bluuebunny/crossref_metadata_2025 huggingface dataset:
SUMOylation impact on synaptotoxicity of tau oligomers
Authors: Fraser Paul , Argyrousi Elentina K , Arancio Ottavio , Fioriti Luana
Published: December 2023

Background

Tau oligomers (oTau) secreted by neurons and astrocytes are linked to the propagation of pathology and negatively affect neuronal activity and viability. oTau‐mediated synaptic loss leads to cognitive deficits and manifests the clinical outcomes of Alzheimer’s disease and related tauopathies. Small Ubiquitin‐like MOdifier (SUMO) proteins regulate multiple cellular events and SUMOylation plays pivotal roles in synaptic biology. Changes in SUMO conjugation and function are also linked to AD and related neurodegenerative disorders such as Huntington’s and Parkinson’s disease. The goal of this investigation is to determine the impact of the two main SUMO isoforms, SUMO1 and SUMO2, on oTau related synaptotoxicity.

Method

SUMO1 and SUMO2 transgenic mice were generated with expression regulated by the neuron‐specific prion cos‐tet promoter. These in vivo models were used to generate double transgenic mice expressing human SUMO proteins and P301S mutant Tau. Changes in synaptic density and activity and the effects of oTau pathology were investigated with respect to cognitive deficits and long term potentiation (LTP).

Result

Elevated expression of human SUMO1 lead to impaired synaptic development and increased tau aggregation. SUMO1 transgenics crossed to Tau mutant mice resulted in an accelerated synaptic loss and a more severe disease phenotype as evidenced by LTP impairments and rapid cognitive decline. Conversely, SUMO2 conjugation levels were decreased in the presence of oTau and phospho‐tau pathology indicating a down‐regulation of its function. Enhanced SUMO2 expression in a mouse model of Tau pathology reversed this process and resulted in a significant reduction in oTau‐mediated synaptotoxicity and the associated LTP and cognitive impairments.

Conclusion

Cumulatively, our findings indicate that SUMO1 negative impacts and exacerbates oTau‐related synaptic dysfunction. In contrast, SUMO2 confers substantial neuroprotection and represents a potential therapeutic avenue to counteract oTau‐induced synaptotoxicity in AD.
Crosstalk between tau and alpha7 nicotinic acetylcholine receptors at the synapse
Authors: Tropea Maria Rosaria , Puma Domenica Donatella Li , Melone Marcello , Gulisano Walter , Vacanti Valeria , Arancio Ottavio , Grassi Claudio , Conti Fiorenzo , Puzzo Daniela
Published: December 2023

Background

The failure of cholinergic transmission and the increase of amyloid‐β peptide (Aβ) and tau protein are key players in Alzheimer’s disease (AD). The interaction between α7 nicotinic acetylcholine receptors (α7‐nAChRs) and Aβ has been previously investigated, but few studies have focused on the crosstalk between α7‐nAChRs and tau. We previously reported that Aβ and tau might act independently or concomitantly to impair synaptic plasticity and memory, converging onto common targets such as amyloid precursor protein (APP). Here we investigated the role of α7‐nAChRs on tau‐mediated impairment of synaptic plasticity and memory, tau neuropathology, and their interplay with APP.

Method

We used WT (C57Bl6/J) and α7 KO at different ages. 3XTg models of AD were used as positive controls. We performed electrophysiology to investigate synaptic transmission and plasticity at the CA3‐CA1 synapses from hippocampal slices, and behavioral studies (Novel Object Recognition and Location, Fear Conditioning) to evaluate memory. We used western blot for the expression of APP, tau (Ser199, Ser396, Thr205) and GSK‐3β (Ser9) phosphorylation. Formation of tau paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) were evaluated by immunohistochemistry and Bielschowsky staining. Immunoreactivity for NeuN was measured to assess neuronal loss.

Result

We found that α7 KO mice presented an AD phenotype characterized by the impairment of Long‐Term Potentiation and Paired Pulse Facilitation, and the reduction of different types of memory starting at 12 months of age. This age‐dependent phenotype was paralleled by an increase of APP expression, hyperphosphorylation of tau, and a decrease of GSK‐3β (Ser9) phosphorylation. α7 KO hippocampi presented a marked tau neuropathology with an increase of PHF‐1 immunoreactivity, the presence of PHFs and NFTs, and neuronal loss.

Conclusion

In summary, the lack of α7‐nAChRs was sufficient to trigger an AD‐like phenotype characterized by a marked tau pathology. Our data also suggest that the concomitant increase of APP expression might contribute to tau neurotoxicity.
Unique cognitive trajectories associated with inflammatory markers of blood‐brain barrier permeability in atrial fibrillation: An analysis of the Cardiovascular Health Study Cohort
Authors: Marion Danielle , Li Zhe , Roseborough Austyn D , Whitehead Shawn N , Freeman Ellen , Birnie David , Elahi Fanny M , Hachinski Vladimir , Elkind Mitchell S.V. , Lopez Oscar L. , Longstreth W.T. , Edwards Jodi D.
Published: December 2023

Background

Atrial fibrillation (AF) increases risk of cognitive decline independent of stroke, but mechanisms remain unclear. Elevated levels of peripheral inflammatory markers common in AF are associated with increased blood‐brain barrier (BBB) permeability and may contribute to neuroinflammation and degeneration. To examine the role of these markers in dementia risk, we estimated associations of plasma C‐reactive protein (CRP), interleukin‐6 (IL‐6), and fibrinogen with dementia and cognitive decline in aging adults with and without AF.

