bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic resonance imaging‐negative cerebral amyloid angiopathy: cerebrospinal fluid amyloid‐β42 over amyloid positron emission tomography
Authors: Pyun Jung‐Min , Kang Min Ju , Baek Seung Jin , Lee Kyungbok , Park Young Ho , Kim SangYun
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer’s disease (AD) because of its potential link to amyloid‐related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI‐negative CAA) is challenging, and novel detection biomarkers are needed.

Method

We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer’s Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid‐β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level.

Result

NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p‐value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p‐value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p‐value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p‐value = 0.606).

Conclusion

CSF Aβ42 is more sensitive to predict MRI‐negative CAA in high NP burden than amyloid PET.
what do reactive astrocytes (really) do?
Authors: Liddelow Shane A.
Published: January 2025

Background

Astrocytes, a major glial cell in the central nervous system (CNS), can become reactive in response to inflammation or injury, and release toxic factors that kill specific subtypes of neurons. Over the past several decades, many groups report that reactive astrocytes are present in the brains of patients with Alzheimer’s disease, as well as several other neurodegenerative diseases. In addition, reactive astrocyte sub‐types most associated with these diseases are now reported to be present during CNS cancers of several types. Given the active role some of these reactive astrocyte sub‐states in these contexts, it suggests that targeting astrocyte reactivity may be a novel therapeutic strategy for multiple disorders. Here we explore the link between astrocyte reactivity and brain cancer, and found that some brain tumors can induce a similar form of reactive astrocytes that promote tumor growth and invasion.

Method

We used a combination of single cell/nuclei RNAseq, ATACseq, spatial transcriptomics, protein and lipid analyses, in both rodent primary and human iPSC‐derived astrocytes, as well as behavioral assays in mice that lack key components of astrocyte reactivity pathways.

Result

Multiple sub‐states of reactive astrocytes first described in the context of acute inflammatory responses, or chronic neurodegenerative disease, are present in the brains of rodent models of cancer. This includes oligodendroglioma and melanoma metastases.

Conclusion

Astrocytes while being very heterogeneous at the measurable 'omics level and with respect to functional output WITHIN an individual disease, can have sub‐states that are homogenous across multiple disease states. This means that functional/dysfunctional outcomes learning in one model may be translatable to further out understanding of disease pathogenesis in another model. This has been historically reported in the comparison of (say) spinal cord injury and stroke ‐ both of which produce a proliferative border/scar formed by reactive astrocytes, but is now appreciated at multiple pro‐inflammatory reactive states including neurotoxic reactive astrocytes, interferon‐responsive reactive astrocytes, and likely many more.
Functional Connectivity and Longitudinal Changes in Amyloid Pathology in Cognitively Healthy Older Adults
Authors: ten Kate Mara , Lorenzini Luigi , Tijms Betty M. , Wink Alle Meije , Konijnenberg Elles , Tomassen Jori , van der Landen Sophie M. , de Geus Eco J.C. , Coomans Emma M. , Collij Lyduine E. , Scheltens Philip , van de Giessen Elsmarieke , Visser Pieter Jelle , den Braber Anouk , Barkhof Frederik
Published: January 2025

Background

Accumulation of amyloid beta in the brain is one of the first events in Alzheimer’s disease (AD) and starts decades before symptoms arise. It has been hypothesized that brain areas with higher levels of neuronal activation (‘hubs’) are more prone to amyloid deposition. In this study, we examined the regional relationship between cortical hubs and longitudinal changes in amyloid pathology in a sample of cognitively healthy older subjects.

Method

Participants were included from the EMIF‐AD PreclinAD cohort, a longitudinal study in cognitively healthy older monozygotic twins. Standard resting state functional MRI pre‐processing was performed with fMRIprep. Individual connectivity matrices were generated as the pairwise timeseries correlation between 100 regions in the Schaeffer atlas, and binarized using a proportional threshold of 0.25. Regional degree, the number of connections of each region, was taken as a continuous measure of functional 'hubness'. Degree was computed within the 100 individual regions, and averaged within 7 resting state networks. Dynamic [18F]Flutemetamol PET scans were used to visually assess amyloid status, and to quantify global and regional binding potential (BPND) at baseline and follow‐up (mean 4.4±0.5 years). We first assessed whether baseline regional degree could predict change in amyloid status using GEE to account for familial clustering. Next, we performed ROI‐wise analyses, assessing the relationship between group‐average regional values of degree and quantitative BPND (baseline and change) in the whole sample and according to amyloid subgroups (negative stable, converter, positive stable).

Result

We included 124 subjects (age 68.3±6.4, female 54%). In baseline amyloid visually negative subjects (n=111), a lower mean degree in the default mode network (β=‐0.26, p=0.008) was associated with higher chance of conversion from negative to positive amyloid status. In the ROI‐wise analyses, a lower degree was associated with higher baseline BPND and larger rate of increase over time (Figure 1). This relationship was most pronounced in the converter group (Figure 2).

