@article {pmid41436393,
year = {2025},
author = {Carare, ROO},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102608},
doi = {10.1002/alz70855_102608},
pmid = {41436393},
issn = {1552-5279},
mesh = {Humans ; Male ; Aged ; Female ; *Alzheimer Disease/pathology/metabolism ; Aged, 80 and over ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; Middle Aged ; *Brain/pathology/metabolism/blood supply ; Receptors, Muscarinic/metabolism ; *Receptors, Adrenergic/metabolism ; Adult ; },
abstract = {BACKGROUND: Sporadic cerebral amyloid angiopathy (CAA) occurs as a result of a failure of Intramural Periarterial Drainage (IPAD) of amyloid-beta (Aβ) along the walls of capillaries and arteries. The motive force for IPAD is provided by the spontaneous contractions of cerebrovascular smooth muscle cells (CVSMC that receive adrenergic and cholinergic innervation from Locus Coeruleus and Nucleus Basalis of Meynert, compromised very early in Alzheimer's disease (AD). Here we tested the hypothesis that adrenergic and cholinergic receptors are downregulated in parenchymal and leptomeningeal arteries with CAA and AD.

METHOD: Sections of postmortem brains from young, old and CAA-AD cases from the Newcastle and Edinburgh Brain Banks UK were used for immunohistochemistry for muscarinic (M1, M2, M3), nicotinic (α7 nicotinic acetylcholine receptor) and adrenergic (α1b/2a/2b) receptors. The percentage area immunostained for each receptor was imaged and analysed (T-test).

RESULT: Cholinergic receptors: There was a significant decrease in the expression of α7 nicotinic acetylcholine receptors in the parenchymal vessels of old vs young and a significant decrease of α7 nicotinic acetylcholine receptors in the leptomeningeal vessels of CAA vs old. There were no changes in the expression of M1, M2 between the different groups and M3 was not present on blood vessels. Adrenergic receptors: There was a significant decrease in the expression of parenchymal α1b adrenergic receptors in old vs young and a significant decrease in the expression of leptomeningeal α2a and α2b adrenergic receptors in leptomeningeal vessels of CAA vs old.

CONCLUSION: As IPAD is dependent on the integrity of the vascular smooth muscle cells, to maintain the integrity of IPAD with ageing, future therapeutic interventions could focus on agonists of α7 nicotinic acetylcholine and α adrenergic receptors.},
}

Humans
Male
Aged
Female
*Alzheimer Disease/pathology/metabolism
Aged, 80 and over
*Cerebral Amyloid Angiopathy/pathology/metabolism
alpha7 Nicotinic Acetylcholine Receptor/metabolism
Middle Aged
*Brain/pathology/metabolism/blood supply
Receptors, Muscarinic/metabolism
*Receptors, Adrenergic/metabolism
Adult

@article {pmid41436387,
year = {2025},
author = {Fajar, R and Putri, SV and Prihantini, P},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102583},
doi = {10.1002/alz70855_102583},
pmid = {41436387},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnostic imaging/psychology ; Male ; Female ; DNA Methylation ; Aged ; *Aging/genetics ; *Stress, Psychological/genetics ; Disease Progression ; Epigenesis, Genetic ; *Transgender Persons/psychology ; Middle Aged ; },
abstract = {BACKGROUND: The intersection of minority stress, epigenetic aging, and Alzheimer's disease (AD) progression is a critical yet underexplored research area, particularly among transgender individuals undergoing gender-affirming hormone therapy (GAHT). Minority stress, defined as chronic stigma and discrimination, is hypothesized to accelerate biological aging and exacerbate neurodegeneration. This study applies an AI-driven multi-modal approach to explore the relationships between minority stress, epigenetic aging, and AD progression.

METHOD: This study integrated publicly available datasets to investigate the research objectives. DNA methylation data specific to Alzheimer's disease patients (n = 161) were sourced from the Gene Expression Omnibus (GSE153712) to identify stress-sensitive CpG sites linked to epigenetic aging. Neuroimaging data were obtained from the Open Access Series of Imaging Studies (OASIS-3, n = 598), focusing on hippocampal atrophy and cortical thinning. Socio-demographic and clinical data from the UK Biobank (n = 2,230) were analyzed to capture mental health metrics, socio-economic factors, and proxies for minority stress. Due to the lack of transgender-specific data, GAHT exposure and minority stress variables were modeled using synthetic augmentation techniques validated with independent cohorts from the National Alzheimer's Coordinating Center (NACC, n = 200). Data harmonization was achieved using a Transformer-based Variational Autoencoder, while epigenetic marker discovery and neurodegeneration modeling utilized ensemble Random Forests and Temporal Graph Convolutional Networks (T-GCN). External validation was performed using cohorts from NACC and OASIS.

