education acts as a risk factor. Conversely, work activities associated with lower educational levels are frequently more physically demanding. Few studies have analyzed the impact of work activities on cognition.

Method

We used data from the Brazilian Longitudinal Study of Aging, with a sample of 8,336 complete cases. Linear regression was performed to assess the impact of physical demand at work on cognitive performance, as measured by a global cognitive score composed of temporal orientation, verbal fluency, and memory tests. Work activities were classified by the question “How would you describe physical demand of the job you had most of your life?”, with the following possible answers: “mostly sitting”, “mostly standing or walking”, “some physical effort” and “intense physical effort”. Age, sex, marital status, educational level, household income per capita, number of comorbidities, smoking and alcohol consumption, and level of physical activity were used as covariates.

Result

When compared to a “mostly sitting” type of work (e.g., office job), a “mostly standing or walking” (e.g., security worker) job did not show any difference in cognitive performance (β = ‐0.03, p = 0.089). On the other hand, a “some physical effort” job (carrying weights or using tools, such as nurse or carpenter) and an “intense physical effort” job (carrying heavy weights, such as miner or construction worker) showed an increasingly worse cognitive performance (respectively, β = ‐0.09, p = 0.000 and β = ‐0.11, p = 0.000).

Conclusion

Although sedentarism has been shown to be associated with a worse cognitive performance and increased dementia risk, physically demanding jobs do not appear to be beneficial. Meanwhile, work stress associated with these activities might exert a negative effect on cognition independent of educational level and physical exercise unrelated to work. Some data suggest mentally demanding jobs, on the contrary, can be beneficial. With development of new technologies, moving from physical work into mental work can potentially reduce dementia risk.
The therapeutic potential of ellagic acid loaded in nanocarriers for the treatment of the Alzheimer’s disease
Authors: Maisto Nunzia , Mango Dalila , Barbato Gaetano , Marianecci Carlotta , Carafa Maria , Rinaldi Federica , Nisticò Robert
Published: December 2023

Background

Ellagic acid (EA) has been shown to have protective effects on Alzheimer’s disease, but it shows poor pharmacokinetic profile. A valid approach is delivering the drug in non‐ionic surfactant vesicles (NBVs) through the nose to brain (N2B) route coupled to focused ultrasound (FUS) improving brain targeting. Several niosomal formulations composed by specific surfactants (potentially enhance neuroprotective effect) have been characterized. The contrast agent was loaded inside the nanocarriers which was subsequently characterized using FUS in vitro technique. The EA will be loaded inside the vesicles and the neuroprotective effect of NBVs and EA‐NBVs will be explored using electrophysiological recordings (field and whole cell patch clamp) of hippocampal synaptic transmission and plasticity in ex‐vivo Alzheimer model.

Method

Empty and loaded NBVs were prepared and deeply characterized. In vitro FUS analysis were performed to evaluate the ability of FUS to induce a stable and prolonged release of probe‐drug loaded. The electrophysiological experiments were conducted using C57BL6/J mice of both sexes aged between 30 and 40 days. We performed electrophysiological recordings in area CA1‐CA3. Paired pulse facilitation was assessed at inter‐stimulus intervals ranging from 50 to 500 ms. An additional recording of baseline was evaluated before inducing Long‐Term Potentiation (LTP) by theta‐burst stimulation. Responses (fEPSP) were recorded for 1 hour after tetanization. In vitro Alzheimer model was obtained applying Aβ1‐42 oligomers (200 nM). As a control, we tested the effect of Aβ1‐42 with a scrambled sequence applied in the same condition of Aβ1‐42. Empty and loaded NBVs were used in presence and not of Aβ1‐42 and of Aβ1‐42 scrambled.

Result

Preliminary results of empty and loaded NBVs present an optimal range of size for N2B delivery and in vitro FUS release shows a stable and controlled release profile of loaded drug. Slices incubated in presence of Aβ1‐42 showed an impairment of LTP, while this effect didn’t occur after incubation of slices with Aβ1‐42 scrambled. Preliminary results show that NBVs formulations didn’t compromise LTP suggesting the possibility of using them as drug carriers in Alzheimer’s disease.