Conclusion

We found that in cognitively healthy individuals, decrease rather than increase in functional hubness is associated with amyloid load and accumulation. Possibly in this population of older adults, functional hubs are already affected by ageing, or early pathology.
Atrial function: Association with cerebrovascular disease and cognitive dysfunction
Authors: Tan Eugene , Hilal Saima , Chan Siew‐Pang , Sim Ming Ann , Lai Mitchell Kim Peng , Chong Joyce R , Robert Caroline , Hazli Hazliza , Gong Lingli , Berboso Josephine , Venketasubramanian Narayanaswamy , Tan Boon Yeow , Richards Arthur Mark , Chen Christopher , Lieng‐Hsi Ling
Published: January 2025

Background

The relationships of left atrial (LA) dysfunction with cognition are poorly understood. We investigated the associations of LA function with cognitive impairment, etiologic‐subtype (neurodegenerative vs. vascular[VCI]), neuroimaging markers of cerebrovascular disease (CeVD) and circulating biomarkers, in subjects without AF.

Method

In this prospective cohort study of subjects recruited from memory clinics with brain magnetic resonance imaging (MRI), neuropsychological assessments, circulating biomarker measurements, LA strain (reservoir [LASr], conduit [LAScd], contractile) was determined using 2D speckle‐tracking echocardiography. VCI was defined as vascular dementia or cognitive impairment no dementia(CIND)/Alzheimer’s dementia with significant CeVD, and neurodegenerative defined as CIND/dementia without significant CeVD on neuroimaging.

Result

Among 251 subjects (age 75±8years, 59% female, 178(71%) had cognitive impairment (37% dementia, 14% moderate CIND, 20% mild CIND), of which 58% were VCI and 42% neurodegenerative. LAScd was the only LA strain parameter independently associated with more severe (moderate CIND/dementia vs. mild CIND/no cognitive impairment) grades of cognitive impairment (lowest vs. highest tertile: adjusted odds ratio[AOR] 2.50, p=0.015), and worse MMSE scores, visuomotor construction and memory on neuropsychological testing (p<0.05). LAScd was independently associated with VCI (vs. neurodegeneration) (lowest vs. highest tertile: AOR 3.16, p=0.006), and showed no associations with markers of neurodegeneration, including circulating pTau‐181 and strictly lobar cerebral microbleeds (p>0.05). LAScd and LASr were both associated with increased burden of CeVD including intracranial stenoses, cortical infarcts, lacunes, cerebral microinfarcts, microbleeds and white matter hyperintensities and correlated with cardiac‐specific biomarkers (p<0.05), but LAScd correlated additionally with a broader range of circulating biomarkers reflecting inflammation, neurotrophic processes and neuronal damage (p<0.05).

Conclusion

Reduced LA conduit function was associated with more severe cognitive impairment, primarily due to CeVD. LA strain, particularly LAScd, may be a useful biomarker of cognitive impairment in at‐risk subjects without AF.
Simple fully convolutional network to detect Alzheimer’s Disease
Authors: Aithal Ninad , Sinha Neelam
Published: January 2025

Background

Deep Neural Networks (DNNs) have emerged as powerful tools in the biomedical field, particularly for the early detection of neurodegenerative diseases. Despite their complexity and data‐intensive nature, simpler fully connected Convolutional Neural Network (SFCN) architectures have shown effectiveness in accurately discerning between subjects affected by Alzheimer’s disease (AD) and healthy controls (HC). This model draws inspiration from the work of Peng H et al. and is trained on the openly available Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset.

Method

In this study, RAW 3T T1‐weighted MPRAGE MRI images with a sagittal acquisition plane and 3D acquisition type were carefully selected, amounting to 807 MRI images categorized into AD and CN classes. These images underwent brain extraction and linear registration (12 degrees of freedom) to a standard 2mm MNI template using FSL, resulting in uniform‐shaped scans of dimensions 1 × 91 × 109 × 91. The model comprises 5 blocks, each incorporating 2 × 3D CNN blocks, 3D batch normalization, and ReLU activation functions. A single MaxPooling layer doubles the channels at each CNN block, followed by a 3D pointwise CNN block reducing channels from 1024 to 256 while introducing non‐linearity. The final block includes 3D adaptive average pooling with a kernel size of 1, dropout set to 0.5, and 2 × 3D point‐ wise CNN layers acting as fully connected layers. This 13‐layer deep network is trained using Weighted Cross Entropy as the loss function and the Adam optimizer with a learning rate initialized to 0.00001. Training involved 100 epochs with a batch size of 16 and a 70‐10‐20 train‐validation‐test split.

Result

The voxel‐based DNN, trained on 278 AD and 288 CN MRI images, achieves a remarkable 95% accuracy on a test dataset of 161, exhibiting precision and recall values of 0.96 and 0.94, respectively.

