bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional characterization of relaxin‐3‐positive neurons in aging and Alzheimer’s disease
Authors: de Avila Camila , Nolz Jennifer , Khatri Divyanshi , Uzum Zerrin , Intorcia Anthony J , Serrano Geidy E , Beach Thomas G. , Gundlach Andrew L , Mastroeni Diego
Published: January 2025

Background

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide and is characterized by clinical symptoms that include deficits in memory and cognition. There is an urgent need to better identify the neural networks that govern cognitive processes in humans and how they are impacted by AD pathology. The brainstem is a critical region that ‘connects’ the forebrain and the spinal cord and contains various nuclei involved in autonomic and complex functions (e.g., locus coeruleus) that are affected during the early stages of AD. In this regard, the brainstem contains the GABAergic nucleus incertus (NI), which has a demonstrated key role in rodents' contextual memory formation by directly inhibiting the hippocampus. Therefore, we mapped the human NI using the neuropeptide relaxin‐3 (RLN3), a neurochemical marker primarily expressed in GABAergic neurons of the NI. In these novel studies, we investigated the transcriptomics of the RLN3‐positive neurons in AD and controls.

Method

Using fresh‐frozen postmortem human tissue provided by the Banner Brain and Body Donation Program, Sun City, Arizona, USA, we isolated RLN3‐positive neurons from the NI of non‐demented controls (N = 6), and subsequently from AD (N = 6) age/sex‐matched subjects. After immunostaining, we will use laser‐capture microdissection to isolate RLN3‐positive neurons, followed by RNA sequencing and computational analysis.

Result

Similarly to rodents, we found that RLN3 positive neurons express relaxin/insulin‐like family peptide receptor 3 (RXFP3), GABA‐related, cholecystokinin, and corticotropin‐releasing factor type 1 receptor mRNA. In addition, RLN3 and phosphorylated tau markers, including the microtubule‐associated protein tau, mRNAs were upregulated while RXFP3 mRNA was downregulated in AD subjects compared to controls. We used RNAscope in situ hybridization as a validation method.

Conclusion

These results suggest that the NI of humans and lower vertebrates share similar neurochemistry. In addition, the NI‐RLN3/RXFP3 system was dysregulated in AD, suggesting RLN3 as a potential biomarker for AD. Further studies investigating RLN3/RXFP3 mRNA changes in pre‐ and early AD are required to understand the time course of its dysregulation.
Structural and functional locus coeruleus‐norepinephrine system metrics are distinctly related to affective and stress‐related reports in the context of AD markers
Authors: Engels Nina , Patsyuk Yuliya , Ashton Nicholas J. , Janelidze Shorena , Blennow Kaj , Hansson Oskar , Zetterberg Henrik , Riphagen Joost M. , Van Egroo Maxime , Jacobs Heidi I.L.
Published: January 2025

Background

The locus coeruleus (LC)‐norepinephrine (NE) system is one of the first systems affected in Alzheimer’s Disease (AD), prior to cortical involvement. LC‐NE system dysregulation has also been associated with neuropsychiatric and stress‐related symptoms, early non‐cognitive signals of AD. This study investigates whether structural and functional LC‐NE system metrics are associated with affective and stress‐related reports among predominantly cognitively healthy adults, and whether these associations are exacerbated by AD fluid biomarkers of tau, neurodegeneration and astrocyte reactivity.

Method

Cross‐sectional data from 116 life‐span study participants (cognitively healthy/MCI: N = 114/2; age range = 30‐87 years; female = 53%; Table 1) who completed affective (DASS–Stress, DASS–Anxiety, HDRS) and stress‐related (MIA–Anxiety, Perceived Stress Scale (PSS), NEO PI‐R–Neuroticism, DASS–Stress) questionnaires. Plasma 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG) and AD‐related markers (ptau217, ptau231, NfL, or GFAP), and 7T LC‐MRI scanning were obtained. MHPG was normalized against NE. LC MRI signal intensity was obtained using an MT‐TFL sequence, standardizing LC signal to the pontine tegmentum (reference), and creating a study‐specific LC template. Bootstrapped linear regression examined associations of affective and stress‐related questionnaires with LC MRI signal intensity alone, or interacted with AD markers. Linear regressions assessed equivalent associations with MHPG instead of LC MRI signal intensity. Analyses were based on complete cases, corrected for age and sex, and FDR‐adjusted.

Results

Lower LC MRI signal intensity related to higher DASS–Anxiety scores (pFDR = 0.008; Table 2/Fig. 1A). This relationship was more pronounced in individuals with higher ptau217 (pFDR = 0.002), ptau231 (p = 0.028), NfL (pFDR = 0.002) or GFAP (pFDR = 0.002; Table 2/Fig. 1B‐E). Higher MHPG was linked to higher PSS scores in individuals with elevated GFAP, while higher MHPG was associated with lower PSS in the context of lower GFAP (p = 0.029, Table 2/Fig. 1F).