Conclusion

A better brain delivery of EA could be a valid approach in pathologies characterized by synaptic dysfunction.
Tau Protein in the Retina
Authors: Kayabasi Umur A.
Published: December 2023

Background

Currently there is no definite cure for Alzheimer’s therefore early detection is critical. Undetected Alzheimer’s Disease (AD) can lead to severe accidents, neglecting to take essential medications, injury to oneself or others, and/or financial problems. Currently, biomarkers are the most promising way to detect Alzheimer’s early on. Biomarkers such as beta‐amyloid and tau levels taken through invasive mehods or brain scans that involve radiation are among them.

As the retina is an extension of the brain and the brain structure, it is possible to detect misfolded proteins via retinal examination non‐invasively. The aim of this study was to discover the binding property of curcumin to both Tau and AB in the retina as a potential biomarker for AD.

Method

In this study, 20 patients were invited with mild AD who had undergone retinal examination within the past 2 years. All the patients had retinal imaging with curcumin which revealed misfolded proteins during the examination and then they were advised to take daily curcumin. The mean age of the patients was 71, and the patients were instructed to take Curcumin Meriva in 500 mg supplements once daily after their prior examinations. All patients had tests repeated with FAF and Heidelberg Spectralis OCT device. The regions with abnormal lesions on FAF were detected and the layer of the defect was scanned by OCT plus compared with the previous imaging of the patients. The images were examined in a masked fashion by 2 specialists.

Result

The images disclosed hyperfluorescent lesions on FAF and OCT revealed accumulations in the inner layers of the retina. Some accumulations had dot shapes and others had fibril‐tangle shapes. Some lesions were present in prior exams, but they were more pronounced and shinier after curcumin use. Their size and shape were in concordance with misfolded proteins in the brain (Figure).

Conclusion

Retinal examination with curcumin revealed AB plaques in the retina in prior studies. Our study is the first that may demonstrate an easy way to detect the culprit plaque Tau inside the retina of live patients.
Renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural older adults in China: a population‐based study
Authors: Wang Nan , Liang Xiaoyan , Fa Wenxin , Ma Yixun , Tian Xunyao , Liu Cuicui , Zhu Min , Tian Na , Liu Keke , Tang Shi , Song Lin , Cong Lin , Wang Yongxiang , Hou Tingting , Du Yifeng , Qiu Chengxuan
Published: December 2023

Background

Emerging evidence has linked impaired renal function with dementia, but the neuropathological mechanisms underlying the association remains poorly understood. We sought to examine the relationships of renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural Chinese older adults.

Method

This population‐based cross‐sectional study included 5715 participants (age ≥60 years; 57.15% women; 40.49% illiteracy) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND‐China). We calculated the estimate glomerular filtration rate (eGFR) using serum creatinine and the simplified modification of diet in renal disease equation specifically for individuals from China, and impaired renal function was defined as eGFR <60 mL/min/1.73 m2. Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were diagnosed following the international criteria. Plasma amyloid‐β (Aβ) 40, Aβ42, total tau, and neurofilament light chain (NfL) concentrations were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, the general linear regression, and mediation models.

Result

Of the 5715 participants, 283 (4.95%) were detected with renal function impairment, and 326 (5.70%) were diagnosed with dementia (195 with AD and 10 with VaD). The multivariable‐adjusted odds ratios of eGFR <60 mL/min/1.73 m2 (vs. >90mL/min/1.73 m2) were 2.43 (95% confidence interval [CI] 1.56‐3.72) for all‐cause dementia, 2.74 (1.64‐4.49) for AD, and 1.30 (0.50‐2.98) for VaD. In the plasma biomarkers subsample, controlling for demographic factors, impaired renal function was significantly associated with higher levels of plasma Aβ40 (demographic‐adjusted β‐coefficient = 59.06; 95%CI 46.93‐71.19), Aβ42 (3.41; 2.62‐4.20), NfL (14.57; 9.08‐20.05), and total tau (0.74; 0.48‐1.01), and the observed associations remained significant even in the multivariable‐adjusted model (P<0.001). The mediation analysis showed that total tau mediated 12.77% of the association between impaired renal function and AD.

