bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships between KLOTHO and APOE4‐associated β‐amyloid and tau alterations across AD continuum
Authors: Cook Noah R. , Driscoll Ira , Gallagher Catherine L. , Johnson Sterling C , Asthana Sanjay , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Carboni Margherita , Wang Dan , Dubal Dena B. , Okonkwo Ozioma
Published: December 2023

Background

Apolipoprotein E ε4 allele (APOE4) is the leading genetic risk factor for Alzheimer’s disease (AD). APOE4 carriers (APOE4+) exhibit greater accumulation of the two AD neuropathological hallmarks, beta‐amyloid (β‐amyloid) and tau. KLOTHO KL‐VS heterozygosity (KL‐VSHET) attenuates APOE4‐related β‐amyloid and age‐related tau burden in cognitively normal individuals. It remains unclear whether this holds true for individuals with mild cognitive impairment (MCI) and AD. Here we investigate whether KL‐VSHET attenuates APOE4‐related cerebrospinal fluid (CSF) AD‐biomarker burden across the AD continuum.

Method

Middle‐aged and older adults (N = 396; MeanAge = 65) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center who were genotyped for KLOTHO and APOE and underwent CSF sampling were included in analyses. General linear models, covarying for sex, age, and AD family history, examined whether APOE4 yielded expected outcomes on β‐amyloid and tau burden. Follow‐up regression analyses, stratified by KL‐VS genotype [non‐carriers(KL‐VSNC,N = 293); KL‐VSHET (N = 103)], evaluated whether the APOE4 associations with β‐amyloid and tau differed between KL‐VSHET and KL‐VSNC. Analyses were stratified further by diagnosis [cognitively normal (N = 308) or MCI/AD (N = 88)] to investigate whether the relationships between APOE4 and β‐amyloid or tau differed among KL‐VSHET and KL‐VSNC in cognitively normal and MCI/AD participants.

Result

Results for the entire sample, as well as stratified by KL‐VS status and diagnosis, are presented in Table 1. When the analysis was stratified by KL‐VS status, the APOE4+ effect on both β‐amyloid and tau burden was seen among KL‐VSNC but not KL‐VSHET. When further stratifying by diagnosis, the same pattern of attenuation among KL‐VSHET was observed for β‐amyloid burden in both cognitively normal individuals and MCI/AD whereas for tau burden, we only observed a non‐significant trend among cognitively normal persons (KL‐VSNC: p = 0.10; KL‐VSHET: p = 0.74).

Conclusion

KL‐VSHET attenuates both APOE4‐related CSF β‐amyloid and tau burden in cognitively normal individuals. This attenuation extends to CSF β‐amyloid but not tau accumulation in MCI/AD. These results add to the literature suggesting that KL‐VS heterozygosity is protective against APOE‐related biomolecular alterations that confer AD risk.
Probabilistic computer‐aided diagnosis of Alzheimer’s disease and frontotemporal dementia based on MRI and biochemical markers
Authors: Pérez‐Millan Agnès , Thirion Bertrand , Borrego‐Écija Sergi , Contador José , Juncà‐Parella Jordi , Bosch Beatriz , Falgàs Neus , Antonell Anna , Ruiz‐García Raquel , Naranjo Laura , Balasa Mircea , Lladó Albert , Sanchez‐Valle Raquel , Sala‐Llonch Roser
Published: December 2023

Background

One of the clinical problems for biomarkers' clinical use is the ability to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), and healthy subjects (CTR). This clearly challenges diagnosis and prognosis. We implemented a ML algorithm that provides individual probabilistic diagnoses for these dementias based on magnetic resonance imaging (MRI) and we correlated the results with biochemical markers.

Method

We studied 3T‐T1w MRI of 432 subjects. A subset of these participants had cerebrospinal fluid (CSF) and plasma biomarkers (Table 1). We obtained regional subcortical gray matter volumes and cortical thickness measures using Freesurfer. We implemented a calibrated classifier with a Support Vector Machine with only the MRI data. We tested paired‐wise classification and classification across the 3 groups. We obtained individual probabilities associated with group correspondence. We studied the correlation between these probabilities and CSF and plasma biomarkers. For this, we subdivided the groups into true‐group (subjects with classification according to clinical diagnosis) and false‐group (subjects which did not coincide with clinical diagnosis). Finally, we implemented a permutation test to find the importance of each region in the classification.

Result

We obtained accuracies of 90.7 ± 6.7% in the CTR vs AD classification, 88.6 ± 4.5% for CTR vs FTD, 79.3 ± 8.8% for AD vs FTD, and 79.9 ± 5.1% when discriminating the 3 groups. We obtained a significant positive correlation for plasma p‐tau181 for the false‐AD in the comparison AD vs CTR (Figure 1). The correlation of the false‐CTR was significantly positive for the CSF and plasma NfL. Finally, in the AD vs FTD, the true‐FTD had a significant negative correlation with CSF NfL. The other biochemical biomarkers did not provide additional information. The most important regions for classification are shown in Figure 2.

