bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintaining Brain Resilience with prevents disease in rat and mouse models of Alzheimer’s disease and restores brain health and cognition in chronic traumatic brain injury
Authors: Pieper Andrew A.
Published: January 2025

Background

Even when patients carry disease‐causing mutations their entire lives, they do not develop Alzheimer’s disease (AD) until later in life. The reason for this loss of brain resilience is not known, and two of the greatest risk factors for developing AD are aging and traumatic brain injury (TBI). Unfortunately, there are currently no protective treatments for patients that prevent the development of AD.

Method

We assessed the ability of early treatment with the NAD+/NADH‐normalizing P7C3 compounds to prevent disease in the 5xFAD mouse and TgF344 AD rat amyloid‐based preclinical models of AD. We also assessed the therapeutic efficacy of delayed treatment with P7C3 compounds in a mouse model of chronic TBI. Lastly, we examined the ability of P7C3 compounds to protect human brain microvascular endothelial cells (HBMVECs) of the blood brain barrier (BBB) from oxidative stress, such as occurs in human AD.

Result

Early administration of P7C3‐A20 to presymptomatic 5xFAD mice prevented plaque accumulation, tau phosphorylation, blood‐brain barrier deterioration, oxidative stress, DNA damage, neuroinflammation, impaired hippocampal neurogenesis, deficient synaptic plasticity, neurodegeneration, and neuropsychiatric and cognitive impairment. Similar protective efficacy was noted in TgF344 AD rats, and delayed treatment with P7C3 compounds in chronic TBI restored the BBB, arrested chronic neurodegeneration, and fully normalized cognitive function one year after injury. Lastly, treatment of HBMVECs with P7C3‐A20 protected them from the deleterious effects of exposure to otherwise overwhelming oxidative stress.

Conclusion

Our results offer a first proof of principle for maintaining brain resilience to protect from developing AD, as well as the ability to reverse pathology and cognitive impairment in chronic TBI.
A Dual‐Color Fluorescent Reporting System for Dynamic Monitoring of Microglial Phagocytosis of Amyloid β Oligomers
Authors: Huang Xin
Published: January 2025

Background

The reduced phagocytosis of amyloid β (Aβ) by microglia is linked to increased cognitive decline in Alzheimer’s disease (AD) patients. Previous methods utilized anti‐Aβ antibodies and flow cytometry to reveal Aβ surface binding without internalization. This study introduces a “Two‐Color Fluorescent Reporting System” to overcome limitations, allowing differentiation between intra‐ and extracellular Aβ.

Method

This novel system utilizes AF647‐conjugated Aducanumab to visualize the surface‐bound amyloid β oligomers (Aβo), while pHrodo red serves to delineate intra‐lysosomal Aβo. Initial investigations focused on pHrodo‐Aβo phagocytosis by neuronal (HT22) and glial (U251) cells, comparing them with microglial cells (BV2). Subsequent examinations assessed the impact of glatiramer acetate (GA), a phagocytosis‐promoting peptide, on BV2 phagocytosis of Aβo in comparison to control without GA (basal) and oxidized ATP (oxATP), a P2X receptor antagonist. Flow cytometry was employed for temporal observations at 0.5, 1, 2, 4, and 24 hours, complemented by real‐time fluorescent microscopy for continuous monitoring of the entire process.

Result

In the initial study, BV2 cells exhibited Aβo surface adhesion and subsequent internalization after 2 hours, with the majority phagocytosed into lysosomes by 24 hours. Conversely, HT22 cells displayed surface adhesion of pHrodo‐Aβo without internalization, and after 24 hours, a modest internalization was observed. U251 cells demonstrated weak internalization after 2 hours and more apparent internalization after 24 hours, distinct from BV2. In the second study, the intralysosomal Aβo vs. surface Aβo ratio revealed significant differences between the basal, GA, and oxATP groups after two and 24 hours. Notably, the GA group exhibited increased pHrodo red‐Aβo in a completely acidified state after 24 hours.

Conclusion

This study introduces an innovative dual‐color fluorescent reporter system, showcasing its potential for standardization in elucidating the intricate dynamics of microglial phagocytosis of Aβo. The results underscore the utility of this system, offering promise for advancing research and enhancing our understanding of Alzheimer’s disease pathology.
Links Between Microvascular and AD‐related pathology in the Medial Temporal Lobe
Authors: Perosa Valentina
Published: January 2025

Background

Cerebral small vessel disease (CSVD), which includes cerebral amyloid angiopathy (CAA) and arteriolosclerosis, often co‐occurs with Alzheimer’s disease (AD) pathology. The medial temporal lobe (MTL) is susceptible to hosting multiple AD pathologies, such as neurofibrillary tangles (NFTs), amyloid‐β plaques, phospho‐Tar‐DNA‐Binding‐Protein‐43 (pTDP‐43), as well as CSVD. Whether a causal relationship between these pathologies exists remains largely unknown, but one potential linking mechanism is the dysfunction of perivascular clearance. Our objective was to examine the burden of CSVD in the MTL of a pathological AD cohort and to establish the associations between CSVD and AD‐related pathologies, as well as between CSVD and enlarged perivascular spaces (EPVS), a potential indicator of clearance dysfunction.