Conclusion

The promising 95% classification accuracy on the ADNI dataset, encompass‐ ing over 800 subjects, underscores the efficacy of the SFCN in distinguishing between AD and NC subjects based on T1‐weighted MRI scans. This ap‐ proach holds potential for robust early detection of Alzheimer’s disease, con‐ tributing to advancements in neuroimaging‐based diagnostic methodologies.
Resting state EEG Abnormalities and their Relationship with TMS‐EEG induced Cortical Excitability in Alzheimer's Dementia
Authors: Alhabbal Hiba , Asare Gifty , Lawson Renee P , Azami Hamed , Zomorrodi Reza , Chen Robert , Blumberger Daniel M. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Kumar Sanjeev
Published: January 2025

Background

Previous literature has identified slowing of resting state electroencephalography (EEG) rhythm and abnormal cortical excitation in Alzheimer’s Dementia (AD). However, the relationship between these two divergent functional abnormalities and cognitive symptoms of AD are not well understood.

Method

Resting state EEG signal was recorded in participants with AD and HCs for 5 minutes with eyes closed. Relative resting state EEG power was measured for the five frequency bands. Participants underwent a single pulse transcranial magnetic stimulation (TMS) combined with EEG. Cortical evoked activity (CEA) was assessed using TMS‐evoked potential (TEP) rectified area under the curve (AUC) from 25 to 80 ms post‐TMS stimulus, and the TEPs peak amplitudes were calculated by taking the maximal peak in the following time windows: 25 – 35 ms (P30), 40 – 50 ms (N45), and 55 – 65 ms (P60).

Result

Compared to 32 HC (18 females; mean ± SD age: 69.3 ± 7.9 years), 52 participants with AD (32 females; 74.2 ± 8.5 years) had higher relative theta power than HCs (t(66.6) = 5.34, p<0.001). AD participants also had a significantly lower alpha power (t(76) = ‐3.03, p=0.003) and beta power (t(76) = ‐2.51, p=0.014) than HCs. Controlling for sex, age and years of education, AD participants showed a positive association between theta power and CEA (rpartial=0.573, p=0.008); and an inverse association between alpha power and CEA (rpartial=‐0.471, p=0.036). Theta power in AD participants showed a positive association with P60 (rpartial=‐0.637, p=0.003) and an inverse association with N45 (rpartial=‐0.512, p=0.025), while alpha power was inversely associated with P60 (rpartial=‐0.531, p=0.016).

Conclusion

This study showed a positive association between resting state EEG slowing and increased cortical excitability in AD, indicating a possible shared mechanistic pathway between these abnormalities.
DNA methylation signatures can predict amyloid‐beta burden
Authors: Vacher Michael
Published: January 2025

Background

A growing body of research has confirmed the presence of epigenetic alterations in Alzheimer’s disease (AD). While the causal relationship between these changes and AD remains uncertain, they offer a novel avenue to explore potential treatments. In this study, we aimed at characterising the methylation signatures of amyloid beta (Aβ) deposition, one of the main hallmarks of AD.

Method

The cohort consists of 654 participants (mean age = 72.8 years (±6.83), N(male/female) = 293/361) with genome‐wide DNA methylation data (Illumina Infinium EPIC 850k array), drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) study. We used a centiloid (CL) threshold of 20CL to dichotomise amyloid status of participants (Aβhigh N = 290, Aβlow N = 364). Two methods, Partial Least Square Discriminant Analysis (PLS‐DA) and Elastic Net (EN) regression, were employed to identify methylation signatures characterising Aβ status. The overlapping set of features between the two methods were then used to build a logistic regression model to predict amyloid burden.

Result

The PLS‐DA and Elastic Net models allowed the identification of 5 key methylation probes specific to low and high amyloid burden. These main features include (cg18032014 and cg17889682, DYNC1; cg06561607, SMYD3; cg03161454, NXPH4, cg06311780). Individually, all these features were significantly differentially methylated between high and low participants. Assessing the collective effect of these biomarkers in a logistic regression model resulted in 71% Area Under Curve (AUC) performance. The AUC increased to 83% when controlling for the main risk factors of AD, age and APOE ε4 genotype of participants.

Conclusion

This study demonstrates the possibility to use a small set of methylation markers as a non‐invasive way to predict Aβ burden. In addition, the features identified could help shed some lights on the mechanisms underpinning Aβ accumulation. Further validation in independent cohorts is required to validate and refine the results presented in this study.
External validity of trials on amyloid‐lowering therapy against Alzheimer’s disease: the population‐based Rotterdam Study
Authors: Claus Jacqueline Josephine , vom Hofe Ilse , Veenstra Annekee van Ijzinga , Licher Silvan , Seelaar Harro , De Jong Frank Jan , Neitzel Julia , Vernooij Meike W. , Ikram Arfan , Wolters Frank J.
Published: January 2025

Background

Treatment with monoclonal antibodies against amyloid‐β slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer’s disease (AD). However, trial eligibility criteria may affect generalizability to clinical practice.

Methods

We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab from published reports, and applied these to participants with MCI and early clinical AD dementia from the population‐based Rotterdam Study. Participants underwent routine, standardized assessment from 2002‐2013, including questionnaires, blood sampling, brain MRI, cognitive testing, cardiovascular assessment, and –in a subset– amyloid‐PET. We determined trial eligibility for all participants, and assessed progression to dementia within 5 years among participants with MCI.