Conclusion

The ML algorithm gave high accuracies. Within wrongly classified AD patients, probabilities correlated positively with plasma p‐tau181, suggesting hidden pathological processes associated with subjects clinically classified as CTR. Finally, the group probability within well‐classified FTD patients in comparison with AD negatively correlated with CSF NfL. We suggest that this approach can be used as a tool to try to develop personalized diagnoses.
The need for a tailored National Dementia Plan in Ethiopia: a call for action
Authors: Ayele Biniyam A.
Published: December 2023

Background

Globally, a rapid demographic transition is occurring with a significant increment in the proportion of older individuals. For the first time in history, individuals aged 65 and above outnumber that of children under five years of age.

Method

A mini review was conducted to assess the burden and types of dementia risk factors in Ethiopia.

Results

In Ethiopia, the life expectancy has shown dramatic improvements in the past few decades and is expected to reach 74 years by mid‐century. Older age is considered the most important non‐modifiable risk factor for dementia. Likewise, other modifiable diseases such as infectious diseases, non‐communicable diseases, particularly cardiovascular diseases, and traumatic brain injuries are associated with dementia. Despite, the high prevalence of dementia risk factors and impending economic and health impact from dementia, no country in the sub‐Saharan Africa (SSA), including Ethiopia, has developed a standalone national dementia strategic plan to guide the overall effort to improve dementia care in the country. It is vital to design and develop a national dementia plan in line with a framework outlined by the 2017 World Health Organization (WHO) global action plan. The health, social, & economic burden from dementia is expected to be high to the developing countries such as Ethiopia unless clear prevention and management strategies are designed at a national level to cascade the care to the primary care level. The planned strategic policy may focus on improving the knowledge and skills of health care professionals. Translation and cultural adaptation of cognitive, functional, and behavioral assessment batteries is of paramount importance in improving the diagnostic accuracy along with availability of advanced imaging, biomarkers, and dementia treatment.

Conclusion

In summary, this call for action paper recommends developing a tailored stand‐alone or an integrated national dementia prevention and care plan which is in congruent with the seven WHO global action plan.
African star apple leaf extract attenuates hyperglycemic mediated cognitive impairment and neurodegeneration in Streptozotocin induced diabetic rats
Authors: Idaguko Chika Anna , Memudu Adejoke Elizabeth , Unit Neuroscience Research , Uzairue Anatomy Department Edo State University
Published: December 2023

Background

Diabetes is a chronic disease affecting millions of people. It is associated dementia. Over the years the use of natural product such African star apple (Chrysophyllum albidum) with strong antioxidant activities has been study for treating of diabetes. This study is carried out to evaluate African star apple possible anti‐diabetic, neuroprotective and effects on neuro‐ cognition in streptozotocin (STZ)‐induced diabetic rats model using Morris water maze to evaluate spatial working memory, Malondialdehyde (MDA) as biomarker for tissue damage while superoxide dismutase (SOD) and catalase (CAT) as antioxidant enzyme markers assayed using spectrophotometer.

Methods

Thirty male Sprague‐Dawley (S‐D) rats used were divided into six groups (n = 5) viz: A‐ control, B‐ Diabetic model (50mg/kg bw STZ), C‐ Diabetic model +2mg/kg bw glibenclamide, D‐Diabetic model +125mg/kg bw African star apple leaf extract, STZ+250mg/kg bw African star apple leaf extract and STZ+500mg/kg bw African star apple leaf extract. Treatment was for 21 days via oral administration. The prefrontal cortices excised were processed for histological examination.

Results

Diabetic model was characterized by a decline in final body weight, spatial memory, antioxidants enzymes (SOD and CAT) with an elevation in MDA and blood glucose levels in addition to marked disruption of the neurons in the prefrontal cortex (PFC) characterized by presence of pkynotic and necrotic pyramidal neurons of the PFC. Furthermore, African star apple leaf extract significantly increased superoxide dismutase (SOD), catalase (CAT), and cognitive functions in a dose‐dependent manner (P>0.05) as compared to the diabetic model.

Conclusion

Diabetes can result in cognitive impairment via hyperglycemic mediated neurodegeneration which is attenuated by African star apple leaf extract ability to increase antioxidant enzymes, reduce neuro‐inflammation thereby improving neuronal function for memory and cognition.
Investigating Selective Neuronal Vulnerability in Alzheimer’s and Parkinson’s Disease with Induced Pluripotent Stem Cells and Pre‐formed Fibrils
Authors: Abey Ajantha S , Ng Bryan , Heon‐Roberts Rachel , Carlyle Becky C. , Bengoa‐Vergniory Nora , Wade‐Martins Richard
Published: December 2023

Background

Alzheimer’s and Parkinson’s disease feature progressive neurodegeneration associated with the accumulation of protein aggregates in a remarkably regionally selective manner. The cortical neurons that are relatively vulnerable in Alzheimer’s Disease (AD) are only affected late in Parkinson’s Disease (PD), whereas midbrain dopaminergic neurons exhibit striking vulnerability in PD, but are relatively spared in AD. Rodent and human post mortem studies have posited a role for cell autonomous mechanisms such as autophagy or calcium buffering deficits driving this, but having a live human cell model that can replicate the phenomenon of selective neuronal vulnerability can help to better determine common and contrasting disease mechanisms and identify therapeutic targets.

Method

Here, we used induced pluripotent stem cell (iPSC) derived neurons as they offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD‐related presenilin‐1 mutations (n = 3), PD‐related leucine rich repeat kinase 2 mutations (G2019S n = 3, R1441C n = 3), and isogenic corrected (n = 3) and healthy controls (n = 4) have been differentiated into both cortical neurons and midbrain dopaminergic neurons to enable comparison of vulnerability phenotypes in different neuronal subtypes from the same patient.