Conclusion

This work suggests that structural and functional LC‐NE system metrics are distinctly related to stress and affective functioning. Lower structural LC integrity is associated with worse anxiety, particularly at elevated AD pathology levels. Among individuals with elevated astrocyte reactivity, higher LC metabolism is no longer protective against stress. These findings are consistent with previous autopsy and metabolite studies, and support the importance of the LC‐NE system in neuropsychiatric symptoms as the earliest AD manifestations.
Indigenous Peruvians’ knowledge and awareness of dementia, risk and protective factors, and barriers to risk reduction
Authors: Caipa Maritza Pintado , Booi Laura , Farina Francesca R
Published: January 2025

Background

Emerging evidence suggests that Indigenous peoples may have disproportionately high rates of Alzheimer’s disease and related dementias (ADRD). However, there is a lack of data on Indigenous peoples’ knowledge and awareness of ADRD, especially in low‐ and middle‐income countries. Our aim was to investigate knowledge and awareness of ADRD, risk and protective factors, and barriers towards risk reduction in a remote Peruvian adult population.

Method

Adults living in Amazonian, Andean highland, coastal Peruvian regions completed a pen and paper survey about dementia knowledge, risk and protective factors, and barriers to risk reduction. Data were analyzed using descriptive statistics.

Result

Participants were 133 young adults (98 female; 1 non‐binary; mean age = 28.6 ± 6.4 years). Most participants identified as mixed race (i.e., Indigenous and European ancestry; 62.4%) or Quechua (28.6%). Six percent of the sample identified as White. Most participants lived in rural areas (60.2%). One third of participants were unemployed and half rated their socioeconomic status as low. Nearly one fifth of participants (18‐20%) reported not having electricity or a bathroom in their house, and one third (37.6%) did not have running water. Most participants (71.4%) said violence was a problem in their community. Half of participants (52.6%) said they were fearful about developing dementia. On average, participants recognized 5 of the 12 modifiable risk factors from the 2020 Lancet Commission on Dementia Prevention. The most endorsed factors were head injury (60.2%), social isolation (52.6%), and depression (51.1%). The least recognized factors were diet (9%) and air pollution (18%). The biggest barriers to risk reduction were lack of knowledge (63.9%), lack of money (55.6%), and pre‐existing health problems (49.6%).

Conclusion

Peruvian adults living in remote areas have moderate knowledge dementia risk factors but identify multiple barriers to risk reduction. Findings are among the first to explore dementia knowledge in Amazonian, Andean highland and coastal regions of Peru.
Systematic Review and Meta‐Analysis of the Efficacy of BIIB080 (IONIS‐MAPTRx): The First Gene Therapy for Patients with Alzheimer’s Disease
Authors: Mahmoud Abdalla Ahmed , Ramadan Hamza Mohamed
Published: January 2025

Objective

This systematic review aims to evaluate the impact of tau synthesis reduction on tau biomarkers in patients receiving BIIB080 (IONIS‐MAPTRx) treatment for mild Alzheimer’s disease (AD).

Background

Alzheimer’s disease is characterized by the accumulation of tau protein aggregates in the brain, leading to cognitive decline. Tau pathology, including abnormal phosphorylation and aggregation of tau protein, is closely associated with disease progression. BIIB080 is a novel therapeutic agent designed to target tau synthesis, potentially modifying the course of AD by reducing tau pathology.

Methods

A comprehensive search was conducted across major scientific databases: Scopus, ScienceDirect, ClinicalKey, Cochrane, Clarivate, and PubMed for relevant studies and clinical trials. Inclusion criteria encompassed studies evaluating the effect of BIIB080 on tau biomarkers in patients with mild AD. Forty‐nine studies and two clinical trials were identified for screening.

Results

Out of 102 evaluated participants, 46 with moderate AD were included; their mean age was 65.8 years (SD 5.70). BIIB080 demonstrated good tolerability and induced a dose‐dependent decrease in cerebrospinal fluid (CSF) total tau (t‐tau) and phosphorylated tau 181 (p‐tau181) throughout the mild AD stage. Significant reductions in t‐tau (56%; 95% CI, 50% to 62%) and p‐tau181 (51%; 95% CI, 38% to 63%) in CSF were observed in the two higher‐dose cohorts. This decline continued or was maintained during the long‐term extension phase with quarterly dosage. At week 25, tau positron emission tomography (PET) imaging showed less buildup in 13 subjects compared to placebo. By week 100, reductions from baseline were evident across all assessed regions (n = 12), with the most pronounced reductions observed in the temporal composite (‐0.71 standardized uptake value ratio; 95% CI, ‐1.40 to ‐0.02). A moderate correlation was noted between model‐predicted cumulative CSF drug exposure and tau PET change.

Conclusion

BIIB080, as a tau synthesis reduction drug, demonstrated promising results on tau biomarkers in individuals with moderate AD, along with favorable tolerability. These findings suggest its potential as a therapeutic intervention to target tau pathology and alter the course of AD. Further research is warranted to establish its clinical effectiveness and long‐term safety profile.
Effects of APOE ε4 on novel blood biomarkers of amyloid‐β pathology and inflammation in midlife adults at risk of Alzheimer’s disease
Authors: Bechke Emily , Park Kyoung Shin , Wideman Laurie , Anderson Travis , Goldenstein Samantha J , Slutsky‐Ganesh Alexis B , Armstrong Brittany D , Etnier Jennifer L
Published: January 2025

Background

In APOE ε4 allele carriers at increased risk for Alzheimer’s disease (AD), midlife (age 40‐65 years) is a critical window when amyloid‐β (Aβ) pathology could progress without overt cognitive decline, but AD‐related biomarkers may be present. Blood measures of phosphorylated tau at Thr217 (p‐tau217) indicate aggregated Aβ pathology in the preclinical stage of AD, whereas ApoE protein levels are associated with the clearance of Aβ. C‐reactive protein (CRP) and serum amyloid A (SAA) are acute phase reactants within the inflammatory pathway, but SAA is also related to ApoE levels and Aβ clearance. This study aims to investigate the cross‐sectional effects of APOE ε4 carriage on blood biomarkers of Aβ pathology (p‐tau217 and ApoE) and inflammation (CRP and SAA) in midlife adults at risk of AD.