Results

Of 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 early clinical AD dementia. Around 40% of participants were ineligible because of amyloid negativity, similar across trials. Overall, at least one clinical exclusion criterion was present in 76.3% of participants for aducanumab, 75.8% for lecanemab, and 59.8% for donanemab. Criteria that most often led to exclusion were cardiovascular disease (35.2%), use of anticoagulants (31.2%), psychotropic or immunological medication (20.4%), psychiatric disease (15.9%), and lack of social support (15.6%). One‐third of participants were ineligible based on their brain MRI alone, which was similar across trials and due predominantly to various manifestations of cerebral small‐vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 8% for aducanumab and lecanemab to 15% for donanemab. Risk of progression to dementia tended to be higher for ineligible than for eligible participants for lecanemab (hazard ratio [95%CI]: 1.64 [0.92‐2.91]), but not aducanumab (HR: 1.17 [0.65‐2.12]) or donanemab (HR: 1.03 [0.67‐1.59]).

Conclusions

Less than 15% of community‐dwelling individuals with MCI and early AD dementia would have been eligible for participation in recent RCTs of monoclonal antibodies against amyloid‐β, due in large part to comorbid vascular pathology. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with AD in routine clinical practice.
Cerebrospinal fluid concentration of furin in patients with Alzheimer’s disease
Authors: Kulczynska‐Przybik Agnieszka , Mroczko Jan , Dulewicz Maciej , Zetterberg Henrik , Hanrieder Jörg , Blennow Kaj , Krawczuk Daria , Doroszkiewicz Julia , Borawska Renata , Slowik Agnieszka , Mroczko Barbara
Published: January 2025

Background

Alzheimer's disease (AD) is an uncurable, heterogeneous, and molecular complex neurodegenerative disease. Emerging evidence indicates that furin could play an essential role in the pathogenesis of neurodegenerative disorders. Furin participates in the proteolytic maturation and processing of large numbers of prohormones and proproteins, which among others play crucial roles in neuronal survival, axon growth, dendritic development, synaptogenesis, neurodegeneration, and inflammation. It is suggested that a stable activity of furin is crucial for maintaining of the central nervous system homeostasis. Some studies revealed reduced expression of mRNA of furin in the brains of Alzheimer's disease patients, which may suggest the implication of the protein in the pathophysiology of AD. However, little is known about changes of furin’s concentration in the cerebrospinal fluid (CSF) patients with AD. Therefore, we aimed to assess the usefulness of CSF furin’s measurement in patients with AD in relation to subjects without cognitive impairment. We also assessed associations between CSF concentrations of furin and neurochemical biomarkers of dementia.

Method

The study enrolled 39 participants, including patients with AD and subjects without cognitive decline. The concentrations of furin and classical biomarkers (amyloid beta 1‐42, amyloid beta 1‐40, Tau, as well as pTau181) were assessed in cerebrospinal fluid using a multiplexing method as well as enzyme‐linked immunosorbent assay.

Result

A significantly higher CSF concentration of furin was noticed in AD patients as compared to subjects without cognitive impairment. Furthermore, in the whole study group of patients, the levels of furin correlated negatively with MMSE test and Aβ‐1‐42/ Aβ‐1‐40 ratio, as well as positively with total Tau and pTau181. Additionally, the CSF levels of furin significantly correlated with pTau181 protein in the AD group.

Conclusion

Our preliminary study indicates the potential role of furin in the pathology of AD and its potential usefulness as a candidate biomarker. However, further investigations on an independent larger group of patients are necessary.
Quantitative Analysis of Choroid Plexus Enlargement in Alzheimer's Dementia: A Study of Automated Volumetric Technique
Authors: Kim Dong‐Hee , Suh Chong Hyun , Jung Wooseok , Lee Seung Hyun , Kim Jinyoung , Cho Hyeonwoo , Lee Yeha , Kim Sang Joon , Moon Won‐Jin
Published: January 2025

Background

Choroid plexus enlargement is implicated in the exacerbation of cognitive impairments characteristic of Alzheimer’s dementia (AD). Manual volumetric assessment by radiologists, while accurate, is impractical for large‐scale application due to its resource‐intensive nature. We examine the use of automated brain volumetry software as an efficient and cost‐effective alternative for quantifying choroid plexus volume.

Method

We collected 3D T1 brain MRI images from 293 patients aged between 44 and 91, with a median age of 73, at Konkuk University Hospital (n = 95), Asan Medical Center (n = 99), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 99). The study comprised 76 normal control (NC), 89 mild cognitive impairment (MCI), and 128 AD cases, with a female majority of 58.4%. Using VUNO‐Med DeepBrain software, we obtained choroid plexus segmentation masks and volumes from both radiologists and neural networks trained with deep learning. All choroid plexus volumes were normalized by intracranial volume (ICV) multiplied by 1000. Additionally, to assess DeepBrain's accuracy, we calculated the Intraclass Correlation Coefficient (ICC(2, k)) between the manually labeled volumes and those labeled by DeepBrain.