Result

AD cortical neurons insulted with alpha‐synuclein pre‐formed fibrils (PFFs) have impaired neurite outgrowth, reduced synaptic density, and extensive aggregate formation. Meanwhile, PFF insulted PD cortical neurons exhibit normal neurite outgrowth and relatively little aggregation, whereas PD dopamine neurons readily produce aggregates.

Conclusion

These preliminary results show relative vulnerability of AD and resilience of PD cortical neurons to alpha synuclein aggregates for the first time. This suggests the selective vulnerability to proteinopathy exhibited in these diseases may be replicated by the iPSC neuronal model, and additionally supports the notion that cell intrinsic factors may partly determine this vulnerability.
From diagnosis to end of life: Evolving training and support needs of caregivers of seniors living with Alzheimer’s disease
Authors: Dubé Véronique , Gaied Nouha Ben , Caron Laurence , Thorn Karine
Published: December 2023

Background

No one is prepared for a diagnosis of Alzheimer’s disease, either the person diagnosed or the caregiver. In order to cope with the disease and support their loved ones, caregivers express numerous needs for training and support. But what are these needs at each stage of the disease?

Method

As part of an action‐research project, 8 focus groups and 28 individual interviews held on the Zoom platform were used to collect the training and support needs of caregivers of seniors living with Alzheimer’s disease in the province of Quebec, Canada. A content analysis inspired by the approach proposed by Miles and Huberman was conducted.

Result

A total of 52 caregivers, aged between 33 and 85 years old (mean = 61,88; SD = 12,42), identified training and support needs: a) surrounding the diagnosis; b) during the assistance of the loved one at home, with and without cohabitation; c) during accommodation in a long‐term care facility and; d) following the death of the person being cared for.

Conclusion

Caregivers have training and support needs that evolve according to the trajectory of their loved one’s Alzheimer’s disease. Interventions tailored and personalized to their pathway are necessary to support them in this long trajectory of caregiving.
Evaluation of the major pathological hallmarks in the humanized APPSAA knock‐in mouse model, in response to drug treatment
Authors: Carmans Sofie , Dejonckheere Wannes , Cornelissen Tom
Published: December 2023

Background

To improve clinical translatability of non‐clinical in‐vivo Alzheimer’s disease (AD) models, a humanized APP knock‐in mouse model (APPSAA) was recently created (Xia, D. et al., 2022). This homozygous APP knock‐in model carries a humanized Aβ1‐42 sequence and 3 disease causing mutations (Swedish, Arctic, and Austrian). These modifications lead to increased Aβ42/40 ratios in AD relevant tissues, resulting in an age‐dependent amyloid deposition in the brain. The highest plaque density is found in cortical and hippocampal regions. APPSAA mice also display clear neuroinflammation and an increase in fluid biomarkers of neurodegeneration (NF‐L and total Tau in CSF). Here we assess the value of this model as a tool for non‐clinical efficacy studies of experimental drugs with diverse mechanisms of action to facilitate the development of novel AD therapeutics.

Method

APPSAA mice and WT controls were aged and sacrificed at various time points. In addition, APPSAA mice were treated with drug or vehicle, on a daily basis for 3 months from the age of 3 months onward. The major pathological hallmarks of this model and the treatment effect will be investigated with biochemical and immunohistological assays. Monthly blood sampling will allow the follow up of pathology progression in individual mice by assessing plasma‐based biomarkers. Since APPSAA mice lack an obvious behavioral phenotype, synaptic plasticity will be investigated to serve as a functional readout.

Result

The treatment is well tolerated by the mice in study. Body weights were not altered between compound and vehicle dosing during the first 2 months of the treatment. Data on pathological outcomes and synaptic plasticity are not yet available but will be shared during the presentation.

Conclusion

A humanized knock‐in model for AD is hypothesized to be a broadly applicable tool to investigate disease‐modifying drugs with diverse modes of actions.
Brain structural changes associated with Apoe2 in 3041 subjects from the UK Biobank
Authors: Rajagopalan Priya
Published: December 2023

Background

Common variants in the apolipoprotein E gene are the greatest known source of genetic risk for late‐onset Alzheimer’s disease (AD). Carriers of one or more copies of the ε4 allele are more likely to develop AD, but carriers of the ε2 allele have a lower incidence of AD (1,2,3). Mechanisms underlying this effect are not fully understood, motivating comparisons of brain imaging data in people carrying different APOE genotypes. Prior voxel‐based morphometry (VBM) studies have reported gray matter alterations in medial temporal and precuneal regions in people with AD (4) and in healthy APOE ε4 carriers (5) but less is known about the effect of APOE ε2 compared to ε4 carrier status on gray matter volume in elderly adults.

Method

The ENIGMA voxel based morphometry (VBM; https://sites.google.com/view/enigmavbm; 6) pipeline was used to perform a large‐scale analysis of 3D T1‐weighted brain MRI data from 3,041 older adult participants (45.5% female; 72.0 (6.2SD) years old) from the UK Biobank (UKBB). Subject demographics are outlined in Table 1. The statistical relationship between voxel‐wise brain gray and white matter volumes and APOE2 genotype was assessed using linear mixed models, adjusting for age, sex, intracranial volume, population structure, and scan site. All associations were corrected for multiple comparisons using the standard false discovery rate method.