Method

The study included 156 autopsy cases (mean age at death 79.4±10.9 years, 90 females) from the Massachusetts Alzheimer’s Disease Research Center (MADRC). One hemisphere was preserved in formalin, and 5 µm‐thick sections were cut from predefined regions of the hippocampal body and entorhinal cortex. These sections were subsequently stained using luxol fast blue with hematoxylin&eosin (LHE), and antibodies against amyloid‐β, hyperphosphorylated tau (At8), and pTDP‐43, following standard histological and immunohistochemical protocols. Utilizing deep‐learning models (Aiforia®), we computed the burden of CAA, amyloid‐β plaques, NFTs, and pTDP‐43 inclusions (Figure 1). Additionally, the severity of arteriolosclerosis and the % area of EPVS were evaluated on the LHE sections.

Result

In linear mixed effects models CAA was positively associated with the density of NFTs (Est = 7.21; p = 0.024; R2 = 69%) and amyloid‐β plaque burden (Est = 3.01; p<0.001; R2 = 61%) in all regions of interest. Arteriolosclerosis had no direct effect on parenchymal AD‐related pathologies but showed a positive interaction with CAA in the association with PVS enlargement. There was no relationship between pTDP‐43 inclusions and arteriolosclerosis.

Conclusion

These results point towards an association between microvascular pathology and AD‐related pathology, possibly mediated by clearance dysfunction.
Arteriolosclerosis and LATE‐NC: two common and inter‐related contributors to Alzheimer’s‐type dementia
Authors: Nelson Peter T , Katsumata Yuriko
Published: January 2025

Background

Brain arteriolosclerosis (B‐ASC) is a pathologic hallmark characterized by dysmorphic brain arteriolar wall thickening. B‐ASC is a common finding at autopsy in aged persons – some degree of B‐ASC is seen in >80% of brains beyond age 80 years – and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B‐ASC. We and others have also found that B‐ASC is associated with limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) and hippocampal sclerosis of aging (HS‐A). Here we re‐test this association using updated data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data set.

Method

Participants were assessed using the standardized NACC Uniform Data Set (UDS) at their local ADRC approximately annually, including participant demographics. Participants over 60 years of age at death (last seen during or after 2010) who met the study’s eligibility criteria were selected from the June 2023 (NACC62) data freeze. TDP‐43 neuropathologies were specified in three brain regions: amygdala, entorhinal/inferior temporal cortex and/or hippocampus, and neocortex. For cerebrovascular pathologies, data were available on arteriolosclerosis (none, mild, moderate, and severe), cerebral amyloid angiopathy (none, mild, moderate, and severe), infarcts and lacunes (no and yes), and microinfarcts (no and yes).

Result

Following exclusions, the final analytic sample included 2558 participants, including brains with none (n = 370), mild (n = 909), moderate (n = 884), and severe (n = 395) B‐ASC severity. The mean age at death was 82.3 years and half were females. More than half of the participants had severe ADNC (Braak NFT stages V or VI). Over 28% of included participants had TDP‐43 pathology in hippocampus, whereas 16.4% had HS‐A. The associations between B‐ASC and both LATE‐NC and HS‐A were strong and specific when controlling for other factors such as age (P<0.001). This association remained robust when a subset analysis was performed only analyzing results from individuals who died after 2014.

Conclusion

There is a strong, replicable association between B‐ASC and LATE‐NC/HS‐A in the NACC Neuropathology Data Set. Microvasculopathy appears to be a component of the LATE‐NC/HS‐A brain condition, which is remarkable because both B‐ASC and LATE‐NC are strongly associated with “Alzheimer’s‐type” amnestic dementia.
Using three‐dimensional histology to visualize vascular tau accumulation in Alzheimer’s disease
Authors: Hoglund Zachary T , Ruiz‐Uribe Nancy E , del Sastre Eric , Woost Benjamin , Bailey Joshua J , Zwang Theodore J , Bennett Rachel E
Published: January 2025

Background

In cerebral amyloid angiopathy, amyloid beta accumulates within the walls of blood vessels and contributes to impaired vascular integrity and function. In this work, we observe that tau protein similarly builds up along blood vessels in Alzheimer’s disease brain.

Method

We obtained frozen inferior temporal cortex from the Massachusetts Alzheimer’s Disease Research Center from n = 7 neuropathological confirmed Alzheimer’s disease donors and n = 6 normal aging controls. Three‐dimensional histology was carried out by cutting thick tissue sections (0.5 ‐ 1 mm) on a vibratome, clearing them using a modified CLARITY protocol, and immunolabeling for blood vessels, tau, neurons, and smooth muscle cells. Whole images were collected on a confocal or light sheet microscope and quantitatively examined using a combination of virtual reality tracing, MATLAB and Imaris. Adjacent tissues and isolated blood vessels were also measured for tau and phospho‐tau species using capillary western blotting to confirm imaging results.

Result

In total, n = 107 Alzheimer’s disease and n = 127 control blood vessels were examined using three‐dimensional histology. Nearly all measured blood vessels in AD brain had regions of enhanced tau accumulation at the vascular surface (within 3 microns). Tau associated with blood vessels was found throughout cortical layers I‐V and was observed to be primarily located on arterioles. Further, isolated blood vessels were significantly enriched for the tau N‐terminus and phospho‐tau 181 and 217.