Result

The median choroid plexus volumes measured by radiologists were 1.328 for NC, 1.354 for MCI, and 1.495 for AD. In contrast, measurements by DeepBrain were 1.163 (NC), 1.284 (MCI), and 1.428 (AD). A one‐way ANOVA analysis (NC vs. MCI vs. AD) revealed that DeepBrain‐based measurements (p < 0.001) may be more significant than manual measurements (p = 0.17) in elucidating the relationship between choroid plexus enlargement and cognitive impairments in AD. Additionally, the Intraclass Correlation Coefficient (ICC(2, k)) between manual and DeepBrain volumes indicated a moderate correlation with a score of 0.69 (p < 0.001).

Conclusion

Our results suggest that automated brain volumetry is a reliable method for assessing choroid plexus volume, correlating with the cognitive impairment continuum in AD. Its implementation could significantly streamline the diagnostic process, offering a scalable and objective approach for clinicians and researchers.
Glutaric acid associates with early detection of cognitive impairment deciphering the association with depression
Authors: Chakraborty Manas , Dhiman Kunal , Sachdev Perminder S. , Brodaty Henry , Draper Brian , Trollor Julian N , Reppermund Simone , Kang Kristan , Mather Karen A , Poljak Anne , Wen Wei , Numbers Katya T. , Kochan Nicole A. , Catts Vibeke S. , Gupta Veer
Published: January 2025

Background

The initiation of cognitive impairment is triggered by a myriad of pathological events occurring decades before clinical symptoms manifest. Perturbed glucose and fatty acid metabolism notably contribute to the development of cognitive impairment, progressing further into clinical dementia. These metabolic alterations are evident in plasma through changes in specific metabolites. Notably, these changes are characteristic features in the pathophysiology of depression, a significant risk factor for cognitive impairment. This project aims to establish a blood‐based biomarker signature for early identification of cognitive changes in individuals with depression. Moreover, it aims to assist in diagnosing and understanding disease progression by quantifying plasma metabolite levels linked to fatty acid metabolism in samples obtained from participants in the Sydney Memory and Ageing Study.

Method

Plasma samples underwent analysis to quantify fatty acids and carnitines using chemical derivatization through UPLC‐MRM/MS coupled with a 4000 QTRAP mass spectrometer which was equipped with an electrospray ion (ESI) source and operated in the multiple‐reaction monitoring (MRM) mode with negative‐ion (‐) detection.10‐μL aliquots of each of the resultant calibration solutions and each of the sample solutions were injected for analysis.

Result

ANCOVA, revealed significant changes in the levels of several biomarkers including glycolic acid (p‐value: 0.033), C181 carnitine (p‐value: 0.013), glutaric acid (p‐value: 0.08) levels in groups with Mild Cognitive Impairment (MCI) and MCI with comorbid depression compared to healthy groups. ROC curve analysis demonstrated that glutaric acid effectively distinguished between MCI and non‐MCI participants. The optimal threshold for classifying participants into MCI and non‐MCI groups was determined using the Youden Index to dichotomize them based on high and low biomarker levels. Logistic regression analysis, adjusting for age, sex, APOE ε4 genotype, and comorbid depression, revealed a significant association between glutaric acid levels and cognitive impairment in the context of depression, with a p‐value of <0.001 and an odds ratio of 2.49.

Conclusion

Glutaric acid proved to be a reliable discriminator between participants with MCI and those without MCI. The aforementioned findings revealed a strong correlation between glutaric acid and cognitive impairment associated with depression which could be used as biomarker for early detection of cognitice impairment.
Obstructive sleep apnea severity is associated with CSF biomarkers of synaptic dysfunction and neuroinflammation in a cohort at risk for AD
Authors: Edmunds Kyle J , Breidenbach Brianne M. , Glittenberg Matthew P , Johnson Sterling C. , Asthana Sanjay , Gallagher Catherine L. , Hermann Bruce P , Sager Mark A. , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B. , Peppard Paul E , Okonkwo Ozioma C
Published: January 2025

Background

Obstructive sleep apnea (OSA) is associated with hypoxia‐induced neuronal impairment and dysfunction—key risk factors for the pathogeneses of age‐related neurodegenerative diseases such as Alzheimer‘s disease (AD). This study examined longitudinal associations between OSA severity and CSF biomarkers associated with AD, synaptic dysfunction, and neuroinflammation in a sample of late‐middle‐aged adults with increased risk for AD.

Method

N=25 cognitively unimpaired adults (64% female, mean age 65.8 ± 7.1 years, 42.3% APOE‐ε4 carriers) from the Wisconsin Alzheimer‘s Disease Research Center (ADRC) participated in overnight polysomnography, where the number of apneas, hypopneas, and respiratory effort related arousals (RERAs) per hour of sleep were recorded. OSA severity was estimated using the base 10 logarithm of the Respiratory Disturbance Index, or log10(RDI+1). Following sleep assessment, CSF samples were acquired via lumbar puncture over two subsequent study visits (mean 5.8 years between visits) and analyzed using the NeuroToolKit (NTK), a panel of robust prototype assays (Roche Diagnostics International Ltd), with measures including core AD biomakers—amyloid beta (Aβ)42, Aβ42:Aβ40, pTau181, pTau181:Aβ42, and tTau—as well as neurogranin, neurofilament light (NfL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), neuronal pentraxin II (NPTX2), and synaptosome associated protein 25 (SNAP25). Linear mixed effects models (with random intercept and random slope) were assembled to test longitudinal associations, adjusting for age, sex, and APOE‐ε4 carriage.