Method

Baseline data from an ongoing clinical trial (NIH R01AG058919) were analyzed. Participants (n = 75, age = 57±6.15 years) were cognitively normal, middle‐aged adults with a family history of AD. APOE ε4 carriage was determined from passive drool saliva samples. Fasting samples were collected, centrifuged at 2,000 g for 12 min at 4°C and 0.5 ml of serum/plasma was aliquoted into tubes and frozen at 80°C. All biomarkers were measured using electro‐chemiluminescence immunoassays. After winsorizing at z = 2‐2.5, analyses of covariance compared the biomarkers between APOE ε4 carriers (n = 31) and non‐carriers (n = 44) with age, sex, education, and BMI as covariates.

Result

After covariate adjustments, APOE ε4 carriage was associated with all serum/plasma biomarkers. APOE ε4 carriers had higher p‐tau217 (p = 0.05), lower ApoE (p<0.0001), lower CRP (p<0.05), and lower SAA (p<0.05) compared with non‐carriers.

Conclusion

Blood biomarkers of greater Aβ aggregation and less systemic inflammation were found in cognitively normal, APOE ε4 carriers in midlife. This data suggests that even in midlife adults at risk for AD due to APOE ε4 carriage, blood biomarkers provide crucial information about early changes in Aβ pathology and provide a potential conduit for maximizing brain health by pinpointing optimal timing for interventions that mitigate risk of progression to AD. The content of this abstract is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
DNA damage and senescence in the aging and Alzheimer’s disease cortex are not uniformly distributed
Authors: Herrup Karl , Gutta Gnanesh , Mehta Jay , Kingston Rody , Ma Fulin
Published: January 2025

Background

Alzheimer’s disease (AD) has a typical age of onset exceeding 65 years. The age‐dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. This connection between aging and genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells increase with ages, and their senescence‐associated secreted products likely contribute to age‐related illnesses.

Method

Immunocytochemistry was performed on 12 µm sections of brain tissue from prefrontal cortex (BA9). We tracked DNA damage with 53BP1 or 𝛾‐H2AX and cellular senescence with p16 or p27 immunostaining. Embryonic mouse cortical neurons were cultured for 14 days in vitro before exposure to etoposide to induce DNA damage. Cell counts and labeling intensity were measured using QuPath.

Result

DNA damage was significantly increased in the BA9 region of the AD cortex compared to the unaffected controls (UC). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell‐by‐cell basis, we found that the intensity of the two markers was tightly linked in the AD, but not the UC brain. To test whether DNA damage was a causal factor in the emergence of senescence, we used etoposide treatment to damage the DNA of cultured mouse primary neurons but found no change in the expression of senescence‐associated markers.

Conclusion

Our work suggests that DNA damage and cellular senescence are increased in the AD brain, and increasingly coupled. We propose that in vivo the relationship between the two age‐related processes is more complex than previously thought.
Phase 2 PIONEER Trial of Oral T3D‐959 for the Treatment of Patients Diagnosed with Mild‐to‐Moderate Alzheimer’s Disease: New Results in a Modified Intent‐to‐Treat Population
Authors: Stanek Jessica , Swearingen Blake , Strittmatter Warren , Chamberlain Stan , Gabriel Hoda , Coutlee Christopher , Lineberry Charles , Didsbury John
Published: January 2025

Background

PIONEER was a Phase 2 randomized, placebo‐controlled, multi‐center trial evaluating efficacy and safety of the dual PPARδ/γ agonist T3D‐959 in patients with mild‐to‐moderate Alzheimer’s disease (AD).

Method

Enrolled patients (N = 250) had mild‐to‐moderate AD per NIA‐AA criteria. No AD biomarker enrollment criteria were defined. Study data revealed a cluster of sites with common data irregularities, including (1) no drug in plasma at end of treatment in patients assigned to drug (2) baseline p‐tau217 ratio inconsistent with biological AD, and (3) placebo response outside of historic norms for mild‐to‐moderate AD. These sites were excluded to form an mITT study population. Primary endpoints were ADAS‐Cog11 and ADCS‐CGIC. Secondary endpoints were plasma Aβ42/40 ratio and Digit Symbol Coding Test. Proteomic biomarkers including p‐tau217 and neurogranin were exploratory endpoints. Efficacy was evaluated as least‐squares mean changes from baseline to week 24.

Result

141 patients were included in the mITT population randomized to placebo (n = 32) or T3D‐959 (15mg, n = 38; 30mg, n = 39; or 45mg, n = 32). Both primary endpoints were met, approaching statistical significance, ADAS‐Cog11 in the 30mg group (0.73 vs 2.70; p = 0.073) and ADCS‐CGIC in the 15mg group (0.39 vs 0.86; P = 0.060), consistent with slowing of clinical decline. Secondary endpoint plasma Aβ42/40 ratio was met, with significant improvement in the T3D‐959 30mg and 45mg groups vs placebo (30mg: P = 0.011; 45mg: P = 0.033), with a similar magnitude of effect as lecanemab at 6‐months. T3D‐959 30mg and 45mg groups significantly improved on neurodegeneration biomarker neurogranin (T3D‐959 30mg: P = 0.035; T3D‐959 45mg: P = 0.051) and changed proteomic markers suggesting pluripotent effects on dysregulated AD pathways including inflammation, oxidative stress and metabolism. T3D‐959 was safe and well‐tolerated.