Conclusion

These data indicate that tau accumulates on blood vessels in the Alzheimer’s disease brain to a greater extent than previously appreciated. Further, they highlight the utility of three‐dimensional histology methods for visualizing and quantifying novel relationships between features in the brain.
Interconnected Dynamics of ‘Obesageing’: Intricate Relationship Between Obesity and Ageing Processes
Authors: Ghosh Shampa , Singh Krishna Kumar , Jha Suchita , Raghunath Manchala , Sinha Jitendra Kumar
Published: January 2025

Background

Obesity and ageing individually pose significant challenges to global public health, leading to preventable deaths. With an increasing geriatric population due to improved medical interventions, the intersection of these health issues becomes a critical concern worldwide. Both developed and developing countries grapple with the consequences of obesity, a major risk factor for various conditions like cardiovascular diseases, hypertension, type 2 diabetes, dementia, and neuropsychiatric diseases. Ageing, a natural process involving the gradual decline in physiological functions, shares similar comorbidities with obesity.

Method

This paper explores the concept of ‘Obesageing,’ highlighting the commonalities between the pathological aspects of obesity and the normal physiological processes of ageing. A unique rodent model, WNIN/Ob, has been established to mimic Obesageing, embodying traits of morbid obesity and premature ageing.

Result

The WNIN/Ob rodent model provides a platform to unravel the intricate interplay of mechanisms shared between obesity and ageing. This novel approach enhances our understanding of the complex relationship, paving the way for future strategies to address the escalating challenges posed by the simultaneous rise of obesity and ageing.

Conclusion

The development of the WNIN/Ob rodent model signifies a breakthrough in comprehending the interconnected dynamics of obesity and ageing. This model serves as a valuable tool for investigating shared mechanisms, enabling the formulation of targeted strategies to mitigate the dual burden of obesity and ageing in the global population.
Unveiling and mapping the immune compartment in human Alzheimer’s disease
Authors: Buss Suzanne , Couper Kevin , Haley Michael , Brookes Emily , Gomez‐Nicola Diego
Published: January 2025

Background

The neuroimmune response, characterised by the proliferation and activation of microglial cells, is a driver of Alzheimer’s disease (AD). However, the extent of immune cell infiltration and interactions in the human AD brain are yet to be established in detail. While microglial cells are at the centre of this neuroimmune response, recent research has explored the possibility of peripheral immune cell involvement, typically focusing on T‐cell infiltration. There is currently a scarcity of studies using human tissues, with most of our understanding being derived from the study of animal models of AD‐like pathology, which lack the complexity and diversity of the human condition. Our study aims to advance our understanding of the complex interplay of immune cells and signals, helping to define how the neuroimmune response plays a role in driving AD pathogenesis.

Methods

We used two complementary techniques that provide a comprehensive map of the immune compartment through providing data rich results and spatial context. Samples were derived from human fresh‐frozen and FFPE post‐mortem tissues at all Braak stages, obtained from UK brain banks. We used fluorescence activated nuclei sorting to isolate the key cellular populations in the brain, as well as other non‐resident immune cells. Single‐nuclei RNA sequencing is used to establish not only the microglial transcriptional diversity in AD but also what other immune populations we see residing in the AD brain. Imaging mass cytometry, a highly quantitative technique that utilises up to 40 metal conjugated antibodies simultaneously, has also been deployed to provide spatial context of the main microglial phenotypes and immune cell interactions via single‐cell bioinformatic analysis.

Results

Preliminary data suggests that there are populations of peripheral immune cells infiltrating into the brain during AD which could be impacting disease outcome. Distinct microglial phenotypes have also been detected which reflect results of recent human single‐cell RNA sequencing studies. Future work includes increasing the sample number to further support our preliminary findings.

Conclusion

By understanding the complex interplay of immune cells, not only with one another but with pathological and physical hallmarks, we could significantly advance our comprehension of AD pathogenesis and steer research into preventative and/or treatment options.
Primary progressive aphasia in Italian and English: a cross‐linguistic cohort study
Authors: Mazzeo Salvatore , Hardy Chris JD , Jiang Jessica , Morinelli Carmen , Moschini Valentina , Johnson Jeremy , Chokesuwattanaskul Anthipa , Volkmer Anna , Rohrer Jonathan D. , Ingannato Assunta , Bagnoli Silvia , Padiglioni Sonia , Nacmias Benedetta , Sorbi Sandro , Bessi Valentina , Warren Jason D
Published: January 2025

Background

Primary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language abilities, with clinical variants (nonfluent/agrammatic variant [nfvPPA], semantic variant [svPPA], logopenic variant [lvPPA], and mixed‐PPA [mPPA]) categorized based on linguistic features. This study aims to compare PPA cohorts of native speakers of two different languages: English (an analytic language with deep orthography) and Italian (a synthetic language with shallow orthography).

Methods

We considered 166 English participants (70 nfvPPA, 45 svPPA, 42 lvPPA, 9 mPPA) and 106 Italian participants (14 nfvPPA, 20 svPPA, 42 lvPPA, 31 mPPA). Starting from the neuropsychological battery used to assess patients, we extracted one test for each cognitive and linguistic function that can be compared between cohorts. Comparisons were adjusted for symptom duration and Mini‐mental State Examination scores.