Conclusion

Impaired renal function is associated with an increased risk of dementia and AD. Plasma total tau may partly underlie the association of renal function with Alzheimer’s dementia.
Amyloid beta and tau pathology compared within different Alzheimer’s disease mouse models after inoculation with Alzheimer’s disease brain tissue
Authors: Turnbull Catherine , Purro Silvia , Collinge John
Published: December 2023

Background

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is associated with two proteins known as amyloid beta (Aβ) and tau. Both proteins are thought to have prion‐like properties, resulting in the seeded propagation and spread of disease‐related assemblies. We have investigated three different AD knock‐in mouse models containing humanised versions of Aβ and tau to further our understanding of how AD progresses after the inoculation of Aβ/tau assemblies or seeds. These transmissions would also aid in deciphering the prion‐like properties of both Aβ and tau. These included the APPNL‐F/NL‐F model, which contains a Swedish and Iberian mutation (NL‐F) in the amyloid precursor protein (APP), expressing elevated levels of human Aβ42, and the human (h)TauKI/KI model, which contains all six human isoforms of human tau. Moreover, the AppNL‐F/NL‐F/hTauKI/KI mouse model expresses both human tau and human Aβ42, allowing a side‐to‐side comparison of all three models to provide an informative insight into the best model to study Aβ and tau pathology after inoculation with AD cases.

Method

We previously characterised three AD cases for prion‐like properties, in terms of protease resistance and conformational stability, and inoculated each of the cases into the different AD mouse models. Aβ and tau seeding was determined via histological and western blot analysis, via probing for 82E1 and AT8, to determine the presence of human Aβ and phosphorylated tau respectively.

Result

Using transmission studies, significant differences were seen for Aβ and tau seeding within the APPNL‐F/NL‐F, human (h)TauKI/KI and AppNL‐F/NL‐F/hTauKI/KI mouse models. We show that the AppNL‐F/NL‐F/hTauKI/KI mouse model demonstrates both Aβ and tau seeding from the inoculation of AD cases at earlier time points compared to its retrospective APPNL‐F/NL‐F and hTauKI/KI mouse models in vivo.

Conclusion

After comparing the three different mouse models, our data suggests that the AppNL‐F/NL‐F/hTauKI/KI mouse model may be a superior model for studying prion‐like behaviour and the role of Aβ and tau assemblies within AD. With regards to future characterisation of possible Aβ and tau strains, we anticipate that this model will be able to distinguish any potential strains indicated from serial passages in vivo using the AppNL‐F/NL‐F/hTauKI/KI model.
Shared and unique effects of ApoEε4 and pathogenic gene mutation on cognition and imaging in preclinical familial Alzheimer’s disease
Authors: Quan Meina , Wang Qi , Qin Wei , Jia Longfei , Jia Jianping
Published: December 2023

Background

Neuropsychology and imaging changes have been reported in the preclinical stage of familial Alzheimer’s disease (FAD). This study investigated the effects of APOEε4 and known pathogenic gene mutation on different cognitive domains and circuit imaging markers in preclinical FAD.

Method

139 asymptomatic subjects in FAD families, including 26 APOEε4 carriers, 17 APP and 20 PS1 mutation carriers, and 76 control subjects, went through a series of neuropsychological tests and MRI scanning. Test scores and imaging measures including volumes, diffusion indices and functional connectivity (FC) of frontostriatal and hippocampus to posterior cingulate cortex pathways were compared between groups, and analyzed for correlation.

Result

Compared with controls, APOEε4 group showed increased hippocampal volume and decreased FC of fronto‐caudate pathway (figure 1). APP group showed increased recall scores in auditory verbal learning test, decreased fiber number, increased radial diffusivity and FC of frontostriatal pathway (figure 1 & 2). All three genetic groups showed decreased fractional anisotropy of hippocampus to posterior cingulate cortex pathway (figure 1). These neuropsychological and imaging measures were able to discriminate genetic groups from controls, with areas under the curve from 0.733 to 0.837 (figure 3). Circuit imaging measures are differentially associated with scores in various cognitive scales in control and genetic groups.