Conclusion

Co‐primary endpoints ADAS‐Cog11 and ADCS‐CGIC were met per protocol, approaching statistical significance at week 24. T3D‐959 demonstrated significant improvement over placebo in plasma Aβ42/40 ratio and in plasma neurogranin. Biomarkers of all three AD diagnostic criteria, Amyloid/Tau/Neurodegeneration, were improved, as well as markers of inflammation, insulin resistance and dysfunctional lipid metabolism. Results demonstrate a strong safety profile and evidence of slowing of clinical and biological decline.
Lower dorsal raphe nucleus activity reflects resilience to Aß‐related cognitive decline in preclinical Alzheimer’s disease individuals with mild depressive symptoms
Authors: Lawn Timothy , Prokopiou Prokopis C. , Heinrich Lukas , Nancy Donovan , Papp Kathryn V , Rentz Dorene M , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L.
Published: January 2025

Background

The neuromodulatory subcortical systems are among the earliest brain regions to accrue pathology in Alzheimer’s disease (AD), contributing to cognitive and non‐cognitive symptoms. Monoaminergic nuclei, such as the dorsal raphe (DRn), modulate mood, cognition, and arousal. Their pathological perturbation is proposed to induce initial hyperexcitability followed by decreased activity, which may therefore be associated with the neuropsychiatric and cognitive symptoms of preclinical AD. Here, we associated novelty‐related activity of the DRn to longitudinal neuropsychiatric and cognitive changes in preclinical AD.

Method

Ninety‐two older adults from the Harvard Aging Brain Study (mean age = 69.4±10, 51 females, Table 1) underwent baseline functional MRI where they were presented unfamiliar and familiar face‐name pairs organized within blocks of novelty and repetition to extract DRn novelty‐related activity. They additionally completed 11C PiB‐PET scanning to assess neocortical Aβ (cut‐off: 1.324 DVR, PVC) as well as annual neuropsychological testing (mean = 5.21±1.91 years). Robust linear regressions tested cross‐sectional associations, and robust linear mixed effects models assessed longitudinal associations, of DRn activity with cognitive decline or increases in depressive symptoms, in interactions with PiB (adjusted for age, sex, and years of education).

Result

DRn and PACC5 were not associated at baseline nor in interaction with PiB (p<0.05). Longitudinally, lower DRn activity was associated with steeper cognitive decline at elevated PiB (Figure 1A,
B = 0.092, t(374) = 2.65, p = 0.008). This was particularly driven by the category fluency and logical memory components of PACC5 (Figure 1B). Conversely, higher DRn activity was associated with worsening of depressive symptomatology at high PiB (Figure 2A, B = 0.42, t(373) = 2.7, p = 0.007). To reconcile these opposing findings, we related both slopes: in preclinical AD with increasing depressive symptoms, individuals with higher DRn activity exhibited steeper cognitive decline, compared to those with lower DRn activity (N = 92, B = ‐0.48, t(81) = ‐5.43, p = 0.000).

Conclusion

These findings indicate that lower DRn activity may reflect resilience to cognitive decline in preclinical AD individuals with worsening depressive symptoms. However, high DRn activity in those with worsening depressive symptomatology signifies cognitive deterioration. Future work including serial imaging is required to model the temporal evolution of serotonergic neuromodulation and its relation to disease progression.
The monoclonal antibody 17E1 selectively labels GFAP in 5xFAD mice
Authors: Norris Christopher M. , Kraner Susan D
Published: January 2025

Background

Our lab recently developed 2 mouse monoclonal antibodies that preferentially react with “distressed astrocytes”. One monoclonal, 26A6, was found to react preferentially with a form of the Ca2+/calmodulin‐dependent protein phosphatase, calcineurin (CN), that has been cleaved by calpain, to generate a 48 kDa CN fragment (∆CN). We recently published a characterization of this antibody. Surprisingly, the second antibody (17E1), generated to the same antigen used to create 26A6, preferentially binds to GFAP and is present at elevated levels in the 5xFAD mouse strain.

Method

A peptide encompassing the calpain sensitive region of the CN carboxyl terminus was used for mouse monoclonal antibody generation.

Result

We identified 2 monoclonal antibodies: 26A6 and 17E1. The 26A6 antibody binds to a recombinant CN fragment (48 kDa) that is generated by calpain‐mediated proteolysis. We’ve shown that this antibody selectively labels subsets of reactive astrocytes in human brain in conjunction with Alzheimer’s and cerebrovascular pathology, but provides very little labeling in healthy control brain tissue. The 17E1 antibody also labels a 48 kDa protein, but does not label recombinant CN, nor does it label calpain generated CN fragments. Western blot analyses found that the 17E1 and 26A6 antibodies exhibit differential labeling of a 48 kDa protein found in 5xFAD mice. Specifically, 26A6 showed no labeling while 17E1 exhibited highly selective labeling. The 48 kDa band was also detected with a commonly used commercial CN antibody from EMD Millipore (1492) that labels full length CN and multiple C terminus truncation products of CN. To our surprise, immunoprecipitation experiments followed by Western and mass spectroscopy showed that the 48 kDa fragment bound by both 17E1 and 1492 was actually GFAP. Both the 17E1 and 1492 Abs label recombinant GFAP, but 26A6 did not. 26A6 also exhibited no substantial labeling in 5xFAD brain tissue.