Method

Dementia free adults aged ≥ 65 years were identified from the Cardiovascular Health Cognition Study. Exposures were plasma CRP, IL‐6, and fibrinogen at baseline and follow‐up and primary outcomes were dementia and cognitive function, measured and adjudicated annually with the Modified Mini‐Mental State Examination (3MS). Competing risks Cox proportional hazards regression was used to estimate associations between time‐varying exposures and dementia. Latent class growth models were used to identify cognitive trajectories adjusted binomial logistic regression to test associations between these trajectories and baseline markers. All models were stratified by AF status, with interaction terms for sex and apolipoprotein E (APOE) ε4 status.

Result

Among 3,375 adults (505 with AF and 2,870 without), 480 developed dementia over a median follow‐up of 9.3 years. No associations between inflammatory markers and dementia hazard were observed, but latent class analyses identified two unique cognitive trajectories, with 82% showing a stable trajectory and 18% showing rapidly progressing decline. Among those with AF, elevated CRP and IL‐6 increased the odds of cognitive decline by 10% (95% CI 1.05 – 1.15) and 32% (95% CI 1.22 – 1.44), respectively. Sex‐specific models indicated that a 1g/L increase in fibrinogen increased the odds of cognitive decline by 57% among females with AF only (95% CI 1.36‐1.81). Among those with AF, inflammatory markers were more positively associated with cognitive decline in the presence of the APOE ε4 allele.

Conclusion

Elevated IL‐6 was associated with cognitive decline in aging adults both with and without AF and elevated CRP and fibrinogen were associated with cognitive decline in those with AF only. Critically, sex and APOE genotype significantly modified these associations. Future work using more sensitive markers of central inflammation is needed.
Racial disparities in Alzheimer’s Disease and Related Dementias (ADRD): The association between early life adversity and ADRD
Authors: Rose Deborah
Published: December 2023

Background

Adverse childhood experiences (ACEs) are an important public health concern that predict neuroanatomical changes in development such as decreased prefrontal cortex and hippocampal volumes, and can lead to poor health outcomes in adulthood, including cognitive impairment. Alzheimer’s disease (AD) is the most common cause of dementia, and it disproportionately affects racial and ethnic minoritized (REM) individuals. Research demonstrates that some of the mechanisms underlying these racial disparities may include differences in exposure to specific types of ACEs (i.e. parental remarriage and/or death). A significant ACE burden can lead to disruption of the hypothalamic‐pituitary adrenal (HPA) axis, our fight‐or‐flight response system to environmental threats and stressors. Growing evidence has shown an association between ACEs and the development of cognitive impairment in older adulthood, including AD and related dementias (ADRD). We do not know, however, how biomarkers related to HPA axis dysregulation in association with ACEs are correlated to ADRD biomarkers (pathology) in a nationally representative, diverse cohort of individuals.

Methods

A preliminary study is being conducted to evaluate the associations between early life adversity (measured retrospectively through surveys) and ADRD in several cohorts, including the Minority Aging in Research Study (MARS) from the Rush University Alzheimer’s Disease Research Center, the Stress and Resilience in Dementia (STRIDE) cohort from the University of Wisconsin, and the Duke University Medical Center clinics using DEDUCE, an on‐line query system in MaestroCare, Duke University Hospital’s electronic medical record system. Statistical analyses will be performed using R software.

Results

Pending statistical analyses.

Conclusion

Validation of ACEs as independent risk factors for AD and contributors to the racial disparities seen in this condition will offer new potential therapeutic targets at the molecular level, new clinical screening modalities for specific ACEs instigating cognitive decline, and public policy insights to address a history of childhood trauma in patients with a clinical diagnosis of ADRD. This is especially for those REM individuals who have historically had a delayed or missed diagnosis and have been disproportionately impacted by ADRD.

The research project described is supported by the National Institute On Aging of the National Institutes of Health under Award Number P30AG072958.
Roadway Weather Challenges Illuminate Real‐World Driving Biomarkers of Dementia Risk
Authors: Hasan Md Zahid , Basulto‐Elias Guillermo , Tan Russell Kai Liang , Chang Jun Ha , Sarkar Soumik , Sharma Anuj , Hallmark Shauna , Rizzo Matthew , Merickel Jennifer
Published: December 2023

Background

Cognitive decline is a leading early predictor of dementia risk and may be evident in real‐world (RW) digital data even before patients ever present to clinic. This study examined the feasibility of using video and digital sensor profiles of real world (RW) driving in adverse weather as a marker of dementia risk.