Results

The English cohort included a higher proportion of nfvPPA patients (42% vs. 13%, p<0.001), while the Italian cohort showed higher proportions of lvPPA (25% vs. 38%, p = 0.019) and mPPA (5% vs. 29%, p<0.001). English nfvPPA patients were more frequently impaired in single‐word comprehension (60% vs. 8%, p = 0.013), while Italian nfvPPA patients exhibited more agrammatism (46% vs. 93%, p = 0.015). English svPPA had a higher proportion of surface dyslexia (68% vs. 30%, p = 0.046) and spelling impairment (38% vs. 10%, p = 0.021). English lvPPA had broader impairments, including single‐word comprehension (89% vs. 29%, p<0.001), repetition of words (61% vs. 26%, p = 0.03), nonverbal working memory (69% vs. 36%, p = 0.005), and visuospatial perception (89% vs. 25%, p<0.001).

Conclusions

This study reveals linguistic and cognitive distinctions between English and Italian PPA cohorts, emphasizing the impact of language‐specific characteristics on symptomatology. Cultural and linguistic nuances should be considered in PPA diagnosis and management, calling for more tailored assessments and criteria.
Correlation Between Atherosclerotic Carotid Plaque Composition and the Neuropathological Lesions of Alzheimer’s Disease: Partial Results
Authors: Barbosa Maria Eduarda , Leite Renata Elaine Paraizo , Grinberg Lea T. , Nitrini Ricardo , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Farias‐Itao Daniela Souza , Pontes Beatriz Carvalho , Braga Maria Eduarda , Justo Alberto Fernando Oliveira , Suemoto Claudia Kimie
Published: January 2025

Background

Previous studies suggest an association between Alzheimer’s disease and carotid artery atherosclerosis. However, the association between atherosclerotic carotid plaque composition and Alzheimer’s disease pathology (neuritic plaques and neurofibrillary tangles) has not been explored yet.

Method

Carotid arteries were dissected and the segments with the largest obstruction in the carotid bifurcation, and the common and internal carotid arteries were obtained. Each segment was immersed in paraffin and stained using Hematoxylin‐Eosin (HE) and Masson’s Trichrome. Each histological slide was photographed using a stereomicroscope (SMZ 1000; Nikon). We analyzed artery obstruction, fibrous cap, the number of vasa vasorum, and plaque components, using the software Atherosclerotic Plaque Analyzer. We characterized the neuritic plaque deposition in the brain using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria and neurofibrillary tangle deposition using the Braak & Braak criteria. We performed ordinal logistic regression models adjusted for age, sex, education, hypertension, diabetes, dyslipidemia, smoking, excessive alcohol consumption, body mass index, and physical inactivity.

Result

Cross‐sectional data from 237 subjects from the Biobank for Aging Studies of the University of Sao Paulo Medical School were analyzed (mean age = 79.0±9.9 yo, 51.5% women, 59.9% white, 35.9% black and 3.8% Asian). As the percentage of smooth muscle cell area increased, neurofibrillary tangles deposition decreased (OR = 0.97, 95% CI = 0.94‐1.00, p = 0.03). Similarly, as the percentage of fibrous cap area increased, neurofibrillary tangles deposition increased (OR = 1.13, 95% CI = 1.00‐1.25, p = 0.04).

Conclusion

Given that the fibrous cap is typically present in advanced atherosclerosis, and considering that smooth muscle cell area was solely assessed in the absence of well‐established atherosclerotic plaque, our examination of atherosclerotic plaque composition in carotid artery segments suggests a connection between atherosclerosis development and the accumulation of neurofibrillary tangles in the brain. We found an association with the fibrous cap proportion of the tunica intima area and an inverse association with the proportion of smooth muscle cells in the tunica intima area.
The role of heparan sulfate proteoglycans for tau pathology in vivo
Authors: Stopschinski Barbara E , Estill‐Terpack Sandi‐Jo , Batra Sushobhna , Pandey Shubhangi , III Jaime Vaquer‐Alicea , Diamond Marc I
Published: January 2025

Background

The prion model of tau propagation in Alzheimer’s Disease predicts that tau seeds are released from cells and taken up by neighboring cells, resulting in spreading of the disease. Our previous work revealed that tau aggregates bind to heparan sulfate proteoglycans (HSPGs) on the cell surface, followed by cellular uptake via macropinocytosis. HSPGs are glycoproteins, consisting of a protein core and decorated with linear glycosaminoglycan (GAG) chains called heparan sulfate (HS) with highly variable sulfation patterns. We have previously used a combination of biochemical, pharmacological and genetic tools to demonstrate that N‐sulfation (mediated by the N‐sulfotransferase NDST1) of the HS chain is critical for tau uptake in cell models. This project is a stepwise approach to validate HSPGs and specifically NDST1 as a therapeutic target to block tau spread in vivo.

Method

We induced NDST1 knockout using CRISPR/Cas9 followed by rescue experiments and tau uptake assays in HEK293T cells. Tau uptake assays with heparin were conducted in murine hippocampal neurons and astrocytes. We employed stereotactic adeno‐associated virus 8 (AAV8)‐mediated intracerebral delivery of small hairpin RNA (shRNA) to target NDST1 in PS19 mice, a tauopathy mouse model (collaboration with Merck).

Result

Our data demonstrates that reduction of the N‐deacetylase activity with selected point mutations within NDST1 can decrease tau uptake substantially (Figure 1). Our experiments in primary murine neurons and astrocytes suggest that HSPGs are crucial for tau uptake in these cell types (Figure 2). NDST1 knockdown with shRNA in PS19 mice achieved >75% reduction of messenger RNA (mRNA) levels and was non‐toxic (Figure 3).