Result

Significantly larger volumes were detected in subcortical gray and deep white matter regions of the brain for the APOE ε2 genotype, while smaller volumes were noted in the peripheral cortex and juxtacortical white matter, when controlling for FDR at q = 0.05 (gray matter critical P‐value 0.008 and white matter critical P‐value 0.01). Significance values and brain maps for the APOE ε2 genotype are outlined in Figure 1 and Figure 2.

Conclusion

We identified alterations in gray and white matter volumes related to presence of at least one APOE2 allele. These results support prior reports that elderly adult carriers of the APOE2 haplotype have, on average, neurostructural alterations in gray matter architecture, even after adjusting for the effects of ancestry and age.
Repurposing anti‐diabetic drugs for neuroprotection
Authors: Harding Edward C
Published: December 2023

Background

Midlife obesity and diabetes are dramatically increasing in prevalence and are significant risk factors for dementia, but the mechanism linking these diseases is largely unknown. We believe that targeting this shared mechanism may represent an untapped therapeutic strategy to slow neurodegeneration

Method

To test this hypothesis, we are utilising a mouse model of prion disease (RML scrapie) that faithfully recapitulates many aspects of the neurodegenerative process common to multiple forms of dementia, including endoplasmic reticulum stress, synaptic loss, and cell death but without disease‐specific overexpression or introducing familial mutations. In these mice, worsening behavioural and motor signs can be quantified using machine learning based pose‐estimation and memory phenotyping. This also forms the basis of a new automated pipeline for screening potential neuroprotective compounds from the pool of previously approved drugs. We aim to understand the potential for repurposing anti‐diabetic and other compounds for dementia risk reduction.

Result

In preliminary experiments, treatment with the commonly used anti‐diabetic drug Metformin reduced the severity of motor disruption in prion‐inoculated mice fed either a control or a high‐fat diet, with evidence of prolonged survival. Furthermore, an unbiased query of the Connectivity Map database predicted numerous related drugs classes, used to treat metabolic disease, that reverse transcriptional signatures observed in the brains of prion‐inoculated mice.

Conclusion

Together these suggest a possible mechanistic convergence of anti‐diabetic compounds on a neuroprotective mechanism. To gain insight into the molecular mechanisms that might be shared in the brain between metabolic and neurodegenerative disease, we are now using multi‐omics approaches to characterise the signatures of drugs that delay prion signs. We aim to improve the prediction and validation of compounds for repurposing in dementia and identify the patient groups most likely to benefit from early intervention.
The role of Kir6.2‐KATP channels in modulating sleep, brain metabolism, and neuronal excitability in AD
Authors: Constnantino Nicholas J , Carroll Caitlin M , Irmen Riley E , Snipes James A , Gould Robert W , Macauley Shannon L
Published: December 2023

Background

ATP sensitive potassium (KATP) channels act as metabolic sensors to regulate cellular excitability. We recently demonstrated that neuronal KATP channels are composed of Kir6.2 subunits, are highly expressed on excitatory and inhibitory neurons, and are differentially expressed in the Alzheimer’s brain (Grizzanti et al. 2022). Mechanistically, we demonstrated that KATP channels couple changes in cerebral metabolism with neuronal activity and amyloid‐beta (Aβ) release, suggesting a role for KATP channels in Alzheimer’s disease. Here, we extend these studies to explore how KATP channels contribute to excitatory/inhibitory (E/I) balance in the brain to impact sleep and Alzheimer’s pathology. How KATP channels coordinate sleep, metabolism, and neuronal activity was examined using the Kir6.2‐/‐ mice, a mouse model lacking neuronal KATP channel activity.

Method

Intracranial biosensors measuring interstitial fluid (ISF) glucose and ISF lactate concurrent with EEG/EMGs were implanted into the hippocampus of wild type (WT) and Kir6.2‐/‐ mice. Diurnal rhythms of ISF glucose, ISF lactate, and EEG/EMG were recorded for 72 hours. Mice were injected with saline, glucose, or glibenclamide to determine effects of metabolic challenges on ISF glucose, ISF lactate, and sleep/wake cycles. Quantitative EEG analysis and sleep staging was performed and correlated with ISF glucose and lactate over the 24 hour light/dark period.

Result

Wildtype mice have diurnal fluctuations in ISF glucose and lactate, with increases during the dark cycle when mice are awake and decreases in the light cycle when mice are asleep. In Kir6.2‐/‐ mice lacking neuronal KATP channel activity, diurnal fluctuations in ISF glucose and lactate are lost. Kir6.2‐/‐ mice spent more time in NREM sleep and less time awake than WT mice. Furthermore, reductions in absolute EEG power suggest changes in the brain’s E/I balance. Lastly, Kir6.2‐/‐ mice were unresponsive to metabolic challenges, demonstrating that ISF lactate, a metabolic trigger for wakefulness, is controlled by KATP channels.