Method

70 older drivers (mean age = 75.6 years) without dementia participated in a RW driving study for 2, 3‐month periods, one year apart (Wang, et al. 2021) . Self‐reported demographics and neuropsychological tests relevant to dementia and driving were collected at study start. Drivers were classed as cognitively neurotypical (N = 33) or impaired (N = 44) based on normed neuropsychological scores. Sensors installed in each driver’s vehicle collected video, speed, and GPS data across 405,104 miles driven. GIS data categorized roadway type (residential, commercial, interstate). A computer vision model (99% accuracy) we developed classed roads as clear or poor (rain, snow). Bayesian mixed‐effect logistic regressions assessed driver speed limit compliance (vehicle speed‐posted speed limit) across driver class, roadway, and weather.

Result

Drivers were 8.01 times more likely to speed on interstates (95% CI: 7.61‐8.61) than residential roads (15‐25 mph). Impaired drivers were 15% more likely to drive slower than neurotypical drivers on clear roadways (95% C: 1.0413‐1.2829). This pattern reversed in poor weather with impaired drivers driving faster than neurotypical (b = 0.74, 95% CI: 0.57‐0.94)

Conclusion

Digital biomarkers from RW data show promise to screen for early dementia risk, advancing research and innovative clinical trials to prevent dementia. Driving challenges, like poor weather, discriminate cognitive decline before dementia. Impaired drivers showed self‐restriction by driving slower on clear roads and reduced self‐restriction by driving faster in poor weather despite risk. Big data strategies, like computer vision, complement driver performance data to identify RW environmental risk, paving the road for the car as a medical diagnostic device.
Klotho protein concentrations as a function of sex, APOE, family history or Alzheimer’s disease biomarker status in an at‐risk cohort
Authors: Driscoll Ira , Betthauser Tobey J , Gallagher Catherine L. , Hermann Bruce P , Sager Mark A. , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Carboni Margherita , Wang Dan , Blennow Kaj , Zetterberg Henrik , Johnson Sterling C , Asthana Sanjay , Dubal Dena B. , Okonkwo Ozioma
Published: December 2023

Background

The KLOTHO gene encodes for a longevity and neuroprotective klotho hormone. The non‐human animal literature suggests that higher levels of klotho promote resilience against Alzheimer’s disease (AD)‐related neuropathology. Human carriers of the functionally advantageous KLOTHO KL‐VS variant have higher serum klotho levels and show attenuation of proteins involved in AD‐related neuropathology (β‐amyloid (Aβ) and tau). How klotho protein relates to AD neuropathology or risk factors (APOE gene, family history, sex) is less well understood.

Method

The sample consists of 318 middle‐aged and older, cognitively normal adults (MeanAge(SD) = 63.8(6.66); range = 44‐80; 65% female) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center studies. Stratifications of the sample into positive vs. negative AD biomarker status were made using local reference cutpoints measured via cerebrospinal fluid (CSF: Aβ40, Aβ42, total tau, phosphorylated tau, and their respective ratios to Aβ42) or positron emission tomography (PET; β‐amyloid: 11C‐Pittsburgh compound B(PiB); tau: 18F‐MK‐6240). We examined whether baseline serum klotho protein concentrations differed based on AD biomarker status (whether positive (i.e., abnormal) for β‐amyloid or tau) or characteristics related to AD risk.

Result

There were no significant differences in baseline serum klotho concentrations between those considered positive vs. negative for β‐amyloid or tau whether by CSF or PET (P’s>0.19). Females (844 pg/mL) compared to males (765 pg/mL) had significantly higher serum klotho concentrations (F
(1,317) = 7.37; P = 0.007). No differences were observed based on APOE4 status or parental AD history (P’s>0.31).

Conclusion

We confirm sex‐dependent difference in serum klotho favoring females. No significant differences in serum klotho protein concentrations were observed based on APOE4, AD family history or AD biomarker status (+/‐) in our cohort of middle‐aged and older, cognitively normal adults, albeit enriched for AD risk. While this may seem in contrast to a recent case‐control study (Grøntvedt, 2022) suggesting that klotho protein is associated with β‐amyloid and tau burden and clinical stages of AD, that study measured circulating klotho in plasma and included participants with MCI and AD diagnoses. Our results add to the growing KLOTHO literature and highlight the need for better understanding of the underlying mechanisms for its effects.
Selective RNA‐targeting of mTORC1 and 2 to ameliorate Alzheimer’s Disease pathogenesis
Authors: Stahl Jack , Joji Aswathy , Khorkova Olga , Volmar Claude‐Henry , Wahlestedt Claes
Published: December 2023

Background

It has been well described that inhibition of the kinase, mechanistic target of rapamycin (mTOR), improves age‐related pathologies including Alzheimer’s Disease (AD). However, mTOR exists as a complex and exerts differential functions depending on its binding partners. Suppression of mTORC1 has yielded positive outcomes for AD‐related measures (decreased amyloid beta/tau pathologies and improved cognition)1. In contrast, increased mTORC2 activity also resulted in positive outcomes in AD models (improved brain insulin sensitivity and neuronal survival)2, suggesting that a therapeutic which inhibits mTORC1 while upregulating mTORC2 may be desirable for AD. However, no such therapeutic exists.