Result

AD biomarker models indicated that RDI was associated with increased CSF levels of tTau (β=0.084, SE=0.013, p=0.014) and pTau181 (β=0.022, SE=0.003, p=0.023), but neither outcome remained robust after Bonferroni correction for multiple comparisons (adjusted α=0.0039). In contrast, models of synaptic dysfunction and neuroinflammation surpassed Bonferroni correction, showing a significant association between RDI and levels of α‐synuclein (β=0.09, SE=0.013, p=0.002) and neurogranin (β=0.13, SE=0.03, p=0.002).

Conclusion

This work provides new evidence for the deleterious influence of OSA on biomarkers of synaptic dysfunction, neuroinflammation, and AD in a sample of late‐middle age to older adults enriched with risk for AD.
PLASMA BD‐TAU AS A SPECIFIC CORRELATE OF DISEASE SEVERITY AND DYNAMIC ACROSS THE ALZHEIMER'S DISEASE SPECTRUM
Authors: Piga Giuseppe , Gonzalez‐Ortiz Fernando , Yuksekel Idil , Houot Marion , Uribe Laura Gonzalez , Rametti‐Lacroux Armelle , Teichmann Marc , Bombois Stéphanie , Ber Isabelle Le , Dubois Bruno , Levy Richard , Lamari Foudil , Blennow Kaj , Villain Nicolas
Published: January 2025

Background

The identification of biomarkers for Alzheimer's disease (AD) remains a significant challenge, particularly for the clinical severity of the disease. Recent studies have shown that plasma brain‐derived‐tau (BD‐Tau) could be a promising biomarker for the identification of AD‐type neurodegeneration. This study aimed to investigate the potential of BD‐Tau in differentiating various clinical stages of AD, ranging from cognitively unimpaired AD to severe dementia AD. Additionally, the study intended to examine the association of BD‐Tau with clinical severity and elucidate its dynamic behavior throughout the natural course of AD.

Method

Cross‐sectional and longitudinal EDTA plasma data, along with clinical information, were utilized from the Pitié‐Salpêtrière hospital INSIGHT (cognitively unimpaired individuals with amyloid PET) and SOCRATES cohorts (AD and non‐AD symptomatic neurodegenerative disease according to up‐to‐date international criteria). Plasma BD‐Tau was analyzed using the Gothenburg University homebrew Quanterix Simoa immunoassay.

Result

The results revealed that BD‐Tau is only elevated in individuals with symptomatic AD, whether the primary or secondary neurodegenerative disease, and not in other neurodegenerative conditions. Additionally, BD‐Tau follows the clinical dynamics of AD, as it is only elevated in symptomatic AD patients, while individuals with AD biological changes but no symptoms have normal levels of BD‐Tau. BD‐Tau levels were also found to be significantly correlated with episodic memory scores and global cognitive performance across a wide range of AD severity. Longitudinal analyses further support BD‐Tau's potential as an AD‐type neurodegeneration biomarker, as it was found to increase over time only in the symptomatic AD group and not in other groups.

Conclusion

These results support the notion that plasma BD‐Tau could be a promising specific biomarker for AD staging, as it follows the AD clinical severity spectrum and is not elevated in asymptomatic amyloidosis.
Proteomic dementia risk assessment in adults with diabetes
Authors: Wang Zhibo , Ning Yuye , Gao Pei‐Yang , Chen Meilin , Jia Jianping
Published: January 2025

Background

The prevalence of dementia among adults with diabetes represents a significant health challenge. Current dementia risk assessment tools are not tailored to the diabetic population. This study aims to develop more precise dementia risk predictive models for patients with diabetes using extensive blood proteomics.

Method

This prospective cohort study utilized UK Biobank data, encompassing baseline assessments from 2006 to 2010 and follow‐up until September 1, 2023. Excluding individuals with pre‐existing dementia, we included 3015 participants with diabetes and they had available Olink blood proteomics data (approximately 3000 proteins). Feature selection was conducted using a least absolute shrinkage and selection operator (LASSO) regression, and Generalized Linear Models (GLM) were applied to create a proteomic risk model. This model was trained on a tested cohort of 2111 diabetic adults and validated on an additional 904 individuals.

Result

Our model, incorporating 48 proteins, outperformed conventional clinical dementia risk assessment tools, including demographic factors (age, sex, education year, APOE ε4 status) and cognitive assessments. In the validation cohort, the model's receiver operating characteristic area under the curve value was 0.83, significantly higher than the 0.56 to 0.73 range for clinical models (Figure 1). The protein models showed effective calibration in the validation cohort (Figure 2). Participants were divided into four groups based on predicted risk, and the results showed that the higher the level of predicted risk, the greater the risk of dementia (Figure 3). Mendelian randomization suggested a causal link between several proteins and dementia, like apolipoprotein E. Pathway analysis emphasized proteins related to the extracellular matrix, endopeptidase inhibition, and neuron projection.