Conclusion

Both 26A6 and 17E1 preferentially interact with “distressed astrocytes”. However, 26A6 labels proteolyzed CN, while 17E1 labels GFAP. The results emphasize the importance of using the correct antibodies to evaluate the role of CN in neurodegenerative disease. Further characterization of 17E1 in human brain tissue and rodent models of disease is underway.
Expo‐AD: An Innovative Alzheimer’s Disease and Related Dementias (ADRD) Research Infrastructure for Secure Data Integration and Exposome Linkage
Authors: Cheng Yixuan , Lyons David , Thursday Nyla , DeWitt Amanda , Bendlin Barbara B. , Kind Amy J.H.
Published: January 2025

Background

Research is needed to understand the impact of the exposome on ADRD, and development of a secure research infrastructure that facilitates linkage of exposome metrics to biological outcomes is critical. Such linkages are challenging because they often require working with protected health information (PHI) covered under the Health Insurance Portability and Accountability Act (HIPAA). In response, we have developed a robust administrative, legal, and cybersecurity infrastructure at the University of Wisconsin (UW) to establish a novel, PHI‐capable, multi‐site service for exposome data linkage for the ADRD research community: “Expo‐AD”.

Method

Expo‐AD is a scalable, cloud‐based environment created and maintained by UW. Data sharing agreements with 22 academic institutions and a specially designed and carefully curated cybersecurity platform provide a secure, PHI‐compliant computing environment.

Expo‐AD utilizes cloud‐based virtual machines (VMs) to ensure isolation of sensitive PHI, maintaining HIPAA compliance and preventing unauthorized access. Data transfer leverages Globus, a research cyberinfrastructure used to reliably and securely share data across institutions. VMs provide a scalable resource which is crucial for managing large datasets and adjusting computational power as needed in exposome research. They also provide disaster recovery capabilities which ensure minimal disruption and safeguard data over time. Access is controlled through both technical and procedural methods and overseen by an external advisory committee

Results

Expo‐AD is currently storing personal identifiers and neuropathology data of 10,875 brain donors acquired from 22 participating brain banks and the National Alzheimer’s Coordinating Center. Residential addresses are geocoded and linked to the Area Deprivation Index to characterize the exposome. Curated data will be released through Globus after each data freeze to requesting researchers. Life course residential history construction for brain donor cases is ongoing.

Conclusion

Expo‐AD is one of the largest multi‐site infrastructures designed specifically to enhance life course exposome intake and linkage to biological ADRD data. Its design facilitates future broad scale sharing of deidentified exposome metrics to non‐PHI capable research resources. Expo‐AD holds the promise of expanding exposome data access across the ADRD field, bringing benefits to the research community and catalyzing collaborative and reproducible exposome research.
Alterations in protein conformation assessed by FTIR in EVs from an AD mimicking model
Authors: Vaz Margarida , Martins Tânia Soares , da Cruz e Silva Odete , Nunes Alexandra , Henriques Ana Gabriela
Published: January 2025

Background

Aβ peptide is a central player in Alzheimer’s disease (AD) pathogenesis, which once generated rapidly tends to aggregate, from oligomers to fibrils and finally deposits into senile plaques, one of the disease hallmarks.

Extracellular vesicles (EVs) are secreted by all cell types and recognized as key intercellular communication mediators. In AD, it has been reported that EVs can carry Aβ and may potentially accelerate its aggregation, thus contributing to the seeding of the toxic peptide.

Hence, the main goal of this work was to evaluate if Aβ itself can impact the secondary structure of proteins carried by EVs, using Fourier Transform Infrared (FTIR) spectroscopy.

Method

N2a neuroblastoma cells were treated with 10 µM of Aβ25‐35 peptide for 48 h, after which EVs were isolated from cell culture medium by ultracentrifugation and then characterized by TEM, NTA and WB. For FTIR analysis, cell suspension samples were also prepared and the FTIR spectra was acquired for N2a and N2a‐derived EVs. The data analysis was focused in the 1700‐1500 cm−1 spectral region, which is mostly assigned to protein conformation.

Result

Differences in peak intensities of this spectral region were observed. After Aβ treatment a tendency for an increase in protein aggregation was observed in N2a cells, whereas for EVs a tendency for an increase in protein secondary structures associated with native proteins and oligomers was mostly evident.

Conclusion

These results demonstrated that Aβ can alter the secondary structure of proteins in cells but can also have an impact on the proteins carried by the EVs, affecting protein structures differently. Data reinforces that EVs may be key players in signaling events, involving proteins misfolding, that leads to AD.

This work was funded by Instituto de Biomedicine (iBiMED) under Grant UIDB/04501/2020 and UIDP/04501/2020; MV is supported by the individual PhD grant UI/BD/151354/2021.
Comorbidity of frontotemporal dementia in the bone evidenced as, gender‐specific alterations in the bone microarchitecture, composition, and biomechanical properties observed in MAPT P301S transgenic mouse model
Authors: Suryadevara Vidyani , Valiya Anuradha Kambrath , Krehbiel Connor J , Karra Swathi , Kluppel Michael , Miller Lisa , Monte Willis S
Published: January 2025

Background

Comorbidities are becoming increasingly evident during various Alzheimer’s disease related pathologies. It was found that patients with AD have a higher risk for fractures and falls. Further people who have an incident of falls/fractures have a higher risk for cognitive decline. This study is focused on investigating the alterations in the bone at the structural and functional level in MAPT P301S Tg+ mouse, a preclinical model for frontotemporal dementia.