Conclusion

Our findings suggest that NDST1 is a potentially druggable target, and that the HSPG pathway plays a role for tau uptake in multiple cell types. We worked with GemPharmatech for the generation of a floxed NDST1 mouse line. We plan to breed the floxed NDST1 mice to PS19 mice and selected neuronal, astrocytic and microglial Cre driver lines. We anticipate that knockout of NDST1 in vivo will reduce tau spread in mouse brain. If successful, our study will inspire multiple lines of follow up work such as the design of enzymatic inhibitors and genetic silencing tools.
Elevated iron levels in the older adult brain are associated with higher R2 relaxation rate in gray matter and more white matter hyperintensities: An ex‐vivo MRI, pathology and mass spectrometry study
Authors: Yasar Md Tahmid , Bush Ashley I. , Ayton Scott , Agarwal Puja , Agrawal Sonal , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Elevated iron in brain is a source of free radicals that causes oxidative stress which has been linked to neuropathologies and cognitive impairment among older adults. The aim of this study was to investigate the association of iron levels with transverse relaxation rate, R2, and white matter hyperintensities (WMH), independent of the effects of other metals and age‐related neuropathologies.

Method

Cerebral hemispheres from 437 older adults participating in the Rush Memory and Aging Project study (Table 1) were imaged ex‐vivo using 3T MRI scanners. R2 maps were generated from multi‐echo spin‐echo data and then registered to an ex‐vivo brain template. WMH were segmented based on T2‐weighted images. WMH volume was normalized by the total hemisphere volume and then log‐transformed. Following ex‐vivo MRI, all hemispheres underwent neuropathologic assessment including Aβ plaques, neurofibrillary tangles, LATE‐NC, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy, gross infarcts, microscopic infarcts, atherosclerosis, and arteriolosclerosis (Table 1).

Inductively coupled plasma mass spectrometry was used to measure brain trace metal levels. The assessed metals included iron, boron, titanium, manganese, copper, zinc, selenium, rubidium, molybdenum, and mercury (Table 1).

Linear regression was used to test the association of R2 and WMH burden with iron levels. All models were controlled for all other metals and neuropathologies listed above, demographics (age at death, sex, years of education), the presence of the APOE‐ε4 allele, postmortem interval to fixation and to imaging, and scanner. Statistical analysis was performed using PALM, with tail‐accelerated 5,000 permutations. Statistical significance was set at p<0.05 after family wise error rate correction.

Result

The voxel‐wise analysis revealed a spatial pattern of higher R2 for higher iron levels, particularly in gray matter (Fig. 1). The pattern included basal ganglia structures such as the globus pallidus and putamen, and cortical regions including the precentral, postcentral and cuneus cortex (Fig. 1). Higher lobar and total WMH burden were also associated with higher iron levels (Fig. 2). No negative associations were observed.

Conclusion

This investigation combined ex‐vivo MRI, neuropathology and mass spectrometry in a community‐based older adults and showed that higher iron levels were independently associated with higher R2 in gray matter and higher WMH burden.
Exploring Sex‐Specific Accelerated Hippocampal Atrophy Across AD Stages beyond APOE‐e4 Assessment in Genetic Risk Evaluation
Authors: Evans Tavia E , Vilor‐Tejedor Natalia , Rodrigo Albert , Genius Patricia , Rodríguez‐Fernández Blanca , Anastasi Federica , Navarro Arcadi , Adams Hieab H.H. , Gispert Juan Domingo ,   For the ADNI
Published: January 2025

Background

Current evidence suggests that hippocampal subfields have partially different genetic architecture and may improve the sensitivity of the detection of Alzheimer’s disease (AD). In this study, we investigated whether genetic predisposition to AD contributes to the accelerated rate of hippocampal volume atrophy across sex and AD stages and how this contribution is specifically driven by functional variants located in the APOE gene.

Methods

The study comprised 1,051 participants from ADNI cohort (75.2 yo; 42.3% women), with complete demographic, genetic, and magnetic resonance imaging scans at baseline and every 6 months for a total of 96 months (Controls (amyloid negative), CUN = 363; mild cognitive impairment, MCIN = 474, AD patients, ADN = 214). Hippocampal subfields were extracted using the longitudinal processing method within FreeSurfer (v6.0). Genetic predisposition to AD was assessed through polygenic scoring with and without considering the APOE región. Effects of polygenicity of plasma APOE, functional APOE brain eQTLs and CSF pQTL were also considered. Linear mixed‐effect models with random‐ time slope and intercept for individuals were used to investigate the association between genetic predisposition to AD and hippocampal subfields volumetric trajectories over time. Models were adjusted by age, sex, AD disease status, years of education and total hippocampal volume. Disease and sex status‐specific trajectories dependent on genetics predisposition were assessed by including an interaction term.

Results

Significant hippocampal subfield volume reductions were observed, with more pronounced atrophy in MCI and AD participants [Figure 1A]. High genetic predisposition to AD was associated with accelerated atrophy in various subfields [Figure 1B]. MCI individuals with high genetic predisposition showed more severe atrophy in several subfields, with sex‐related differences observed, particularly in women [Figure 2]. Notably, these effects were non‐significant when excluding APOE variants. Further functional analyses pinpointed CSF pQTLS of the APOE gene and APOE‐e4 carriership status as primary drivers [Figure 3].