Conclusion

We describe the role of neuronal KATP channels as metabolic sensors in coordinating sleep/wake architecture in mice. Ongoing studies are exploring the impact of KATP channels on sleep and brain excitability in AD.
PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease
Authors: Zheng Chao , Nicholson LaShae , Chen Baosheng , Toyonaga Takuya , Liu Michael , Strittmatter Stephen M , Carson Richard E. , Huang Yiyun , Cai Zhengxin
Published: December 2023

Background

Rho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.

Methods

The ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.

Results

Uptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).

Conclusions

We demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.
Sleep health disparities and its impact on Alzheimer’s disease risk: Examining race specific physiologic mechanisms
Authors: Bubu Omonigho Michael M
Published: December 2023

Blacks/African‐Americans (blacks) take longer to fall asleep, have lower sleep efficiency and spend a smaller proportion of time in deep stages of non‐rapid eye movement (NREM) slow wave sleep/activity [SWS]), relative to non‐Hispanic whites (whites). Notably, blacks have a higher burden of severe obstructive sleep apnea [OSA] with excessive daytime sleepiness (EDS). These sleep metrics have been linked to increased vascular risks, inflammation, brain injury, and cognitive impairment, all known risk factors for Alzheimer’s disease (AD). This presentation will provide an update on putative mechanisms that underlie the association between sleep and risk of developing AD, both from a mechanistic (primarily preclinical) as well as a clinical/epidemiological perspective, with a focus on how disturbed sleep might be a race‐dependent physiologic risk conferring increased AD‐risk in blacks. It is vital to examine how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks. Data presented will include cross‐sectional and longitudinal studies. Utilizing data from various cohorts including NYU cohort of older‐adults participating in studies of sleep, aging and memory, and the National Alzheimer’s Coordinating Center, we will describe novel evidence implicating sleep health disparities [SHD] (i.e., shorter sleep duration [SD], smaller proportion of time in deep stages of NREM SWS/SWA and disproportionate burden of symptomatic OSA, that are more prevalent among racial/ethnic minorities, as a risk factor for AD; as a physiologic marker associated with AD pathology/biomarkers (i.e. amyloid and tau), and as a modifier of AD‐risk. We will describe race and sex specific mechanisms underlying SHD‐AD risk, including independent and synergistic effects with Aβ and/or tau, as well as vascular risk. Race‐specific associations of micro and macro‐architectural sleep parameters with novel plasma AD biomarkers will also be presented. Findings will show that social determinants of health factors mediate heterogeneity in sleep and AD outcomes, with Black subjects having worse SHD metrics i.e., shorter SD, reduced NREM SWS/SWA and greater OSA severity, and exhibiting worse race‐specific AD pathology and CVD risk markers (i.e., worse office‐based Framingham Heart Study general CVD [FHS‐CVD] risk scores, & greater WML and abnormal DKI indices) potentially leading to AD disparities.
Impaired mitochondrial dynamics in the blood of patients with Alzheimer’s disease and Lewy body dementia
Authors: Millot Perine , Pujol Claire , Paquet Claire , Mouton‐Liger Francois
Published: December 2023

Background

Mitochondrial dysfunction is an early event in Alzheimer’s disease (AD) physiopathology and may contribute to neuronal loss in several neurodegenerative diseases, such as Lewy body dementia (LBD). The role of mitochondrial dysfunction in AD have been mostly explored in brain post‐mortem tissues. These studies have particularly highlighted abnormal expression levels of mitochondrial fission and fusion protein. The balance between fission and fusion mechanisms is essential to maintain a pool of functional mitochondria inside the cell. Further studies suggest that this dysfunction may also be observed in immune cells, both in the central nervous system as in blood compartment.

In this context, we investigate if mitochondrial dysfunction, in particularly, imbalance of mitochondrial fusion and fission could be detected in peripheral blood mononuclear cells (PBMCs) from AD and LBD patients compared to PBMCs from healthy control subjects.

Method

Our study is a monocentric retrospective study, using blood derived PBMCs from AD, LBD patients and neurological controls followed at the Cognitive Neurology Center (CNC) in Paris. PBMCs were isolated and stored in Lariboisière hospital’s biobank. Mitochondrial protein level were measured using immunoblot technique.

Result

Our results show a significant alteration of fusion (MFN2 and OPA1) and fission proteins level (FIS1) in PBMCs of AD and LBD patients.

Conclusion

These new findings pave the way to explore the proteins implicated in mitochondrial homeostasis at peripheral levels, and may provide a new tool to follow the progression of mitochondrial dysfunction in neurodegenerative diseases.
DNA Damage as an Early Marker of Senescence in Tauopathies
Authors: Harris Anner T.
Published: December 2023

Background

Hyperphosphorylated tau accumulation in neurons and astrocytes is a pathological hallmark of a class of neurodegenerative disorders known as “tauopathies”, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Previous research investigating the toxic effects of astrocytic tau pathology identified the DNA damage marker p16 in astrocytes from post‐mortem human cases of AD and FTD. DNA damage is one of many markers of cellular senescence, a state in which cells undergo irreversible cell cycle arrest. Senescence initiation can also be identified via the expression of phosphorylated histone H2AX (gamma‐H2AX) and cyclin‐dependent kinase inhibitor p21. Senescence in astrocytes leads to reduced functional support for neurons. While recognized, the role of senescent astrocytes in tauopathies is not well understood. Here, we sought to determine how expression of other DNA damage markers, such as gamma‐H2AX and p21, and the DAMP protein HMGB1 varies across different tauopathies.