Conclusion

There are neuropsychological and imaging changes in the preclinical stage of FAD, some of which are shared by APOEε4 and known pathogenic gene mutation, while some are unique to different genetic groups. These findings are helpful for the early identification of Alzheimer’s disease, and for developing generalized and individualized prevention and intervention strategies.
Manual Motor Function as a Classifier for Alzheimer’s Disease
Authors: Koppelmans Vincent , Ruitenberg Marit F. L. , Tasdizen Togla , Duff Kevin
Published: December 2023

Background

In contrast to numerous reports of gross motor problems in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), fine motor function has been relatively understudied. We examined if performance on manual motor tasks can distinguish between cognitively normal (CN) subjects, and individuals with MCI or AD, and which fine motor features are most informative.

Method

47 CN, 25 MCI, and 16 AD participants completed computerized tests of unimanual (dominant and non‐dominant hand) tapping, synchronous bimanual tapping, and alternate bimanual tapping. Outcome measures included initial reaction time, tapping speed, and variance. We used imbalanced random forest learning for classification modeling. The model was trained on 70% of the data and tested on the remaining 30% using 5‐fold cross‐validation. To investigate the contribution of individual variables to the classification model, we conducted permutation feature importance analysis.

Result

The overall classification accuracy of the training data was 56%, while the overall classification accuracy of the test data was 70%. The group‐specific accuracy, defined as the proportion of subjects predicted to belong to a certain group who are truly a member of that group, was 76% for CN, 33% of amnestic MCI, and 86% for AD. In 50% of the cases amnestic MCI subjects were classified as control subjects, and in 17% of the cases as AD subjects. The group‐specific precision, defined as the proportion of subjects who received a certain group label who truly belonged to that group (i.e., ‘true positives’) was 76% for controls, 100% for amnestic MCI, and 45% for AD. The three most important features that were used for classification of the test hold‐out data were 1) variance in tapping speed during dominant hand finger tapping; 2) the number of dual tapping trials without gaps or onset delays; and 3) initial reaction time for non‐dominant hand finger tapping.

Conclusion

Supervised machine learning can discriminate CN and AD subjects based on finger tapping performance features, but is less effective for distinguishing MCI subjects from CN and AD subjects. Finger tapping performance could be a cost‐effective tool for augmenting existing AD biomarkers.
High School and Beyond: Cohort Data for Studying the Effects of Education on Midlife Cognition
Authors: Brickman Adam M. , Grodsky Eric , Manly Jennifer J. , Muller Chandra , Warren John Robert
Published: December 2023

Background

The objective of our presentation is to describe the utility of data from the High School and Beyond (HSB) cohort for studying the impact of early life circumstances and experiences—especially related to education—on risk of midlife cognitive impairment. HSB is a cohort study of a large (n∼25,500), diverse, nationally‐representative probability sample of American high school students in 1980. Participants were surveyed in 1980, 1982, 1984, 1986, 1992, and 2014/2015 with high rates of response; teachers and school administrators were also surveyed, and transcripts provide information about secondary and postsecondary course taking. HSB data from 1980 through 1992 include detailed information about educational contexts, opportunities, and outcomes as well as about family circumstances, labor force activities, and other early life factors.

Method

A 2021/2022 follow‐up survey with surviving cohort members featured lengthy interviews; a home health visit that included blood and saliva collection and anthropometric measures; and linkages to administrative records (e.g., mortality records, prescription records). Interviews included immediate and delayed recall tasks; a phonemic fluency task; a semantic fluency task; working memory tasks; self‐reported memory complaints; and detailed information about health conditions.