Conclusions

Our findings underscore the significance of genetic predisposition, especially functional APOE variants, in understanding AD progression and sex‐specific trajectories. The results reveal varying atrophy patterns across disease stages, offering crucial insights for refining AD detection and tailoring interventions for more effective management.
Failure to replicate detection of grid‐cell like representations in human fMRI
Authors: Kransberg Jonas , Markus Sneve H , Falch Emilie Sogn , Bråthen Anne Cecilie Sjøli , Fjell Anders M , Walhovd Kristine B
Published: January 2025

Background

Grid cells are spatially modulated cells in the entorhinal cortex (EC) that fire in a hexagonally patterned grid which tiles the environment. These cells are assumed important in human spatial navigation. The EC is vulnerable to neurodegenerative processes in both normal aging and Alzheimer’s disease and decline in grid cell function may be a key factor in understanding age‐related navigational decline.

Recent work suggests that conjunctive grid and head direction cells can allow for the detection of grid‐like activity based on movement direction. If moving in alignment with a hexagonal grid, EC activation should be higher than movement not aligned with the grid. The present study attempts replicate findings from previous studies of grid‐like signals detected through fMRI.

Methods

The sample included 64 (40 female, 24 male) adults, ages ranging from 18 to 78 (M = 37.67). Participants were subject to a fMRI grid cell paradigm, tasked to passively navigate through a room and remember the location of objects. The movement directions in the virtual environment were used to find the mean grid orientation for each participant set through a general linear model with the sixfold pattern as a regressor, and this was used as a regressor in a second GLM to calculate the grid magnitude, a measure of the stability of the grid codes.

Results

A one‐sample t‐test showed no significant grid code magnitudes (M = 0.002, SD = 0.091) compared to zero for a sixfold symmetry t(63) = 0.19, p = .85. For age‐related analysis, the sample was divided into a younger and older sample through a median split using the median of 30.5 years. A Two Sample t‐test did not show any difference between the younger (M = 0.021, SD = 0.089) and older (M = ‐0.017, SD = 0.090) groups, t(61.99) = ‐1.68, p = .097. Figure 1 shows the mean grid code magnitudes for both age groups.

Conclusion

Preliminary results suggest no evidence for stable grid‐like representations in the present sample. The present study is reasonably powered relative to the previous study, and possible reasons and limitations hindering identification of grid‐like representations should be discussed and further researched.
The population of high CTLA‐4 expressing with CD56 positive T cell is diminished in Alzheimer’s disease patients
Authors: Chu Cheng‐I , Wu Ching‐Tse , Yu Wang Feng‐ , Yu Yang Hui‐ , Chang Chien‐Chung , Chang Chuang‐Rung
Published: January 2025

Background

Abnormal brain inflammation is an important feature of Alzheimer’s disease (AD). Central nervous system (CNS) inflammation is highly related to immune cell activation. Homeostasis of immune cell activity regulation is crucial for CNS autoimmune response. Our previous study found that the expression of immune checkpoint PD‐L1/PD‐1 on T cells changed along with different stages of AD patients. We assayed the other immune checkpoint molecule, CTLA‐4, and its functional characteristics to characterize the changes of T cell populations of peripheral blood in AD patients.

Method

AD patients (n = 14) and healthy elderly (n = 16) were enrolled. White blood cells collecting from blood were labelled with fluorescent antibodies and assayed by flow cytometry. To characterize changes in specific T‐cell populations and features, we used t‐distributed stochastic neighbor embedding (tSNE). The analysis results of all volunteers were pooled, aggregated, and integrated with different phenotypic and functional characteristics. Distribution patterns were delineated between AD and healthy elderly, differences were compared, and molecular features were identified for further subpopulation analysis.

Result

(A) In the phenotypic and functional characteristics feature distribution of T cells, the subpopulation distribution difference between AD and healthy elderly was related to the expression intensity of NCAM (Neural cell adhesion molecule, CD56). (B) Further distinguishing the T cell population with positive expression of CD56, three subpopulations were found, subpopulation A, B and C. Subpopulation A decreased in AD patients, subpopulation C increased in AD patients, and subpopulation B had no obvious difference. Prominent difference of these three subpopulations was the expression level of CTLA‐4. Subpopulation A was CTLA‐4HighCD56+ T cell subset; subpopulation B was CTLA‐4DimCD56+ T cell subset; subpopulation C was CTLA‐4MediumCD56+ T cell subset.

Conclusion

CD56 (NCAM) positive T cells with high expression of CTLA‐4 decreased in AD patients. CTLA‐4 played important role in T cell priming brake, and competed B7 ligand with CD28 to suppress T cell activation. Decrease of CTLA‐4 expression on CD56+ T cells indirectly promote the immune activation. Our research indicated immune imbalance in peripheral blood of AD patients. Changes of T cell subpopulations may be biomarkers of AD, and maintaining homeostasis of immunity may be potential treatment of AD in future.
APOE3 Christchurch influences amyloid induced tau seeding and spreading via effects on microglia
Authors: Chen Yun , Song Sihui , Parhizkar Samira , Lord Jennifer , Zhu Yiyang , Strickland Michael R , Wang Chanung , Park Jiyu , Tabor G. Travis , Jiang Hong , Li Kevin , Davis Albert A , Yuede Carla M , Colonna Marco , Ulrich Jason D , Holtzman David M.
Published: January 2025

Background

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer’s Disease (AD) caused by a PSEN1‐E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear.