Method

Immunohistochemistry (IHC) was performed on postmortem human frontal cortex tissue of CTE (n = 3), AD (N = 3), PSP (n = 3), CBD (n = 3), Healthy (n = 1) and glioblastoma (GBM) (n = 1) cases with antibodies against markers of early senescence gamma H2A.x (yH2A.x) and p21, late senescence, p16, and a senescence‐associated secretory phenotype, HMGB1. Positively stained nuclei were quantified. Immunofluorescence (IF) was employed on postmortem cases using either glial fibrillary acidic protein (GFAP) or Neurofilament H (NF‐H) antibodies with yH2A.x, p16, p21 and HMGB1 markers in order to qualitatively and quantitatively measure the prevalence of senescent astrocytes and neurons in tauopathies.

Result

Immunohistochemistry revealed yH2Ax expression was observed in AD, PSP, and CBD cases. Immunofluorescence experiments employing yH2AX co‐stained with astrocytic and neuronal markers revealed expression in AD, PSP and CBD cases. Minimal expression of yH2Ax was revealed in the CTE and healthy control cases. Results from p21 stains were inconclusive. Preliminary evidence reveals HMGB1 expression in CBD and PSP cases utilizing IF techniques, and p16 expression in cells employing IHC.

Conclusion

Overall, results indicate that DNA damage may be broadly associated with astrocytes in tauopathies. Utilizing alternative approaches to recognize and evaluate astrocyte senescence in post‐mortem human tissue will provide further insight into these findings.
A prospective study evaluating the clinical utility of tau‐PET in the diagnostic work‐up of patients with cognitive symptoms
Authors: Smith Ruben , Hägerström Douglas , Pawlik Daria , Klein Gregory , Jögi Jonas , Ohlsson Tomas , Stomrud Erik , Hansson Oskar
Published: December 2023

Background

Determining the added value of tau‐PET in the diagnostic work‐up of patients with cognitive symptoms is of great importance before implementation of the method in clinical practice. We therefore aimed to prospectively study the added clinical value of including tau‐PET in the clinical work‐up.

Method

878 patients referred for cognitive complaints to secondary Memory clinics in southern Sweden were consecutively recruited to the Swedish BioFINDER‐2 cohort study (May 2017 – Sept 2021). Participants underwent a baseline diagnostic work‐up including clinical examination, medical history, cognitive testing, blood and CSF sampling, and MRI of the brain. A tau‐PET ([18F]RO948) scan was added onto this clinical diagnostic work‐up. The tau‐PET scans were visually read as: normal, early AD pattern, late AD pattern or inconclusive scan. The primary end points were change in diagnosis and change in Alzheimer disease drug therapy or other drug treatment between the pre‐ and post‐PET visits. Secondary end point was the change in diagnostic certainty between the pre‐ and post‐PET visits.

Result

The tau‐PET visual read result led to a change in diagnoses in 66 participants (7.5%, p<0.001) and a change in medication in 48 participants (5.5%, p<0.001) (Figure 1). There was an overall increase in the diagnostic certainty after tau‐PET in the whole dataset [6.9±2.3 vs 7.4±2.4; p<0.0001]. The certainty was higher in participants with a pre‐PET diagnosis of AD [7.6±1.7 vs 8.2±2.0; p<0.0001] (Figure 2) and increased, as expected, even further in participants with a tau‐PET positive result supporting an AD diagnosis [8.0±1.4 vs 9.0±0.9; p<0.0001]. The impact of tau‐PET results was strongest in participants with pathological Ab‐status, whereas no significant change in diagnoses was seen in participants with normal Ab‐status.

Conclusion

We report a significant change in diagnoses and medication of patients when tau‐PET is added to an already extensive diagnostic work‐up that included CSF AD biomarkers. Tau‐PET led to a significant increase in certainty of underlying etiology. The additive effect on certainty of etiology and to diagnosis was predominantly seen in Ab‐positives and we suggest that clinical use of tau‐PET is limited to populations with biomarkers indicating Ab‐positivity.
Testing reflective tools to support care home residents living with dementia with their spiritual needs
Authors: Luijnenburg Olivia Anna
Published: December 2023

The needs of older people with a ‘diverse’ cultural or faith background are not well represented in social care research in general, and particularly of those living in care homes where an estimated 70% of residents are living with dementia. Additionally, the spiritual needs of care home residents are often overlooked or misunderstood by care workers, resulting in a double lack of recognition. It is common for care workers to relate spirituality primarily to religion. This can be the case, but spirituality mainly reflects (the need for) a purpose and meaning in life. Evidence demonstrates that spirituality and religion can help reduce or stabilise cognitive disorders or enable people to develop coping strategies to help accept a cognitive disorder, maintain relationships, hope, and find meaning in their lives, thus improving their sense of wellbeing. Recent studies have highlighted the importance of creating dementia‐specific spiritual assessment tools and stakeholder training. This proposed study helps fill that gap.