Result

Of the ∼24,330 surviving HSB panelists, ∼13,900 completed surveys in 2021/2022. Of the ∼13,900 sample members completing surveys, ∼4,880 completed a home health visit; an additional ∼1,560 mailed back saliva kits. HSB ultimately received ∼4,430 blood samples by the time fieldwork concluded in late 2022. Blood collected in 2022 is being used to construct (1) measures that define the main pathological features of ADRD (e.g., Aβ42, Aβ40, p‐tau 181, total tau, NFL, and gFAP); (2) measures that reflect cognition‐relevant pathologies (e.g., hemoglobin A1c, inflammatory markers, markers of endothelial function, markers of blood‐brain barrier disfunction, and blood lead levels); and (3) measures of biological aging (e.g., the GrimAge clock, DunedinPACE pace of aging, the Hannum clock).

Conclusion

HSB is now an extraordinary resource for studying—using a large, diverse national sample—the effects of educational contexts, opportunities, and outcomes on midlife cognitive functioning and biological markers of ADRD risk.
Sustained connectivity correlates of motor function in Alzheimer’s disease
Authors: King Jace B , Duff Kevin , Hoffman John M.
Published: December 2023

Background

In addition to cognitive deficits, issues with motor control are present across the dementia spectrum. Traditional functional connectivity measures synchrony of intrinsic activity between brain regions and is altered in patients with Alzheimer’s disease in regions supporting motor function; however, less is known regarding the temporal stability of that synchrony. Sustained connectivity uses the width of cross correlation curves of BOLD time series to reflect the relative duration of synchronous activity between brain regions. This study investigates sustained connectivity across the dementia spectrum in motor regions.

Method

109 participants were included in this analysis and included 32 individuals with mild cognitive impairment (MCI) (18 F, 73.84 ± 5.14), 30 with Alzheimer’s disease (AD) (19 F, 77.37 ± 6.45), and 47 control individuals (29 F, mean age 72.13 ± 4.68). All study participants completed MP2RAGE structural imaging and two 15‐minute resting fMRI scans. Preprocessing steps included segmentation, motion realignment, registration to MNI space, and regression of motion parameters. Sustained connectivity values were averaged across both scans and only participants with more than 50% volumes remaining after censoring were included in analysis. A 17 resting‐state network parcellation was used to evaluate sustained connectivity across the brain with each network treated as a single ROI. A linear regression analysis was used to compare sustained connectivity across groups controlling for mean head motion, age, and sex. T statistics and p‐values are reported for across group sustained connectivity values.

Result

Across all three groups, sustained connectivity with the dorsal and ventral somatomotor networks was significantly increased across a number of resting‐state networks including the central visual, anterior ventral attention, and lateral temporal default mode network (DMN; all dorsal) and the somatomotor association, anterior ventral attention, medial frontoparietal, lateral temporal and lateral DMN (all ventral; Figure 1; pFDR < .05).

Conclusion

These data suggest sustained connectivity may be a potential metric for assessing progressive cognitive decline in dementia. Our results indicate that sustained connectivity may be used to track changes in the temporal duration of functional connectivity in motor networks in individuals with intact cognition, mild cognitive impairment, and Alzheimer’s disease.
PD‐L1 blockade therapeutic effect in Tau P301S (line PS19) mouse model of tauopathy
Authors: Baruch Kuti , Kertser Alexander , Medina Sedi , Arad Michal , Yoles Eti , Schwartz Michal
Published: December 2023

Background

There is a growing understanding that Alzheimer’s disease (AD) and tauopathies are not merely brain‐centric conditions, but encompass also dysfunction of the peripheral immune system that impacts disease onset and progression. We have previously shown, in several mouse models of AD, that blockade of the PD‐1/PD‐L1 immune checkpoint pathway facilitates homing of specialized immune cells to the brain, where these cells mitigate different pathomechanisms, ultimately leading to function improvement. Here, we tested PD‐L1 blockade in the Tau P301S (line PS19) mouse model of tauopathy.