Methods

The MAPT P301S Tg+ mouse expresses a human 4‐repeat mutant MAPT P301S and was developed to model NFTs secondary to tau aggregations. The femur from N = 20 (equal number of male and female) MAPT P301S Tg+ and C57BL/6J mice at 12‐months age were scanned with µCT to characterize the bone microarchitecture. Further three‐point bending test was performed to assess the biomechanical properties and FTIR was used to determine the material properties of the bone. The expression of genes regulating the bone matrix composition was determined by using RTPCR.

Results

The male MAPT P301S Tg+ mice have a significant decrease in bone geometrical parameters (both cortical and trabecular properties) than the females, as compared to their respective wild type. Interestingly the biomechanical properties were altered in both the males and females, wherein there was an increase in the pre‐yield properties, but decrease in the post‐yield properties. This correlated with the alterations in the material properties of the male bone determined by FTIR and the changes in the genes regulating the extracellular matrix of the bone. Tauopathies lead to loss of bone structure and functionality by altering it’s material composition. Further, we found protein expression

Conclusion

This is a first study indicating the presence of Tau in the bone, which impacts the function and this opens up the prospective of Tau impacting other organs, in addition or concurrently with neurodegenerative diseases.
Alzheimer’s Caregiver Psychoeducation‐Based Psychological Support Telerehabilitation
Authors: Doğan İdil Arasan , Sayar Feride Gökben Hızlı
Published: January 2025

Background

Alzheimer’s Caregiver Psychoeducation‐Based Psychological Support Telerehabilitation; is an online program where the caregiver is educated about the disease and processes and supported therapeutically. This program also aims to promote the psychological well‐being of the caregiver and ensure a positive prognosis.

Method

The study was conducted with 20 caregivers (relatives of patients) who applied to various branches of the Alzheimer Association of Turkey and received services, in a group setting using the Zoom Platform online. The control group consisted of 20 people who attended the association’s routine information meetings. Data collection tools were determined as the Sociodemographic Form, Brief Symptom Scale, Psychological Resilience Scale, and Zarit Caregiver Burden Scale. The study, based on psychoeducation, utilized Cognitive Behavioral Therapy Techniques and Positive Psychology Positive Interventions as therapeutic methods. The program was structured to last 6 weeks, with 12 sessions, twice a week for 90 minutes each. The telerehabilitation applied in a group setting was also supported with individual sessions. One support session per month was organized for 6 months following the completion of the program.

Result

The age distribution of the caregivers was predominantly in the 45‐54 range, with a majority being female. In the experimental group, the scores for psychological symptoms such as Depression, Anxiety, Negative Self, Somatization, and Hostility in the final test were significantly lower compared to the pre‐test. No significant difference was observed in this context in the control group. Zarit Caregiver Burden scores in the experimental group also significantly decreased compared to the pre‐test. Regarding Psychological Resilience scores in the experimental group, the final test results showed an increase in psychological resilience levels.

Conclusion

As a result of the implementation of the telerehabilitation program, caregivers' knowledge and awareness of Alzheimer’s Disease and the care process increased, their psychological resilience was strengthened, and their social support networks expanded. Additionally, the caregivers' burden of care decreased, and symptoms of depression and anxiety were alleviated. These findings emphasize the importance of accessible, applicable, and sustainable telerehabilitation programs.
Passive amylin immunotherapy improves brain function and reduces brain β‐amyloid pathology in APP/PS1 mice
Authors: Kotiya Deepak , Despa Florin
Published: January 2025

Background

Amylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells. Amylin co‐aggregates with brain parenchymal and vascular β‐amyloid in persons with Alzheimer’s dementia. The present pilot study sought to assess the safety and side effects during and after the treatment period of passive amylin immunotherapy in the APP/PS1 mouse model of Alzheimer’s disease.

Method

We have generated a polyclonal anti‐amylin antibody (P2) in rabbits using the N‐terminal of amylin peptide as an immunogen. In this pilot study at 5 months of age, male APP/PS1 mice were randomly assigned into rabbit Ig‐G vehicle‐control and P2 amylin antibody injected group (n = 4/group). Anti‐amylin antibody was injected at a dose of 10 mg/kg of body weight three times a week for six weeks. During the six weeks of amylin immunotherapy, we monitored the mice for visible side effects and immunocomplex disease‐related visible symptoms. Six weeks later, we assessed body weight, blood glucose level, and brain function with the novel object recognition test and performed comparative immunochemical Aβ analyses of hippocampal tissue by using MSD ELISA.

Result

During the period of passive amylin immunotherapy, we did not observe visible symptoms of immunocomplex disease such as rash, urticaria, and malaise along with any sudden drop in body weight. Mice with anti‐amylin antibody injected showed an enhanced trend of recognition memory index (p = 0.1121) along with a lower blood glucose level (p = 0.2602) as compared to those that were injected with rabbit Ig‐G vehicle control. This was associated with decreasing trend of hippocampal levels of Aβ42 (p = 0.7872), Aβ40 (p = 0.4609), Aβ38 (p = 0.4473) in brain sup fraction, and Aβ42 levels (p = 0.6336) in brain pellet fraction measured by MSD ELISA.