Conclusion

Our proteomic risk model has high predictive accuracy in identifying dementia risk in adults with diabetes. Because this model uses only blood proteins, it is easier to generalize to the general population and thus easier to guide preventive care in patients with diabetes.
Identification of Chromone Hybrids as Interleukin‐6 and Acetylcholinesterase Inhibitor for treatment of Alzheimer’s Disease
Authors: Kaur Sukhvir , Bansal Yogita
Published: January 2025

Background

Neuroinflammation plays an important role in progression of Alzheimer’s disease (AD). Interlukin‐6 (IL‐6) is well identified marker in initiating and regulating inflammation, and formation of senile plaques in brain. Therefore, simultaneous inhibition of both IL‐6 and acetylcholinesterase (AChE) may be an effective strategy for AD.

Method

Four series of molecules are designed by coupling a chromone, and a N, N‐disubstituted amine as pharmacophore for IL‐6 and AChE inhibition, respectively through an alkyl linker of different lengths (1‐4 carbon atoms). Designed compounds were docked into AChE to identify the best fit compounds for calculating ADME, synthesis and evaluation of AChE inhibitory activity. The compounds showing >45% inhibition of EeAChE are selected for evaluation of IL‐6, AChE and butyrylcholinesterase (BuChE) inhibitory activities. The compound found to be most potent against was finally evaluated in vivo using STZ‐induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg).

Result

Docking of all designed compounds in AChE pocket identify the 16 best fit compounds (Docking score > 8.3). The data suggests that a 2‐ or 3‐carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 16 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti‐AChE activity. Six compounds, showing >45% inhibition of AChE, are further evaluated for AChE, BuChE and IL‐6 inhibitory activities. Compound YS3g is found to be the most potent inhibitor of EeAChE (IC50 0.54 μM/ml) as well as IL‐6 (IC50 0.57 μM/ml). YS3g was evaluated in vivo at three different doses (0.2, 0.4 and 0.8 mg/kg) and show dose‐dependent effects. At higher dose (0.8 mg/kg), it reverses the STZ‐induced memory deficit in vivo and shows histopathology similar to that shown by normal‐control animal.

Conclusion

The results implied hybrid compounds formed by combing chromone with piperazine ring through a three‐carbon atom chain might act as promising small‐molecule agent for further investigation against AD.
Associations between education attainment and brain‐predicted age difference: a population‐based study
Authors: Huang Huijie , Wang Jiao , Ma Jun , Xu Weili
Published: January 2025

Background

Education, as a proxy for cognitive reserves, has been linked to dementia; however, the association between education attainment and brain health remains unclear. We aim to investigate the association between education attainment and neuroimaging based brain‐predicted age difference (BPAD, the difference between brain age and chronological age).

Method

The study included 32,322 chronic neurological disease‐free participants (mean age 54.74 ± 7.49 years, 46.58% female) who underwent brain MRI scans 9+ years after baseline. Years of education were self‐reported and categorized as low (7 and 10 years), medium (13, 15, and 19 years), and high (20 years) according to the International Standard Classification of Education. BPAD was predicted based on 1,079 multimodal imaging‐derived phenotypes (including structural and functional MRI) by a LASSO machine learning model. Alzheimer's disease‐related polygenic risk score (PRSAD) was tertiled as low, moderate and high. Data were analyzed using linear regressions.

Result

At baseline, 6,332 (19.59%), 10,872 (33.64%), and 15,118 (46.77%) participants had low, medium, and high education, separately. Compared to low education, high education (β [95% CI]: ‐0.230 [‐0.392, ‐0.067]) was related to more negative BPAD. In joint‐effect analysis, the β (95% CI) of BPAD was ‐0.542 (‐0.796, ‐0.289) among participants with high education and low‐to‐moderate PRSAD, compared to those with low education and high PRSAD.

Conclusion

High education attainment was associated with more negative BPAD, particularly among people with a low‐to‐moderate genetic susceptibility for dementia.
The direct effect of type 2 diabetes on neurodegenerative processes in the absence of other cardiovascular risk factors
Authors: Nowell Joseph , Gentleman Steve , Edison Paul
Published: January 2025

Background

Diabetes is associated with an increased risk of developing neurodegenerative conditions, including Alzheimer’s disease. Abnormal insulin signalling can lead to impaired phosphorylation of protein kinase B and activation of phosphatidylinositol 3‐kinase, resulting in hyperphosphorylation of tau and activation of inflammatory pathways. However, people living with diabetes commonly exhibit comorbid cardiovascular risk, which are also linked with cognitive decline. Here we sought to establish the influence of diabetes on global brain atrophy in the absence of comorbid cardiovascular disease.

Method

Participants diagnosed with diabetes and a matched sample of non‐diabetic control participants were enrolled from the UK biobank database. To reduce the influence of confounding risk factors, diabetic and control participants with additional cardiovascular risk were excluded. Participants diagnosed with cardiovascular/heart problems including high blood pressure, cardiac arrest, stroke, and angina were excluded. Non‐diabetic controls were matched based on age, sex and APOE genotype to enhance statistical precision. Voxel‐based morphometry was performed on T1‐weighted structural magnetic resonance images to evaluate the macrostructural changes associated with diabetes across the cortex. A voxel‐wise t‐test was performed between diabetic and non‐diabetic controls implemented on FSL.