Methods

Tau P301S mice were treated with anti‐PD‐L1 antibody, or isotype control, and tested for the functional effect of the treatment on parameters of cognitive performance and brain pathology, at different time points after treatment. Pharmacokinetic and pharmacodynamic events following treatment were evaluated to monitor the peripheral and central immune response. Treatment effects were also evaluated in TREM2 knockout Tau P301S mice.

Results

Dose‐dependent effect of anti‐PD‐L1 treatment was detected at 14‐ and 28‐days post‐treatment, with respect to cognitive performance of PS19 mice, as measured by T maze task. At the different timepoints following treatment we found reduction in cerebrospinal fluid total tau protein levels, and reduction in cortical phosphorylated tau (Ser404) protein levels. The functional effect on improvement of cognitive performance following anti‐PD‐L1 administration was also observed in TREM2 knockout Tau P301S mice, suggesting that the therapeutic effect of anti‐PD‐L1, is independent of TREM2 expression.

Conclusions

PD‐L1 blockade evokes an immune response that leads to functional improvement on cognitive performance and reduced brain pathology in Tau P301S mice. These findings, taken together with our previous reports of anti‐PD‐L1 therapeutic effect in other AD or tauopathy mouse models, substantiate the generalization of this treatment approach ‐ targeting the peripheral immune system in order to drive brain tissue repair in neurodegenerative conditions.
A rapid realist review of co‐producing and co‐facilitating Recovery College Dementia Courses
Authors: Handley Melanie , Wheeler Charlotte , Duddy Claire , Wong Geoff , Moniz‐Cook Esme , Hackmann Corinna , Fox Chris , West Juniper
Published: December 2023

Background

Recovery Colleges have been established internationally as a service model for people with mental health conditions based on the principles of recovery, co‐production and adult learning. In the UK, NHS mental health services and third sector organisations are widening their use to include post‐diagnostic support for people with dementia. However, guidance for how to adapt the Recovery College model for people with dementia is lacking.

Method

A Rapid Realist Review built an initial programme theory for how and why Recovery College Dementia Courses worked for people who co‐produced and attended them. Using a realist logic of analysis, we synthesised evidence from academic and grey literature. The initial programme theory was refined in four online workshops with people with dementia and staff with experience of recovery colleges.

Result

Staff committed to recovery‐focused approaches recognised co‐producing Recovery College Dementia Courses as an opportunity to work within their core values. Course development is often additional to staff’s caseload, therefore time for this needed to be agreed with managers who recognised the potential for courses to foster person‐centred service cultures. Staff attendance to courses altered perceptions of service‐user/service‐provider relationships. Through co‐facilitated courses, people with dementia shared their experiences of living with the condition, giving staff the opportunity to understand people’s challenges and strengths beyond a set of clinical presentations.

Registration and attendance depended on staff knowing about courses and understanding who might benefit. Additionally, receiving a diagnosis of dementia was recognised as overwhelming and follow‐up contact with services varied. This meant there was no consistent approach for who received information about courses or when. Discussion with someone knowledgeable about the course was considered important to overcome internalised negative perceptions about dementia and feelings of hopelessness. These responses to diagnosis were major barriers to attendance and were experiences that Recovery College Dementia Courses sought to tackle.

Conclusion

Improving access to post‐diagnosis support for people with dementia and those who support them is important for helping people live well with their diagnosis. This initial programme theory provides the foundation for a primary study of Recovery College Dementia Courses to inform guidelines of international relevance.
The role of Alzheimer’s risk factor ApoE4 on intracellular Aβ aggregation
Authors: Konings Sabine C , Martinsson Isak , Nyberg Emma MC , Gouras Gunnar K , Klementieva Oxana
Published: December 2023

Background

Apolipoprotein E4 (ApoE4) is the main genetic risk factor for Alzheimer’s disease (AD). Previous research supports that ApoE4 increases amyloid‐β (Aβ) aggregation and plaque deposition. However, it remains poorly understood how ApoE4 affects the aggregation of Aβ prior to plaque seeding on a cellular level. The aim of this project is to use high‐resolution techniques to study intraneuronal Aβ accumulation at a synaptic and subcellular level and investigate how different ApoE isoforms influence this.