RESULT: The T-GCN model showed strong predictive performance (AUC: 0.86, 95% CI: 0.81-0.89; F1-score: 78.4%). Minority stress was associated with an average epigenetic age acceleration of 6.2 years (95% CI: 5.4-7.0), with significant CpG methylation changes in FKBP5 and NR3C1 genes (p <0.001). Accelerated epigenetic aging correlated with reduced hippocampal volume (β=-0.30, p <0.001) and increased amyloid-β deposition (p = 0.004). Social support mitigated epigenetic aging by 21% (95% CI: 15-27%). Validation confirmed the consistency of these findings across cohorts.

CONCLUSION: This study presents a novel AI-driven framework for understanding minority stress-induced epigenetic aging and its impact on AD progression. By using advanced computational techniques, it addresses critical gaps in inclusive AD research and contributes to precision healthcare.},
}

Humans
*Alzheimer Disease/genetics/pathology/diagnostic imaging/psychology
Male
Female
DNA Methylation
Aged
*Aging/genetics
*Stress, Psychological/genetics
Disease Progression
Epigenesis, Genetic
*Transgender Persons/psychology
Middle Aged

@article {pmid41436383,
year = {2025},
author = {Zhang, X and Zhong, S and Zhao, S and Jia, S and Yan, Y and Chen, Y and Zhang, B},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101964},
doi = {10.1002/alz70855_101964},
pmid = {41436383},
issn = {1552-5279},
mesh = {Animals ; *tau Proteins/metabolism ; Humans ; Mice ; *Alzheimer Disease/pathology/metabolism ; *Brain/pathology/metabolism ; HEK293 Cells ; Neurofibrillary Tangles/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Protein Phosphatase 2/metabolism ; Phosphorylation ; Microglia/metabolism ; Cysteine Endopeptidases ; },
abstract = {BACKGROUND: The pathogenesis of Alzheimer's Disease (AD) remains unknown, which is multifactorial. Neurofibrillary tangles (NFTs) is one of the main pathological changes. Chronic cerebral hypoperfusion (CCH) precedes tau pathology by years and may accelerate its progression. However, the underlying mechanisms remain elusive. Therefore, in the current study, we intended to investigate the effects of CCH on tau propagation.

METHOD: Tau-HEK293 cells, stably expressing tau microtubule-binding repeat domain with yellow fluorescent protein, were transduced with tau PFFs to assess tau aggregation under oxygen-glucose deprivation (OGD). Tau PFFs were injected into the brains of 2- to 3-month-old PS19 mice, and unilateral common carotid artery occlusion (UCCAO) was performed to examine the effect of CCH on tau pathology. Western blotting and immunofluorescence staining were used to analyze tau pathology, AEP, I2 [PP2A], BBB-associated proteins, and the activation of microglia in the brain.

RESULT: We found increased levels of tau aggregates, aspartate endopeptidase (AEP), and I2 [PP2A] in OGD treated tau-HEK293 cells. CCH promoted the propagation of tau pathology in PS19 mice by enhancing the phosphorylation of insoluble tau. Notably, the levels of AEP and I2 [PP2A] were increased in the brains of tau PFF-injected PS19 mice treated with CCH. Additionaly, AEP was found translocate from the lysosome to cytoplasma, and I2 [PP2A] translocated from the nucleus to cytoplasma. Moreover, CCH also affected the levels of tight junction proteins, the activation of microglia, and the gene expression profiles in tau PFF-injected PS19 mice.

CONCLUSION: These data suggests the involvement of AEP-I2 [PP2A] in enhanced hyperphosphorylation and propagation of tau pathology associated with CCH.},
}

Animals
*tau Proteins/metabolism
Humans
Mice
*Alzheimer Disease/pathology/metabolism
*Brain/pathology/metabolism
HEK293 Cells
Neurofibrillary Tangles/pathology/metabolism
Mice, Transgenic
Disease Models, Animal
Protein Phosphatase 2/metabolism
Phosphorylation
Microglia/metabolism
Cysteine Endopeptidases

@article {pmid41436381,
year = {2025},
author = {Mook-Jung, I},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102546},
doi = {10.1002/alz70855_102546},
pmid = {41436381},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Magnetic Resonance Imaging ; Republic of Korea ; Biomarkers/blood ; Positron-Emission Tomography ; *Registries ; Brain/diagnostic imaging ; Databases, Factual ; },
abstract = {BACKGROUND: Numerous studies on Alzheimer's disease (AD) are currently underway, and Korea possesses a wealth of high-quality clinical data and resources on AD. However, the lack of thorough standardization has made these resources difficult to utilize effectively. To address this, the Trial Ready Registry (TRR) and K-Dementia platform were established to identify potential therapeutic targets and biomarkers for AD. These initiatives aim to advance the AD research field in Korea by standardizing and integrating dementia-related datasets.