Method

We generated a humanized APOE3ch knock‐in mouse and crossed it to an amyloid‐β (Aβ) plaque‐depositing model. We injected AD‐tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Mouse samples were collected and used for multiple measurements including cholesterol test, WB, ELISA, IF, etc. We also designed and performed in vitro assays to evaluate the phagocytosis, degradation, competitive uptake, exocytosis, etc.

Result

APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque‐associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans in vitro.

Conclusion

APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ‐induced tau seeding and spreading.
Alzheimer’s disease APOE neuropathology‐based score, amyloid, and ptau polygenic scores’ association with amyloid PET positivity
Authors: Hammad Yazan , Deming Yuetiva , Morse Jacob , Grover Ethan , Bendlin Barbara B. , Betthauser Tobey J.
Published: January 2025

Background

APOE is the greatest genetic risk factor for AD, however, other smaller genetic effects are often ignored. In this work, endophenotype‐informed polygenic scores (PGS) that exclude the APOE region were tested along with a separate, previously published, APOE neuropathology‐based score (APOEscore). The APOEscore serves as a more nuanced quantification of APOE genetic risk that considers the effects of the different haplotypes. PGS and APOEscore were compared to amyloid positivity, determined via PET imaging, which is used as a measure for AD risk and progression.

Methods

Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with genetic data and Florbetapir (18F‐AV‐45) amyloid PET summary SUVR (whole cerebellum reference region) values were included in analyses. Amyloid positivity (A+) was defined as SUVR > 1.11. PGS were calculated using the weights from genome‐wide association studies (GWAS) of CSF Aβ42 (amyloid‐PGS) or ptau181 (ptau‐PGS), after excluding the APOE region (±500kb). APOE effects were accounted for using the APOEscore that was calculated following Deming et al (2023).

Results

1094 participants (618 A+) were included in the analyses (Table 1). The APOEscore was significantly associated with A+ after accounting for sex and age at scan (OR = 2.931, P = 6.38e‐45; Table 2). The amyloid‐PGS was also significantly associated with A+ (OR = 0.492, P = 0.026), whereas the ptau‐PGS did not quite reach significance (OR = 3.218, P = 0.054). After adding the APOEscore, the effect of amyloid‐PGS on A+ remained but did not quite reach significance (OR = 0.515, P = 0.072) and ptau‐PGS was not significant (OR = 1.845, P = 0.375).

Conclusion

These results validate the utility of the APOEscore with PET amyloid as well as the potential value of including non‐APOE genes in quantifying the genetic risk for amyloid accumulation and AD. The significant association between amyloid‐PGS and A+, and near significance after adding the APOEscore, demonstrates the existence of additional genetic effects outside of APOE that have an impact on amyloid accumulation. While the ptau‐PGS did not reach significance, possibly due to sample size, the OR (3.218) was greater in magnitude than the amyloid‐PGS (1/OR = 2.033). Future work will explore these relationships in other cohorts and with other PET AD biomarkers.
SCARF2 in the CSF of Asymptomatic subjects With a Parental History of AD and in the Cortex of Autopsy‐Confirmed Alzheimer’s Disease Cases
Authors: Aumont‐Rodrigue Gabriel , Picard Cynthia , Labonté Anne , Poirier Judes ,   PREVENT‐AD research Group
Published: January 2025

Background

Scavenger receptors (SR) are a group of receptors involved in the endocytosis of various ligands, such as modified LDL and soluble β‐amyloid, which connects them to Alzheimer’s disease (AD). SCARF2 (SREC‐II) is part of the SR family, but unlike other scavenger receptors, internalizes a low amount of modified LDL. Its main function revolves around the binding of Aβ (Vo et al. 2023). Other studies found SCARF2 to be a SCARF1 inhibitor (Ishii et al. 2002). This study compares gene expression and protein levels of SCARF2 in post‐mortem brain tissue of AD and control subjects, as well as in the CSF of participants with a family history of AD. The goal is to track the progression of AD using the expression pattern of SCARF2.

Method

SCARF2 CSF protein levels were assessed in the PREVENT‐AD (PRe‐symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease) cohort which is composed of asymptomatic subjects with parental history of AD. SCARF2 has been measured with a primer extension assay using Olink technology. ELISA immunoassay has been used to quantify SCARF2 protein levels in frontal cortex homogenates of 86 brains from the Douglas Bell Canada Brain Bank (DBCBB). mRNA prevalence was measured using Gene Chip Clariom D human microarray. All statistical analyses were performed using JMP pro 17 software.

Result

SCARF2 Protein levels, but not mRNA, are significantly lower in brains with AD (p<0.001). SCARF2 protein display a strong negative association with plaques bound Aβ, despite being a well‐established Aβ receptor (R2 = 0.277, p<0.0001). Interestingly, CSF protein levels correlate positively with AD biomarkers such as total and phosphorylated(181) tau (R2 = 0.235, p<0.0001; R2 = 0.288, p<0.0001) and Aβ to a lesser extent (R2 = 0.045, p = 0.0318).