Method

The aggregation of Aβ in cultured primary neurons expressing human APP/Aβ will be studied using a correlative approach combining infrared spectroscopy and super‐resolution microscopy. Infrared spectroscopy allows us to study protein aggregation by looking at alterations in β‐sheet structures. Super‐resolution microscopy gives insights into the subcellular localization of Aβ and in changes in synaptic phenotypes. Human ApoE3 and ApoE4, derived from ApoE3 knock‐in (ApoE3‐KI) and ApoE4‐KI primary astrocyte cultures, are used as a physiological source to treat APP/Aβ primary neurons with human ApoE isoforms.

Result

We established an approach to obtain human ApoE3 and ApoE4 from primary mouse astrocytes and previously showed that Aβ and ApoE intersect inside neurons. In addition, we established a high‐resolution infrared spectroscopy approach for studying individual amyloid structures directly in neurons. In primary neurons generated from an human APP(NL‐F/NL‐F) knock‐in model we characterized the aggregation of intracellular Aβ and synaptic phenotypes with age. Additionally, an approach to supply primary neurons with human ApoE for longer time periods has been tested and allows to study chronic effects of human ApoE on Aβ aggregation inside neurons.

Conclusion

Our novel approach to study intraneuronal Aβ aggregation in cultured neurons potentially will contribute to new insights into where and how Aβ aggregates and will help to better understand how ApoE isoforms affect Aβ aggregation.
IBC‐Ab002 Fc modifications for fast clearance are associated with advantageous safety profile
Authors: Kertser Alexander , Baruch Kuti , Yoles Eti , Schwartz Michal
Published: December 2023

Background

Immune checkpoint inhibitors (ICI) have been suggested as a unique therapy for treating neurodegenerative diseases. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody developed by ImmunoBrain Checkpoint (IBC) for the treatment of Alzheimer’s disease (AD).

In cancer patients, ICI treatments are often associated with immune‐related adverse events (irAEs), which are side effects that manifest as either temporary or permanent autoimmune conditions caused by drug administration. One example of such an event is T cell‐mediated pancreatic tissue damage leading to autoimmune diabetes. The management of irAE often involves treatment discontinuation until symptoms relief, which has unwanted impact on the effectiveness of therapies that depend on continuous drug exposure.

Unlike common ICI used in oncology, PD‐L1 blockade mechanism of action in mouse models of neurodegenerative diseases was shown to be dependent on transient immune system stimulation. Accordingly, IBC‐Ab002 antibody was designed with modifications on its Fc backbone that shorten its circulation half‐life, to meet the pharmacokinetic and pharmacodynamic characteristics needed for treating AD.

Method

Surrogate antibodies that block mouse PD‐L1 and share the same hIgG1 Fc‐modifications as IBC‐Ab002 were generated and tested for their propensity to accelerate the onset of autoimmune diabetes in NOD transgenic mice, which spontaneously develop type 1 diabetes. Mice were monitored for their blood‐glucose levels, weight, and survival – for both the acute and long‐term duration following antibody administration.

Result

We found that administration of a therapeutically effective dose of IBC‐Ab002’s surrogate antibody led to fewer cases of premature diabetes onset in NOD mice, when compared with an antibody variant that contains no Fc‐modifications. Furthermore, no excessive weight loss, change in the time‐course of spontaneous diabetes onset or early mortality, were found following IBC‐Ab002’s surrogate treatment, compared with isotype‐control treated mice, in a 200‐days follow‐up assessment.

Conclusion

We demonstrate that the clearance rate of the antibody inversely‐relates to the probability of developing an adverse immune response, and that no delayed long‐term irAEs are expected once full clearance of the antibody was achieved. Overall, these findings suggest that shortening the half‐life of anti‐PD‐L1 antibodies in treatments that do not necessitate continuous exposure can considerably increase the safety profile.
Causal association between circulating angiopoietin‐1 levels and the risk of Alzheimer’s disease
Authors: Guo Xingzhi , Li Rui
Published: December 2023

Background

Alzheimer’s disease (AD), characterized by cognitive decline and memory loss, is the most common neurodegenerative disorder. Angiopoietin‐1 is a protein that plays a role in the formation and maintenance of blood vessels and has been suggested to be involved in the development of AD. However, the causal relationship between angiopoietin‐1 and AD is not well understood.