Conclusion

Passive amylin immunotherapy in APP/PS1 mice shows that used immunotherapy procedure might be safe for further investigation. Future experiments will be performed in APP/PS1 mouse model in which the mouse amylin gene is replaced by the human amylin gene in the pancreas and is conditionally downregulated by tamoxifen (TMX) injection, intraperitoneally.
Assessing Sleep hours in Participants with Alzheimer’s Disease: Findings from a Phase I MAD Study of IGC‐AD1
Authors: Venegas Margarita , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Gutiérrez Evelyn , Naranjo María Paula , Rao Jagadeesh S , Shahnawaz Saadia , Sánchez Laura Tatiana , Ghazaryan Varduhi , Camargo Fabio , De Jesus William Julio , Hong Elliot , Grimaldi Claudia , Mukunda Ram , Arbelaez Maria Juanita
Published: January 2025

Background

Sleep disturbances are prevalent in Alzheimer’s disease (AD), impacting cognition and quality of life. Trials have also shown increased subjective sleepiness with melatonin doses compared to placebo. High melatonin doses may increase drowsiness, headache, and dizziness, as indicated by a systematic review. A Phase I trial assessed the safety and tolerability of IGC‐AD1, comprising delta‐9 tetrahydrocannabinol (THC) and melatonin. Preliminary findings suggest IGC‐AD1’s safety, with fewer reports of somnolence and dizziness than placebo and no increase in sleep hours. Concerns about melatonin’s sedative properties are addressed through sleep duration assessment.

Method

Data is presented from a Phase 1 Multiple Ascending Dose MAD trial. Caregivers reported participant sleep hours and nocturnal awakenings during daily safety calls. Average sleep hours for each cohort were computed, calculating nightly averages over the 14‐day drug intake period, and then by cohort and treatment group (1 ml for cohort 1, 2 ml for cohort 2, and 3 ml for cohort 3).

Result

Variations in average sleep duration across cohorts were observed. Cohort 1 showed average sleep hours of 8.97 (active) and 8.77 (placebo), while cohort 2 exhibited averages of 8.11 (active) and 9.43 (placebo). Cohort 3 displayed averages of 7.90 (active) and 9.24 (placebo). These findings suggest that the administration of IGC‐AD1 did not meet expectations regarding increased sleep duration, despite containing melatonin.

Conclusion

Although exogenous melatonin is often associated with sedation, the study indicates that IGC‐AD1, containing melatonin, did not lead to the anticipated increase in sleep duration. Further research is needed to understand the underlying mechanisms and optimize therapeutic interventions for sleep disturbances in AD patients.
Spatial proteomic analysis of single amyloid plaques in brain tissue using laser capture microdissection and mass spectrometry
Authors: Jiao yun
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by the accumulation of pathological amyloid protein deposits in the brain. Analyzing the proteomic composition amyloid plaques is essential for advancing biomedical research on Alzheimer’s disease. Laser capture microdissection (LCM) is a technique that enables precise isolation and collection of specific cells or structures from tissue samples. In this study, we developed a method utilizing LCM to capture single amyloid plaques from fresh frozen brain tissue for subsequent profiling using Data‐independent acquisition (DIA) proteomics.

Methods

1: Tissue sections (10‐12 µm) were collected from fresh frozen mouse and human brain tissue and stored at ‐80°C.2: Fresh frozen tissue sections were fixed with 70% alcohol and stained for plaques using X‐34 dye with series dehydration. 3: One plaque and one non‐plaque areas from the same section were captured using LCM (approximately 50 µm diameter). 4: Perform proteomic analysis using a modified LC‐MS/MS method.

Results

1: We developed an optimized method for isolating single amyloid plaques from fresh frozen brain tissue samples. 2: We established a proteomic platform for analyzing single plaque samples at a sub‐microgram level, representing one of the studies with the deepest coverage of single plaque proteome. This platform utilized liquid chromatography and tandem mass spectrometry (LC‐MS/MS) in conjunction with data‐independent acquisition (DIA) proteomic profiling. 3: Due to the low protein level in plaques (∼5ng/plaque), we use 0.2%DCA as a lysis buffer. This buffer can precipitate upon acidification, eliminating the need for a desalting step and minimizing sample loss. Finally, ∼20,000 peptides and ∼5,000 proteins have been identified from ∼5ng initial protein per sample. 4: Notably, we observed several key proteins, such as Abeta, Apoe, Mdk, and Ntn1, consistently appeared in the plaque areas. The enriched protein pathways and protein‐protein interaction modules were also reported.

Conclusion

Our approach provides an optimized platform for conducting in‐depth profiling of LCM‐captured single amyloid plaque in Alzheimer’s disease. This method enables a comprehensive understanding of the proteomic composition of these plaques, contributing to the advancement of Alzheimer’s disease research.
Exploring the Potential Link between Occupational Circadian Rhythm Dysfunction as a Risk Factor for Alzheimer’s Dementia: A novel hypothesis
Authors: El‐Satar Youssef M. Abd , Mohamed Hazim , Ismail Youssef A. , Haitham Youssef , Walid Mohammad
Published: January 2025

Background

The circadian rhythm controls physiological functions across by responding to environmental light cues. fluctuations in this rhythm, such as those induced by irregular work schedules, have been associated with adverse health outcomes, this study aims to assess the increased likelihood risk of developing Alzheimer’s dementia for workers with irregular work schedules.

Methods

Exploring and referencing studies on Alzheimer disease (AD) which had proved an undeniable relationship between dopamine levels with AD onset, this study showcases the relationship of dopamine levels and circadian rhythm and its effect indirectly on Alzheimer as a predisposing factor of AD.