Conclusion

Our study unveils a distinctive role for SCARF2 in AD pathogenesis. Despite being a known Aβ receptor, SCARF2 exhibits lower cortical protein levels in AD brains, inversely linked to plaques bound Aβ. In contrast, elevated CSF SCARF2 protein levels correlate positively with CSF AD biomarkers in the presymptomatic phase of the disease; suggesting differential response to amyloid and tau deposition. These findings shed light on the intricate interplay of SCARF2 in AD pathophysiology, offering potential avenues for further research.
Mitochondrial Calcium Uniporter Beta in Alzheimer’s Disease
Authors: Kaye Sarah D , Raghav Darpan , Kadam Ashlesha , Elrod John W , Tomar Dhanendra , Jadiya Pooja
Published: January 2025

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by progressive memory loss and cognitive decline. The precise molecular mechanisms underlying AD pathogenesis remain uncertain, underscoring the need for further investigation to identify novel therapeutic targets. We recently demonstrated that mitochondrial calcium (mCa2+) overload significantly contributes to the development of AD, capable of independently driving AD‐like pathology. Modulating mCa2+ dynamics, such as blocking mCa2+ uptake, holds promise in reducing neuronal cell death in AD. However, these approaches challenge bioenergetic processes due to the role mCa2+ plays in metabolic regulation. Therefore, it is essential to identify a regulator that can maintain mCa2+ homeostasis while preserving bioenergetic functions.

Methods

To identify a new molecular regulatory mechanism for reducing mCa2+ overload and preserving bioenergetics in AD, we focused on Mitochondrial Calcium Uniporter Beta (MCUB), a negative regulator of mCa2+ uptake. Initially, we examined MCUB expression in AD patient samples, AD model mice, and AD cell lines. Observing reduced MCUB expression in AD, we used 5xFAD mutant mice with neuronal‐specific MCUB overexpression to assess age‐associated changes in cognitive function, neuropathology, and mitochondrial bioenergetics. A neuroblastoma cell line expressing human amyloid precursor protein with the Swedish mutation (N2a/APPswe) and adenovirus encoded MCUB was examined for alterations in mitochondrial Ca2+ dynamics and functions.

Results

Our findings revealed that expression of MCUB is lost in non‐familial AD samples, AD mouse models, and AD cell lines. MCUB overexpression in 5xFAD mice rescued spatial and fear‐associated memory impairments and alleviated amyloid beta pathology at 9 months of age. Furthermore, MCUB overexpression mitigated mCa2+ overload, preserved crucial mitochondrial bioenergetic functions including oxidative phosphorylation (OXPHOS) and ATP production, and prevented neuronal cell loss.

Conclusions

This study demonstrates for the first time that modulating MCUB holds therapeutic promise in preserving bioenergetics and mitigating neuronal damage and AD progression. These findings have the potential to significantly advance our understanding of AD pathogenesis and pave the way for effective treatments for AD.
Circular RNA DENND1B contributes to cognitive impairment in Alzheimer’s disease by enhancing blood‐brain barrier permeability via transcellular regulatory axis
Authors: Cheng Zhi , Zhang Yuling , Wang Feng
Published: January 2025

Background

Circular RNA represents a distinctive form of noncoding RNA resulting from back‐splicing of exons and introns in mRNA. CircRNA has been shown play important roles in neurological diseases, such as Alzheimer’s disease (AD). Some recent studies also have demonstrated circRNA is enriched in the mammal brain and differentially altered during AD. However, little is known the characteristics and functions of key circRNAs directly linked to cognitive of AD. Herein, we identified circDENND1B as a novel circRNA implicated in AD and elucidated its role in cognitive impairment.

Methods

We generated rRNA and linear RNA depleted, and RNA sequencing data from 12‐month‐old 5 × FAD mice hippocampus. The circDENND1B knockdown nanoparticles were applied in 10‐month‐old 5 × FAD mice. The novel object recognition and Morris water maze tests were used to observe cognitive function in these 12‐month‐old mice, and conducting electrophysiological experiments, Golgi‐Cox staining, and measuring blood‐brain barrier permeability improvement also performed in the 5 × FAD mice after circDENND1B knockdown. The fluorescence staining, RNA in situ hybridization, RNA antisense purification, RNA pull‐down, RT‐qPCR, Western blot were quantify the functions of circDENND1B in mice brain and vitro human BBB model.

Results

CircDENND1B, a circRNA enriched in hippocampal neurons, was significantly up‐regulated in AD mice and patients. Knockdown of circDENND1B markedly improved cognitive dysfunctions associated with AD. Additionally we revealed that miR‐17‐5p served as a crucial downstream mediator of circDENND1B‐regulated Blood‐brain barrier (BBB) permeability. Notably, key targets of miR‐17‐5p included lncKCNQ1OT1/VegfA, which involved in the regulation of BBB as well as learning and memory. Overexpression of miR‐17‐5p altered circDENND1B and lncKCNQ1OT1 transcellular shuttling, thereby regulating VegfA expression in brain microvascular endothelial cells leading to changes in BBB permeability.

Conclusion

In conclusion, we demonstrated elevated circDENND1B levels in AD patients and provided evidence that the circDENND1B/lncRNA KCNQ1OT1/miR‐17‐5p/VegfA transcellular regulatory axis plays a role in regulating BBB permeability and neuron inflammatory response in both in vivo and in vitro AD models. This identified that circDENND1B/lncRNA KCNQ1OT1/miR‐17‐5p/VegfA transcellular regulatory axis may serve as a novel biomarker for AD, offering new insights for prediction, prognosis, and treatment of AD patients.