Method

To investigate the causal relationship between angiopoietin‐1 levels and AD risk, we performed a Mendelian randomization (MR) analysis using instrumental variables (IV) identified from genome‐wide association studies (GWAS) summary statistics on blood angiopoietin‐1 levels (N = 3,301) and AD (N = 63,926). Seven different methods, including inverse variance weighted (IVW), MR‐Egger, weighted median, simple median, maximum likelihood, simple mode, and weighted mode, were applied to calculate the causal estimate. Pleiotropic test and heterogeneity analysis were also assessed to evaluate the stability of the estimates.

Result

Using the IVW method, genetically determined human blood angiopoietin‐1 levels were causally associated with a decreased risk of AD (odds ratio [OR] = 0.86, 95%CI = 0.78‐0.94, P = 0.001), which was further validated using other approaches (Figure 1A). The leave‐one‐out analysis plot showed that there was no significant outlier driving the overall causal estimate between angiopoietin‐1 levels and AD (Figure 1B). The results of MR‐PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global, MR‐Egger intercept test, and Cochran’s Q test showed that there were no obvious directional horizontal pleiotropy and heterogeneity, indicating good stability of the present MR study.

Conclusion

Our study provides evidence for a causal relationship between angiopoietin‐1 levels and a reduced risk of AD. However, further validation and replication of these findings are needed to confirm our results.
Neuro‐immune and behavioral consequences of low dose radiation, social isolation and sex differences in the longevity MCAT mouse model
Authors: Rubinstein Linda , Paul Amber , Mhatre Siddhita D. , Iyer Janani , Puukila Stephanie , Ruiz Steffy Tabares , Alwood Joshua , Tahimic Camdice , Ronca April
Published: December 2023

Background

The multi‐organ physiological responses to spaceflight stressors resemble aging on Earth. We simulate space environment together with environmental stress, as a model of accelerated aging. Redox dys‐homeostasis was shown to contribute to aging‐related pathologies such as Alzheimer’s and Parkinson’s. The MCAT transgenic mice (overexpressing human catalase in the mitochondria), have increased life span, delayed age‐related pathology and enhanced hippocampal spatial learning and memory.

Method

Our study uses 1‐year old C57BL/6NJ male and female mice that underwent exposure to 0.5 gray of gamma radiation together with social isolation. In order to determine ROS contribution to neuro‐behavioral stress response, we used the longevity MCAT mouse model in which human catalase is overexpressed in the mitochondria. We aimed to determine whether in older mice quenching ROS, will mitigate the neuro‐behavioral consequences of low dose ionizing radiation and social isolation and whether sex differences will be detected. We have performed multiple behavioral tests which focused on performance, memory, physical stance, and stress, together with plasma and hippocampal neuro‐immune panels.

Result

We have detected both sex and radiation/isolation effects; the older females look physically better, are faster and perform better almost in all behavioral tasks compared to their male counterparts. On the other hand, they are more sensitive to low dose radiation and isolation in many cases. Interestingly, many of the neuro‐immune changes caused by radiation and social isolation were mitigated in the MCAT mice. In a plasma multiplex cytokine panel, corticosterone (7‐ and 90‐days post radiation), and hippocampal cytokine and microglial activation at the end of the experiment, we have detected significant changes due to radiation, isolation, sex and genotype in both short and long post radiation period. Our focus is now on applying advanced statistical modeling to correlate the behavioral tests with our recent molecular findings to look for specific biomarkers that could predict behavioral deficits caused by various environmental stresses.

Conclusion

Quenching ROS in older mice partially mitigates neuro‐immune consequences of environmental stresses. Significant sex differences were detected, pointing out the importance of examining both sexes, for better personal medicine. The study points out that anti‐oxydant meassures could help older isolated population.