Method

To inhibit mTORC1, we used a raptor siRNA which has been chemically modified to be stable for in vivo purposes. To upregulate mTORC2, we bioinformatically identified natural antisense transcripts (NATs) of rictor and designed custom siRNAs to target the various transcripts. Following an in vitro screen of the custom siRNAs, we determined which NATs yield upregulation of rictor when targeted and designed more siRNAs targeting the same transcript to optimize our mTORC2‐upregulating siRNA. Cellular RNA and protein were quantified using RT‐qPCR and western blot, respectively.

Result

We demonstrate efficient knockdown of raptor in all transfected cell lines, as well as in mouse brain. Raptor knockdown has been confirmed at both the RNA and protein level. Furthermore, we successfully upregulated expression of rictor using rictor NAT‐targeting siRNAs (AntagoNATs) in multiple cell lines. Downstream analyses suggest a therapeutic effect for both raptor knockdown and rictor upregulation in the context of AD.

Conclusion

Nucleic acid‐based therapeutics which target RNA have been outcompeting and replacing small molecule protein‐targeting drugs in recent years. However, RNA‐targeted therapeutics have been largely unexplored for AD. Chemical linkage of raptor siRNA to rictor AntagoNAT siRNA yields the first therapeutic to selectively inhibit mTORC1 and upregulate mTORC2, providing a modern RNA‐targeting therapeutic for AD.

References

1. Querfurth, H., Lee, HK. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegeneration 16, 44 (2021).

2. Lee, H.‐K. et al. mTORC2 (Rictor) in Alzheimer’s Disease and Reversal of Amyloid‐β Expression‐Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. J Alzheimers Dis 56, 1015‐1036 (2017).
Associations of subcortical shapes with age‐related neuropathologies in community‐based older adults
Authors: Saifullah Khalid , Makkinejad Nazanin , Evia Arnold M , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos
Published: December 2023

Background

Age‐related neuropathologies lead to substantial atrophy of subcortical brain regions. However, the effects of age‐related neuropathologies on the shape of subcortical brain structures are not well understood because a) definitive diagnosis of most neuropathologies is only possible at autopsy and b) multiple neuropathologies often coexist in the brain of older adults. The purpose of this work was to integrate ex‐vivo MRI and detailed neuropathologic examination in a large number of community‐based older adults.

Method

Participants and Data

Cerebral hemispheres from 842 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), the Minority Aging Research Study (MARS) and the Clinical Core (CC) of the Rush Alzheimer’s Disease Research Center (ADRC)1,2 (Fig.1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners approximately 30 days postmortem. After ex‐vivo MRI, each hemisphere underwent detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1).

Ex‐vivo MRI and Shape Estimation

The subcortical structures were segmented in ex‐vivo T2‐weighted MR images from all participants. Shape analysis was performed using SPHARM‐PDM3. For each subcortical structure, signed shape differences were computed from the average mesh for all vertices and all participants.

Statistical Analysis

Vertex‐wise linear regression was performed for each subcortical structure, modeling the signed shape difference at each vertex (dependent variable) as a function of neuropathologies (specifically amyloid‐β plaques, neurofibrillary tangles, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts, and cerebral amyloid angiopathy), and controlling for age at death, sex, years of education, postmortem interval to fixation, postmortem interval to imaging, and scanner. The statistical analysis was conducted using PALM4 with family‐wise error rate correction.

Result

The results are shown in Figure 2. These findings for tangles and LATE‐NC were in good agreement with our previous work5,6. Finally, although MRI was conducted ex‐vivo, we expect the results to translate well to in‐vivo7.

Conclusion

The differences in spatial patterns of the effects of various neuropathologies may contribute towards the development of tools for in‐vivo prediction of these neuropathologies.
Resilience to Alzheimer’s Disease: Unraveling the Molecular Mechanisms From Post‐Mortem Tissue
Authors: de Vries Luuk E , Carulli Daniela , Jongejan Aldo , Moerland Perry D , Rozemuller Annemieke J.M. , Huitinga Inge , Swaab Dick F , Verhaagen Joost
Published: December 2023

Background

Approximately one‐third of elderly individuals remain cognitively intact, despite substantial Alzheimer’s Disease (AD) neuropathological changes. The exact, molecular underpinnings towards resilience in AD remain to be elucidated. Here, we set out to investigate changes in gene expression in the prefrontal cortex of cognitively intact donors with AD pathology, referred to as resilient, and compare them to AD and control subjects.

Method

Post‐mortem tissue of individuals with an intermediate or high AD neuropathological score according to the NIA‐AA, but with intact cognition, AD patients with high pathology and low cognition, and age‐matched controls (i.e. cognitively intact subjects without a neurological or psychological disorders) was obtained from the Netherlands Brain Bank. Bulk RNA sequencing was performed on RNA isolated from the prefrontal cortex. Several molecular mechanisms of interest were further immunohistochemically confirmed in post‐mortem tissue.

Result

Analysis revealed transcriptional changes between resilient and AD donors including mitochondrial functioning, metallothionein signaling and the Tyrobp network. Additionally, we found profound changes in the extracellular matrix, including changes in perineuronal nets (PNNs) between resilient, AD and control donors. Using immunohistochemistry, we demonstrated altered morphology and a reduction of PNNs in AD while PNNs were more preserved in resilient donors compared to control donors.