Result

A total of 503 diabetic participants and a matched sample of 503 control participants met the inclusion criteria and were enrolled on the study. Even in the absence of comorbid cardiovascular disease, participants with diabetes exhibited widespread reductions in grey matter volume in comparison to non‐diabetic participants. Volumetric reductions were demonstrated in 97% of grey matter (volume = 191605 mm³), indicating neurodegeneration in all major brain lobes. Reductions of brain volume in diabetic participants remained following family‐wise error correction.

Conclusion

In the absence of other comorbid cardiovascular diseases, type 2 diabetes mellitus induces widespread neurodegeneration in cortical regions. Impairment to insulin signalling and the initiation of the inflammation response may initiate neurodegenerative processes resulting in the loss of brain cells. The widespread nature of atrophy indicates the potential risk for future cognitive impairment. Targeting molecular mechanisms involved in diabetes, including insulin resistance and inflammation, are important to prevent the development of neurodegenerative conditions. This exemplifies the potential for antidiabetic agents for the treatment of neurodegenerative diseases.
Our youth, our compass: families walking with younger‐onset dementia shine light on stigma
Authors: Cose Diana Shulla , Fitzgerald Stephanie , LaFleur Patti , Ruge Bree
Published: January 2025

Purpose

For youth walking with a parent’s younger‐onset dementia diagnosis, our voices are the softest, yet our journey is often the hardest. We are helping to open the shades and bring light. We are telling the stories of our Mother’s and our Father’s. We are the survivors who choose to advocate for a more just world for our families. Through the EmpowermentPLUS Model, we are bringing strength to stigma.

Project Plan

The three components of the EmpowermentPLUS Model include (1) recognize, (2) respond, and (3) empowerx2. For example, when I feel I am experiencing stigma as a daughter of my parent living with dementia–at a family party, grocery store, park or hospital, I am (A) able to recognize it, and (B) I have the tools to respond, rather than responding with fight, flight, or freeze and (C) the last piece is that my mindful and informed response empowers me as a daughter, and the PLUS symbolizes that the person who triggered the stigma is also empowered by being educated.

Outcomes

During our international Youth Summit, with support from Alzheimer’s Society of Canada, Alzheimer’s Disease International and London School of Economics, nearly 100 youth worldwide shared personal stories of when they experienced stigma as a younger family walking with dementia, and we taught the EmpowermentPLUS Model as a way to grapple and dismantle it.

Conclusion

We are building our alliance of empowered young ambassadors, and expect more than 200 youth at Lorenzo’s Youth Summit 2024. Our Founding Executive Director, Diana Shulla Cose, and another member of our Lorenzo’s House community will share the youth voices and details of Lorenzo’s House strength to stigma work.
Differences in amyloid positivity rates among racial groups with cognitive impairment in a suburban‐rural Southeast community
Authors: Chacon Eduardo Garcia , Woodring Annalise C , Crane Monica K
Published: January 2025

Background

Underrepresented racial and ethnic groups have higher rates of clinical dementia symptoms and are given clinical diagnoses of Alzheimer’s disease without confirmatory AD biomarkers.

Method

We compared amyloid PET positivity in cohort of all rural and suburban Southeastern participants from a single clinical practice who met appropriate‐use criteria for amyloid PET imaging between January 2020‐December 2024. We used a paired nominal date test McNemar test to compare amyloid PET positivity proportions between matched racial and ethnic groups and multivariable logistic regression to assess the odds of having a positive amyloid PET scan.

Result

Data from 94 individuals (6 Asian/Pacific Islander(Other), 42 Black, 7 Hispanic, and 39 White) with MCI or dementia and amyloid PET were analyzed between April 2020 and December 2023. The median (range) age of participants was 75 (68‐82) years; 51 participants (54.3%) were female and 43 (45.7%) were male. For patient amyloid status, 49 participants (52.1%) had a validated negative amyloid result, and 45 participants (47.9%) had a validated positive amyloid result. In the optimal 1:1 matching analysis (n = 81, White participants had a greater proportion of positive amyloid PET scans analyzed but did not achieve statistical significance when compared with Black participants (24 of 39; 61.5%; 95% CI, 0.38‐0.72 vs 14 of 42; 33.3%; 95% CI, 0.19‐0.51, respectively) p>0.05. In the adjusted model, the odds of having a positive amyloid PET scan were lower for Black participants (OR, 0.313; 95% CI, 0.126‐0.776; P =0.012), and Hispanic participants (OR, 0.33; 95% CI, 0.163‐4.253; P>0.05) compared with White participants.

Conclusion

The proportion of amyloid positive PET scan was greater among White as compared with Black and Hispanic participants when controlling for social and demographic factors. These findings may reflect differences in underlying pathology and raises concern that other factors may be contributing to higher levels of cognitive impairment in underrepresented groups.