Pre‐liminary findings will be presented on a Reflective Spirituality Tool (RST) that is tested in care homes in England. Through interviews with care home residents living with dementia, their relatives/friends, care home staff, managers, and faith leaders, the RST will be re‐developed to ensure it reflects the diversity of people living in residential care. Furthermore, care home residents were asked to bring an artefact to their interview that represented a sense of peace, safety, or wellbeing to them. The artefacts were then photographed and collected in a ‘Gallery of Spiritualities’. These two tools aim to inform people involved in dementia care and reflect upon the diverse spiritual needs that care home residents have. Furthermore, the tools help inform care home managements, care home staff, nursing students and policy makers on how to improve spiritual care for people living with dementia in residential care.
Genetics to MRI‐DTI: HFE mutation delays AD white matter degeneration in ApoE4 carriers
Authors: Pang Ran , Wang Jianli , Karunanayaka Prasanna , Kanekar Sangam , Beselia Gela , Kaneka Samika , Connor James R , Yang Qing
Published: December 2023

Background

The HFE gene involves iron metabolism that directly participates in white matter (WM) myelination process. ApoE4 are known to affect normal myelination through disruptions of iron and lipid metabolism in AD. Thus, we investigated the effect of HFE SNP concurred with the ApoE4 gene mutation in AD WM degeneration. Associations of a neuronal inflammation marker, CSF sTREM2, with DTI measures and cognitive decline were explored for a mechanism under the context of iron metabolism in AD WM degeneration.

Method

White matter degeneration of ApoE4 carriers with and without HFEH63D polymorphism was investigated using DTI from ADNI database.1 Soluble TREM2 (sTREM2) and pathological protein concentrations in CSF were measured for each CN and AD patients with and without HFE SNP concurred with the ApoE4 gene mutation.

Result

Mean diffusivity and radial diffusivity of DTI demonstrated an extensive and precipitous age‐related WM degeneration in ADWT/ApoE4+ carriers (as shown in Figure1). This WM degeneration was significantly attenuated in the ADH63D/ApoE4+ subjects with lessened cognitive decline (as shown in Table1, Figure1). The decreased CDR‐cognitive impairment in AD subjects was negatively associated with sTREM2 and positively associated with RD of bilateral inferior longitudinal fasciculus and PTAU (as shown in Table2).

Conclusion

The attenuation of WM degeneration and cognitive decline by HFEH63D in AD ApoE4 carriers during aging may involve an effect of reducing neuroinflammation during aging, consistent with reports that HFEH63D establishes a neuroprotective milieu2 and attenuates AD WM neurodegeneration.3 Our in‐vivo data establish a link between interactions of genetic mutation of ApoE with HFE and AD WM degeneration during aging.

Reference

1. Meadowcroft MD, Wang J, Purnell CJ, et al. Reduced Cerebral White Matter Integrity Assessed by DTI in Cognitively Normal H63D‐HFE Polymorphism Carriers. J Neuroimaging. 2018;28:126‐133.

2. Wang L, Johnson EE, Shi HN, Walker WA, Wessling‐Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008;181:2723‐2731.

3. Urrutia PJ, Hirsch EC, González‐Billault C, Núñez MT. Hepcidin attenuates amyloid beta‐induced inflammatory and pro‐oxidant responses in astrocytes and microglia. J Neurochem. 2017; 142:140‐152.
4. An innovative clinical trial designed to evaluate the effects of ACI‐24.060 in Alzheimer’s Disease and in Down syndrome (ABATE Study)
Authors: Sol Olivier , Lê Bénédicte , Wagg Jonathan , Delpretti Saskia , Fiorini Emma , Vukicevic Marija , MacSweeney Emer , Borejko Olga , Aarsland Dag , Arús Xavier Morató , Boada Mercè , Matias‐Guiu Jordi A , Lleo Alberto , Fournier Nicolas , Valatsou Elena , Feige Agnès , Rongere Julien , Gray Julian JG , Hliva Valerie , Fortea Juan , Strydom Andre , Rafii Michael S , Kosco‐Vilbois Marie , Pfeifer Andrea , Streffer Johannes
Published: December 2023

Background

Sporadic Alzheimer’s disease (AD) and Down syndrome related AD (DSAD) share a common neuropathologic picture, with hallmark amyloid plaques and neurofibrillary tangles. The key constituents, amyloid beta (Abeta) and tau, respectively, define the biomarker picture shared between sporadic AD, DSAD and autosomal dominant AD. Small Abeta oligomers and fragments such as Abeta 1‐42 and pyroglutamate Abeta3‐42 (pGlu‐Abeta3‐42) are key for disease initiation and neurotoxicity. ACI‐24 is a liposomal vaccine targeting Abeta. Initial clinical data demonstrated safety and pharmacodynamic response, both in sporadic AD and people with DS. Preclinical data recently demonstrated that a new, optimized formulation of ACI‐24 (ACI‐24.060) has significantly improved immunogenicity against key toxic species, i.e., Abeta oligomers, Abeta 1‐42 and pGlu‐Abeta3‐42.

Method

Recent clinical trials evaluating monoclonal antibodies targeting Abeta in AD have successfully employed translational biomarkers, including amyloid PET, as surrogate markers to predict clinical benefit. These biomarkers can now be more effectively used in clinical trials for both patient selection and demonstrating treatment efficacy.