Conclusion

Our data indicates that changes in mitochondria, altered signaling in astrocytes and microglia via metallothionein and Tyrobp, respectively, and preservation of PNNs were associated with intact cognition despite the presence of AD pathology and could ultimately point to novel targets for therapeutic development.
Cognitive resilience at 3 years after stroke depends on pre‐ and post‐stroke factors
Authors: Khlif Mohamed Salah , Werden Emilio , Bird Laura J. , Brodtmann Amy
Published: December 2023

Background

The incidence of dementia in stroke survivors is greater than in stroke‐free people. However, some stroke survivors show cognitive resilience, withstanding the detrimental effects of stroke. In this study, we explored the differences between cognitively‐impaired (CI) and cognitively‐normal (CN) survivors in comparison with healthy controls (HC).

Method

Participants were sampled from the Cognition And Neocortical Volume After Stroke (CANVAS) study. Sociodemographic, clinical, neuropsychological, cognitive, neuroimaging, sleep, and physical activity data were obtained for 93 stroke participants at 3‐months and 3‐years post‐stroke and for 35 HC at equivalent timepoints. Stroke participants were classified as CN (n = 71) or CI (n = 22) at 3‐years based on mood scores, clinical interviews, and z‐scores of performance in five cognitive domains: attention, memory, language, executive and visuospatial functions. Structural brain volumes were estimated from T1‐weighted MRI using longitudinal FreeSurfer segmentation. Linear random‐intercept mixed‐effects modelling was used to compare between groups and timepoints accounting for differences in age, sex, years‐of‐education, and total‐intracranial volume.

Result

The stroke group overall had higher incidence of atrial fibrillation, scored higher on anxiety and depression, and had lower sleep efficiency compared to HC. Stroke survivors had thinner cortex, less cerebellar grey‐matter (GM), and larger choroid plexuses, and greater enlargement of the ventricles, at both timepoints. The CI survivors had more comorbidities, were older, were less active at both timepoints, and had lower years‐of‐education compared to both CN survivors and HC. They had more vascular risk factors and APOE‐ε4 allele carriage status compared to controls.

Only the CI group showed deficits in ipsilesional cortical GM, hippocampal and thalamic volumes, and reduced total brain volume at 3‐months compared to controls. The CI survivors had larger stroke lesions compared to CN survivors and showed a greater increase in white matter hyperintensities between timepoints.

At 3 months in CN survivors, cognitive performance in assessed domains was significantly lower, except for language. While performance in the CN survivors improved over time especially in language and visuospatial function, cognitive scores remained lower in the CI survivors, with a decline in memory scores.

Conclusion

Post‐stroke cognitive resilience appears dependent on clinical, sociodemographic, and neuroimaging factors, which assist in post‐stroke prognostication.
Dementia knowledge in African immigrants with personal experiences of dementia
Authors: Nkimbeng Manka
Published: December 2023

Background

There is a dearth of research on dementia knowledge, care and caregiving with African immigrants. This study describes current understanding of dementia and its correlates with first and second generation African immigrants who have personal experiences of dementia. Our data comes from the Immigrant Memory Collaborative; a community‐based participatory research project that explored dementia care needs and resources in the African immigrant community.

Method

Linear regression models were used to describe factors associated with dementia knowledge, including causes and characteristics, communication and behavior, care considerations, and risks and health promotion.

Result

Of the 193 participants, 64% were male and 81% were caregivers. The mean age of the sample was 36 (±13.8) years, but first‐generation participants were older (44.3 ±17.2 years; compared to 30.6±7.1years). Women had lower dementia knowledge (b: ‐1.39 95% CI [‐2.58, ‐0.202]) compared to men, while people who were single had higher dementia knowledge (b: 1.36, 96% CI [0.28, 2.43]) and those who would seek care at health related organizations and community based networks had higher dementia knowledge compared to those who would turn to community based networks alone (b: 1.53 95% CI [0.499, 2.56]).

Conclusion

Understanding the correlates of dementia knowledge will inform target areas for dementia literacy interventions with the growing African immigrant population. Our results show that individual factors (sex and marital status) and where an individual would seek care are important correlates of dementia knowledge. Informal community based networks are an important target area for dementia and other health literacy interventions.
The cardiovascular risk factors, aging and dementia risk score and Australian national university Alzheimer’s disease risk index among Ethiopians
Authors: Gugssa Seid Ali
Published: December 2023

Introduction

The burden of dementia is highest in LMICs, and the dementia prevention potential is greater than in high‐income countries. However, the burden of modifiable dementia risk factors is not determined in Ethiopia. The objective of this study is to determine the need for personalized dementia risk reduction among high risk patients in Ethiopia using the Cardiovascular Risk Factors, Aging and Dementia Risk Score (CAIDE) and Australian National University Alzheimer’s Disease Risk Index (ANU‐ADRI) for midlife and late life.

Methods

Of the 381 participants in the Amharic Dementia Tool –Ethiopia, 182 (48%) were at their midlife (40‐64 years of age) and studied for CAIDE, and 200 (52%) were at their late‐life (65‐90 years of age) and studied for ANU‐ADRI. Baseline data was collected on exposure to 6 of the 7 risk factors included in the CAIDE study and to 10 of the 12 risk factors included in the ANU‐ADRI study.