Discussion and Result

Traditionally thought to be the result of neurodegenerative processes, disturbances of the circadian rhythm and sleep‐wake cycle are common symptoms seen in people with AD. However, there may be a possible reciprocal association between circadian abnormalities and the development of AD, suggesting that they may also be risk factors. Circadian rhythms significantly influence dopamine levels throughout the day. This is demonstrated by in vivo studies that show heightened dopamine neuronal firing during the day (7:00‐11:00 h) and at the start of the night (19:00‐23:00 h), with significantly fewer spikes firing in between (11:00‐15:00 h). Furthermore The dopaminergic system has been implicated in the pathogenesis of Alzheimer’s disease and its progression, with patients who suffer from Alzheimer showing low dopamine levels.

Conclusion

Considering the influence of circadian rhythm on dopamine levels, there seems to be a potential interplay between circadian disruptions and neurological health, warranting further investigation into the relationship between circadian rhythm disturbances and the risk of Alzheimer’s dementia onset.
Understanding apathy: behavioral and neural correlates of apathy in neurodegenerative disorders
Authors: Nsor Neke , Brown Casey
Published: January 2025

Background

Apathy, a common neuropsychiatric symptom of neurodegenerative disorders, involves a lack of motivation and reduced interest in positive activities, along with diminished concern for others. Deficits in basic aspects of emotional functioning including difficulties recognizing emotions (emotion recognition) and generating positive or negative emotions (positive and negative emotional reactivity) may underpin neuropsychiatric symptom clusters like apathy. Neural systems (i.e., anterior cingulate cortex, putamen, ventral striatum) that support emotional functioning may also be implicated in apathy. This study examined the behavioral and neural correlates of apathy in dementia.

Method

The study included 434 care‐recipients with a variety of neurodegenerative disorders (n = 275), individuals at risk of transitioning to a neurodegenerative disease (n = 123), and healthy controls (n = 36). Care‐recipients underwent neuropsychological testing, neuroimaging, and clinical interviews to obtain a diagnosis. Caregivers reported on their care recipient’s emotional functioning using a well‐validated questionnaire and apathy was assessed using a clinical interview. We first tested whether the three aspects of emotional functioning (emotion recognition, positive emotional reactivity, and negative emotional reactivity) were associated with apathy using a linear regression. Then we examined the neural correlates of apathy with voxel‐based morphometry.

Result

Greater apathy correlated with diminished positive emotional reactivity and emotion recognition, even after accounting for a number of covariates (i.e., care recipient age, gender, education, race, cognitive impairment, and diagnosis). Apathy was not significantly associated with negative emotional reactivity. At the neural level, increased apathy was associated with reduced grey matter in the ventral striatum and anterior cingulate cortex, while reduced emotion recognition was associated with reduced grey matter in the temporal cortex (Fusiform Gyrus & Temporal Pole). We did not find any significant association between grey matter volume and positive reactivity.

Conclusion

Findings suggest that the abilities to recognize emotions and generate positive emotions are linked to apathy symptoms. Apathy in dementia may be associated with deficient activation in brain regions involved in reward and salience detection, whereas deficits in emotion recognition were linked to regions involved in face perception and social cognition. Further disentangling the associations between emotional functioning and neuropsychiatric symptoms may improve differential diagnosis and promote more targeted interventions.
Acute cerebrovascular injury drives chronic reactive heterogeneity of microglia in a mouse model of mixed etiology dementia
Authors: Dimas Sophia H , Roberts Jill , Goulding Danielle S. , Saito Kai , Cryer Carlie , Wendell Ben , Whitnel‐Smith Laura , Morganti Josh M.
Published: January 2025

Background

Vascular contributions to cognitive impairment and dementia (VCID) results from cerebrovascular injuries, significantly contributing to age‐related cognitive decline, and coexists with Alzheimer’s disease (AD) in excess of 70% of AD patients. These co‐occurring neuropathological subtypes are referred to as mixed‐etiology dementia (MED). Despite the prevalence of MED little is known regarding the neuroinflammatory responses of microglia in the context of vascular injury in tissues already containing AD‐related cerebral amyloidosis. In order to begin to understand the susceptibility of microglia in this MED environment we generated a mouse model of MED combining transient stroke in the 5xFAD mouse model of cerebral amyloidosis

Method

Male 5xFAD mice received sham or tandem CCA/MCA unilateral occlusion surgery to induce transient cerebral hypoperfusion model of MED. Post‐surgical intervals spanning sub‐acute (7 days) and chronic (28 days) were examined using histological techniques in tandem with single cell RNA sequencing and spatial transcriptomics.

Result

MED drives progressive cerebral amyloid angiopathy (CAA) accumulation as a function time resulting in a shift of amyloid plaque load from parenchymal domains to significantly higher vascular loads at 28 days. Microglial reactivity is markedly changed due to MED with disruptions in markers associated with homeostatic‐ like reactivity (e.g. P2ry12) towards accumulation of disease‐associated reactivity (e.g. Clec7a). Similarly, we demonstrate that MED drives differential accumulation of vascular injury‐reactive subsets of microglia at both single cell and spatial transcriptomic levels beyond the DAM signatures present in the sham mice and varying as a function of post‐injury interval

Conclusion

MED drives chronic microglial heterogeneity beyond classic DAM signatures, highlighting potential new mechanistic and targetable routes underlying MED neuropathological sequelae