Result

The ABATE study’s (NCT05462106) innovative translational clinical trial design evaluates the effects of ACI‐24.060 in sporadic AD (Part 1) and in people with DS (Part2). The biomarker‐based design with multiple interim analyses, enables (I) early assessment of safety and immunogenicity, (II) appropriate dose selection using readouts on translational biomarkers including amyloid PET, (III) the safe transition into the DS population and (IV) informed transition into pivotal studies. The use of these shared biomarkers in predictable and pre‐specified trajectories allows effective cross‐learnings between sporadic AD and DSAD and has been enabled by the recent results with anti‐Abeta monoclonal antibodies, strongly enabling this translational approach for an amyloid immunotherapy. Initial safety and immunogenicity data will be presented.

Conclusion

The field of biomarker‐based translational medicine has been mobilized by the clinical evaluation of targeting of toxic abeta fragments and aggregates in monoclonal antibody trials. As shown we are utilizing these advances in an innovative clinical trial design for an efficient, evidence‐based translational medicine approach to test ACI‐24.060 as a novel Abeta vaccine candidate. This approach allows the parallel investigation of ACI‐24.060 for the treatment and prevention of both sporadic AD and DSAD.
Examining the overlap between patterns of tau deposition and cortical neurite microstructure in preclinical Alzheimer’s disease
Authors: Gozdas Elveda , Avelar‐Pereira Bárbara , Hosseini Hadi
Published: December 2023

Background

Increased Amyloid‐beta (Aβ) is associated with the neuropathological features of Alzheimer’s disease (AD), and it has been suggested to amplify tau spreading in the brain that leads to neurodegeneration. However, little is known about how the pattern of tau spreading overlaps with that of cortical microstructural neurodegeneration in the preclinical stages of the disease. Here, we utilized molecular imaging and neurite orientation dispersion and density imaging (NODDI) to identify the spreading pattern of tau pathology with the disease progression in cross‐sectional data and interaction with the degradation of cortical neurite microstructures.

Methods

The study consisted of normal controls (CN) and patients with mild cognitive impairments (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Table 1). All participants had structural and multi‐shell diffusion magnetic resonance imaging (MRI), and positron emission tomography (PET) scans using 18F‐florbetapir (AV45) for and 18F‐flortaucipir (AV1451) for tau. The preprocessed PET images were used to generate the standardized uptake value ratio (SUVR) values in each hemisphere consisting of 180 cerebral cortical brain regions defined by the Glasser atlas. The preprocessed dMRI data were used to compute cortical NODDI coefficients (neurite density (intracellular volume fraction; ICVF), orientation dispersion index (ODI), and isotropic volume fraction (FISO)). The tau and NODDI microstructural values are then normalized compared to the Aβ− CN group by adjusting the values for age and sex. The tau spreading order was defined based on the frequencies of the normalized tau values that exceeded the given threshold and compared the patterns with the neurite microstructures.

Results

We found a sharp increase of tau deposition in patients with Aβ+ MCI, and the medial temporal regions were identified as the earliest region to become tau positive and continue to spread to inferior temporal and inferior parietal regions. Most importantly, we found significant patterns of cortical ODI degradation with the tau spreading in the right entorhinal cortex (p = 0.004) and the right hippocampus (p = 0.02).

Conclusion

The findings of this cross‐sectional study provide that regional cortical neurite imaging could provide higher sensitivity to changes in the pathological process of tau spreading in tau epicenters in AD.
Impact of rater change on data variability in ADAS‐Cog and CDR assessments
Authors: Negash Selam , Echevarria Barbara , Blattner Raymond , DiGregorio Danielle T , Randolph Christopher
Published: December 2023

Background

The past decade has seen numerous research trial failures in Alzheimer’s Disease. The CDR and ADAS‐Cog are the two most frequently used primary outcome measures of memory and cognition in clinical trials of Alzheimer’s Disease (AD). Given the high number of failed AD trials in recent years, data reliability of these measures is paramount. In an effort to minimize data variability and increase data quality, study designs often require the same rater assesses the subject/caregiver at each study visit. However, the impact of rater change on data reliability of these measures is largely unknown. This analysis investigates the impact of rater change on data variability in these measures.

Method

Data from 13 multinational clinical trials of early symptomatic and mild to moderate AD were analyzed. ADAS‐Cog and CDR assessments conducted by site raters were arranged according to visit sequence and divided into two groups: Rater Change (different raters administered subject’s consecutive visits) and No Rater Change (same rater administered consecutive visits). Visit‐to‐visit absolute score changes for CDR‐SB and ADAS‐Cog Total Score were calculated, and frequency distributions were evaluated.

Result

Welch corrected, two sample t‐tests were conducted to compare score changes between rater change groups. For CDR, the Rater Change group showed a higher mean visit‐to‐visit score change (mean = 1.26, SD = 1.32) compared to the No Rater Change (mean = 1.02, SD = 1.13) group. The Rater Change group also showed a higher mean score change on ADAS‐Cog (mean = 4.44, SD: 3.77 and mean ‐ 4.06, SD = 3.50, for Rater Change and No Rater Change Groups, respectively). These group differences reached significance for both ADAS‐Cog (t = ‐7.2925, df = 9769.1, p < .001) and CDR (t = ‐11.228, df = 6122.7, p < .001).

Conclusion

The analysis indicates significantly different score changes when there is a rater change between visits than not for both CDR and ADAS‐Cog assessments. These findings highlight the importance of rater consistency in reducing variability in an effort to improve data quality in AD trials.