Results

The mean midlife CAIDE score was 6.97 (SD 2.1), and a quarter of midlife study participants (25.5%) had a score value of 9‐12. The mean late life ANU‐ADRI score was 15.3 (SD 11.9) for males and 14.2 (SD 8.5) for females respectively.

Conclusion

A quarter of midlife CAIDE study participants of our study have a higher risk of progressing to dementia. The calculated mean ANU‐ADRI score 15.3 (SD 11.9) for our study was lower than the calculated mean ANU‐ADRI score for the Rush Memory and Aging Project 20.3 (SD 11.78), and the Kungsholmen Project 32.38 (SD 7.67), but higher than the calculated mean for the Cardiovascular Health Cognition Study 8.86 (SD 8.77). We strongly propose the need for the establishment of Brain Health Services (BHS) in Ethiopia alongside with the memory clinic to assess risk, risk profiling and communication, and interventions.
Investigating the Associations of Cardiovascular Risk Factors, Conditions, and Interventions with Cerebrovascular Diseases: The 90+ study
Authors: Rajmohan Ravi , Al‐Darsani Zeinah , Ho ChuChing , Wong Joey , Montine Thomas J. , Corrada María M. M. , Kawas Claudia H.
Published: December 2023

Background

In the oldest‐old (those >90 years) cerebrovascular diseases are highly prevalent and independently associated with dementia. Although cardiovascular risk factors like hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) are thought to be major contributors to the development of cerebrovascular diseases, autopsy studies in the oldest‐old show weak associations with HTN, no association with DM, and HLD remains understudied. We expanded upon existing studies by investigating the associations of cardiovascular risk factors, conditions, interventions, and APOE genotype with the presence of cerebrovascular diseases in participants >90‐years‐old.

Methods

Participants are from The 90+ study, a population‐based epidemiology study of dementia and aging whose participants were survivors of the Leisure World cohort (n = 267). The self‐reported cardiovascular risk factors were DM, HLD, and HTN. Cardiovascular conditions were arrhythmia, coronary artery disease, congestive heart failure (CHF), heart valve disease, myocardial infarction, stroke, and transient ischemic attack. Cardiovascular interventions were coronary artery bypass, pacemaker placement, and statin use. Cerebrovascular diseases were arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy (CAA), and microvascular lesions (MVLs) on autopsy. Neuropathologic evaluation followed NIA‐AA guidelines. We investigated the association between individual cardiovascular risk factors, conditions, interventions, and APOE genotype with individual cerebrovascular pathologies using logistic regressions adjusted for age of death, sex, and education.

Results

Participants were on average 98.1 years at death and 75% were female (Table 1). None of the cardiovascular features were associated with arteriolosclerosis or atherosclerosis (Figure 1). APOE‐ε4 was positively associated with CAA [OR = 3.62] while DM [OR = 0.23] and statin use [OR = 0.57] were negatively associated (Figure 2). CHF was negatively associated with the likelihood of MVLs [OR = 0.39] (figure 2).

Conclusions

Cardiovascular risk factors were not associated with cerebrovascular pathologies in our age group, leading to three potential interpretations: 1) they are not risk factors for cerebrovascular pathologies, 2) they have been mitigated through treatment, or 3) they are not associated due to survival bias, as these conditions reduce life expectancy. Associations of APOE‐ε4, DM, and statin use with CAA may relate to β‐amyloid metabolism while CHF’s negative association with MVLs may relate to decreased blood pressure variability. These initial findings on the limited associations warrant further exploration.
1. Validity and reliability of CAMCOG‐DS2 and other cognitive outcomes measures for clinical trials of AD in DS
Authors: Baksh Asaad , Strydom Andre , Tamayo‐Elizalde Miren , Fortea Juan , Benejam Bessy , Zaman Shahid , Beresford‐Webb Jessica , Rebillat Anne‐Sophie , Levin Johannes , Loosli Sandra V. , McCarron Mary , McGlinchey Eimear , Langballe Ellen Melbye , Larsen Frode Kibsgaard , Pape Sarah , Coppus Antonia , Ivain Phoebe , Baldimtsi Eleni
Published: December 2023

Background

Down syndrome (DS) is an important population to include in clinical trials aiming to prevent or delay Alzheimer’s disease (AD). This talk will summarise previous work in trajectory modelling to identify the earliest ages of change in cognition and the optimal sample sizes needed for clinical trials in DS. It will present validate data on the new version of the Cambridge Cognitive Examination–Down syndrome version II (CAMCOG‐DS‐II) alongside established cognitive tests. The CAMCOG‐DS‐II has been developed to assess cognitive impairments associated with dementia in people with DS.

Method

This was an observational, multicentre, longitudinal study (n = 174) across seven existing cohorts in six different European languages to validate cognitive tests in adults with DS aged 25 years and older. It assessed the relationships between tests of cognition, behaviour, function, and health. Cognitive assessments included the CAMCOG‐DS‐II, the CANTAB Paired Associates Learning (PAL) Task, the modified Cued Recall Test (mCRT) and the Purdue Pegboard Test. We examined correlations between tests, group differences between those with and without dementia and explored test‐retest reliability of the CAMCOG‐DS‐II.

Result

Our results showed that completion rates for the CAMCOG‐DS‐II were high, and floor and ceiling effects were low. The CAMCOG‐DS‐II memory sub‐score correlated significantly with the mCRT total recall score (Spearman’s ∼0.5), and the praxis sub‐score significantly correlated with the Purdue Pegboard total score (Spearman’s >0.7).

Conclusion

There is currently a critical lack of suitable diagnostic and outcome measures that can be used in clinical trials. These results show that the CAMCOG‐DS‐II is a feasible test of cognition and will help to provide sensitive cognitive endpoints for clinical trials which are seeking to find suitable treatments for AD in adults with DS. Future analysis will include trajectories of change from baseline to one year of follow up for each primary outcome measure.
Examining the interplay between AD pathology and intracellular/extracellular properties of cortical tissue in preclinical AD
Authors: Hosseini Hadi , Avelar‐Pereira Bárbara , Gozdas Elveda
Published: December 2023

Background

AD pathology affects neuronal microstructural decades before clinical manifestation of the disease. Amyloid plaques and tau tangles are key contributors to alterations in brain microstructural properties such as neurite morphology and axonal transport and packing, among others. It takes many years for these microstructural changes to build up and be reliably detected using volumetric MRI measures of neurodegeneration. Here, we examined the utility of neurite imaging – a biologically inspired model for examining cortical microstructure – to examine the impact of amyloid and tau pathology on intra‐ and extra‐cellular properties of cortical tissue and to further improve our mechanistic understanding of AD development.

Method

We utilized multimodal imaging data collected as part of ADNI‐3 including structural, multi‐shell diffusion MRI, and amyloid (18F‐florbetapir) and tau (18F‐flortaucipir) PET. The sample included 90 cognitively normal older adults (CN:23/67 amyloid‐positive/negative, age = 72.0(8.8) years) and 65 older adults with mild cognitive impairment (MCI: 36/29 amyloid‐positive/negative, 73.3(7.2) years). Neurite orientation dispersion and density imaging (NODDI) measures including intracellular volume fraction (ICVF), neurite orientation and dispersion index (ODI) in gray matter, standardized uptake value ratio (SUVR) for amyloid/tau PET and cortical thickness were extracted for 360 regions defined by surface‐based HCP atlas. We performed mediation analyses to examine the interplay between AD pathology and intracellular/extracellular properties of brain tissue and also compared the clinical utility of cortical neurite measures against volumetric MRI in detecting brain changes associated with AD pathology (tau burden) in preclinical AD.

Result

Mediation analyses showed that tau burden mediates the impact of amyloid on intracellular properties of brain tissue (ICVF) in medial and lateral temporal structures (Fig.1A) whereas ODI is a significant mediator of the effect of extracellular amyloid accumulation on intra‐cellular tau burden in entorhinal cortex (Fig.1B) in amyloid‐positive older adults. Further, among the regions with highest tau burden in amyloid‐positive CN group, ICVF changes in lateral temporal cortex successfully distinguished preclinical AD from amyloid‐negative CN and was associated with tau pathology.

Conclusion

Overall, these preliminary results suggest that accumulation of amyloid plaques results in reduction of neurite complexity while build‐up of tau reduces the intracellular volume fraction in preclinical stage of AD.
Unraveling the transcriptomic landscape of healthy aging
Authors: Girdhar Kiran , Bendl Jaroslav , Hoffman Gabriel E , Lee Donghoon , M Prashant N , Bennett David A. A , Haroutunian Vahram , Fullard John F , Roussos Panos
Published: December 2023

Background

Aging leads to physiological deterioration and structural changes in the human brain that might lead to cognitive decline. Also, aging in the brain has been associated with a decrease in the number of neurons and synapses. Additionally, the risk of developing neurodegenerative diseases such as Alzheimer’s and Parkinson’s increases with age. This close relationship between aging and neurodegenerative diseases suggests the existence of common molecular mechanisms that regulate gene expression in specific cell types in the brain. It has been challenging to identify these cell specific changes using current gene expression data, as it tends to be confounded by cellular heterogeneity.

Method

Here we generate and analyze single‐nucleus RNA libraries from prefrontal cortex of n = 269 postmortem controls of age ranging from 2.5‐100 years from various ethnic groups (n = 153 Caucasian, n = 93 Afro‐American, n = 19 Hispanic, n = 4 Asian). Based on age, we stratified the samples into 5 stages ranging from 1) 2.5‐12 years, 2)13‐39 years, 3) 40‐59 years, 4) 60‐80 years and 5) >80 years to compare the transcriptomic changes.

Result

We compared changes in gene expression in different cell types across 5 stages and identified genes that changed as a function of age. We also looked at sex‐specific transcriptomic changes across these stages. After that, we used age specific genes to predict the biological age of samples across all cell types. Finally, we used a method called WGCNA (weighted gene co‐expression network analysis) to investigate specific molecular mechanisms that are unique to each stage.

Conclusion

Our study provides the comprehensive view of changes in specific cell types that underlies the aging process. Also, provides a cell‐specific list of biomarkers for every stage that can predict normal age that has no effect of disease and is independent of chronological age.
Estimation of Long‐term Care Utilization and Lifetime Distribution of Medical Cost for Dementia in Korea
Authors: Lee Jun Hong
Published: December 2023

Background

To investigate the current status of long‐term care services for patients with dementia and lifetime medical costs for dementia in South Korea.

Method

This study utilized the National Health Insurance Service‐National Health Information Database (NHIS‐NHID) from January 2017 to December 2021. The prevalence and incidence of dementia was estimated by extracting people who were diagnosed and treated with dementia (age ?45 years) from the database. The use of long‐term care services for the elderly with newly diagnosed dementia was also investigated. Additionally, the lifetime medical expenses for dementia were estimated using data on single year’s medical costs, population data, and a life table from Statistics Korea.

Result

The prevalence of dementia increased over three years from 2015 to 2017, while the incidence of dementia gradually decreased. Among the patients with newly diagnosed dementia, approximately 30% used the long‐term care services, while 4th graders accounted for the highest proportion every year. The older the age and the lower the income quartile, the shorter the time it took to apply for long‐term care services after diagnosis of dementia. The total medical expenses per capita increased steadily every year, and the lifetime medical expenses were higher for females than males. Half of the lifetime medical costs of dementia occurred after 67 years of age for males and 83 years for females.

Conclusion

This study suggests that medical, social, and political measures are needed to effectively manage long‐term care service recipients and prepare for rising medical costs for dementia.
A human stem cell model of development and pathology of basal forebrain cholinergic neurons
Authors: Martinez Jose , Xu Ke , Bhattacharyya Anita
Published: December 2023

Background

Basal forebrain cholinergic neurons (BFCNs) in the nucleus basalis regulate attention, memory, learning and processing of information related to cognitive function throughout the lifespan. Degeneration of BFCNs is strongly correlated with cognitive function and degeneration of the BFCN projection system is an early event in Alzheimer’s disease (AD) pathogenesis and in Down syndrome (DS, trisomy 21) that is characterized by intellectual impairment at birth and AD pathology in middle age. Understanding the vulnerability of BFCN neurons will help us understand the underlying mechanisms of neurodegeneration in both AD and DS.

Method

We generated BFCNs from trisomy 21 induced pluripotent stem cells (iPSCs) and isogenic controls through addition of morphogens and growth factors following developmental principles. The efficiency of the protocol was assessed through immunofluorescence for choline acetyl transferase (ChAT).

Result

We established a protocol to generate BFCNs from control and trisomy 21 iPSCs through a stepwise process of 1) ventralization of neural progenitors with SHH or SHH agonist, 2) regulation of LHX8 expression with NGF and, 3) regulation of ISLET1 expression and BFCN survival with BMP9. The protocol generated approximately 60% BFCNs from both trisomy 21 and control iPSCs.

Conclusion

Few differentiation protocols have been established to derive BFCNs from iPSCs. Our iPSC model enables analysis of pathological markers, identification of disrupted molecular pathways, manipulation of conditions to affect neurodegeneration and screening of potential therapeutics in human BFCNs.
Visceral Abdominal Adipose Tissue and Insulin Resistance Respectively Influence Alzheimer Disease Amyloid Pathology and Neurodegeneration in Midlife
Authors: Dolatshahi Mahsa , Commean Paul K. , Nguyen Caitlyn , Ippolito Joseph , Benzinger Tammie L.S. , Raji Cyrus A.
Published: December 2023

Background

Obesity and adiposity at midlife, evidenced by high body mass index (BMI), are increasingly understood as a risk factor for Alzheimer’s disease (AD). Importantly, visceral fat is known to be associated with insulin resistance and proinflammatory state, the mechanisms involved in AD pathology. Herein, we aimed to assess the association between brain MRI volumes as well as amyloid and tau uptake with obesity, insulin resistance, and abdominal adipose tissue in cognitively normal midlife population.

Method

A total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI, as well as amyloid and tau PET scan. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) > 1.9 was used as a measure of insulin resistance. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi‐automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas. Dynamic amyloid imaging was performed with a bolus injection of ∼15 mCi of [11C]PiB, followed by a 60‐min scan. A single intravenous bolus of between 7.2‐10.8 mCi of AV‐1451 was administered. Data from the 30‐60 minute, and 80‐100 minute post‐injection window for PiB and AV‐1451 were used for the analysis, respectively. The association of brain volumes and PiB and AV‐1451 SUVRs within the default mode network areas with BMI and VAT/SAT ratio were assessed using linear regression models.

Result

We observed lower right entorhinal white matter volumes in obese participants with insulin resistance compared to metabolically normal non‐obese group (p = 0.004), without any significant difference in PiB or AV‐1451 SUVRs. Regression models with sex, age and education as covariates showed a significant positive association between VAT/SAT ratio and left precuneus white matter PiB SUVRs (R2 = 0.31, p = 0.005), but no significant associations with AV‐1451 SUVRs.

Conclusion

In our midlife obese sample with insulin resistance, there were lower right entorhinal white matter volume, which is involved in relaying information to the hippocampus. We also demonstrate higher early amyloid pathology in AD‐signature areas such as the precuneus in mid‐life persons with high VAT/SAT ratio, a marker of visceral obesity.