METHOD: To collect human-derived materials, we developed the Minimum Common Dataset (MCD), which includes clinical evaluations, cognitive assessments, magnetic resonance imaging (MRI), Florbetaben (FBB)-PET, Flutemetamol (FMM)-PET, and blood tests. Dementia data from both prospective and retrospective cohorts were collected using a standardized model based on MCD and SNOMED-CT. A centralized database system was created to manage data storage, exchange, and integration. This system supports comprehensive data analysis, including visualization, statistical evaluation, and deep learning, to enhance data usability.

RESULT: The TRR-DPK system aims to recruit 3,000 participants for MCD evaluations, blood tests, and brain imaging by 2028. As of December 2024, over 2,000 participants have been enrolled in the TRR since its launch in 2020. Of the target participants, approximately 1,800 will undergo longitudinal follow-up every two years for additional data and blood sample collection. The K-Dementia platform has retrospectively secured over 10,000 datasets from Korea and established a database schema informed by global dementia databases. Additionally, a cloud-based system integrated with AWS was developed to enable secure data analysis, allowing researchers to perform analyses in a protected environment where only the results can be downloaded.

CONCLUSION: The TRR and K-Dementia platform are expected to significantly advance AD research by providing researchers with access to high-quality, human-derived materials and standardized datasets. Furthermore, these initiatives will foster global collaboration, particularly with platforms such as the Dementias Platform UK (DPUK), through the development of standardized data and secure analytical environments.},
}

Humans
*Alzheimer Disease/diagnostic imaging
Magnetic Resonance Imaging
Republic of Korea
Biomarkers/blood
Positron-Emission Tomography
*Registries
Brain/diagnostic imaging
Databases, Factual

@article {pmid41436374,
year = {2025},
author = {Thal, DR and Ronisz, A and Ospitalieri, S and Ginderdeuren, RV and Tsaka, G and Tomé, SO and Lemmens, S and Stalmans, I and Vandenberghe, R and von Arnim, CAF and Schymkowitz, J and Rousseau, F and Hoozemans, JJM and Rozemuller, AJM and de Ruyter, FJH and Morrema, T and Bouwman, FH and Groef, L and Walkiewicz, G},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102036},
doi = {10.1002/alz70855_102036},
pmid = {41436374},
issn = {1552-5279},
mesh = {Humans ; Animals ; *Tauopathies/pathology/metabolism ; *tau Proteins/metabolism ; *Retina/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Mice ; Phosphorylation ; Brain/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; },
abstract = {The accumulation of abnormal phosphorylated tau (p-τ) protein in neurons is a hallmark of Alzheimer's disease (AD) and primary tauopathies. Both conditions involve p-τ accumulation in retinal neurons. Here, we explore the role of p-τ pathology in visual performance and the interplay between retinal and cerebral p-τ pathology. In the human retina, p-τ is frequently found. This retinal tauopathy evolves in three stages: stage 1 involves p-τ aggregates in the outer plexiform layer, stage 2 affects neurons in the inner nuclear layer, and stage 3 involves the inner plexiform layer. Various phosphorylation sites (S202/T205, T231, S396/404) and conformational τ epitopes are present in human retinal tauopathy, but no argyrophilic fibrils are seen. Western blot analysis shows a distinct molecular pattern of p-τ species in the retina compared to cerebral tauopathies like AD and primary age-related tauopathy (PART). The stages of this primary retinal tauopathy (PReT) correlate with altered visual performance and dementia symptoms. In transgenic mouse models, p-τ is prominent in retinal ganglion cells, which can develop fibrillar aggregates, unlike in human retinal tauopathy. In the TAU58 mouse model, tauopathic changes in the retina are associated with ganglion cell loss. TAU58 mice show enhanced tau pathology in the retina after AD brain lysate injection, with increased tau changes in the contralateral superior colliculus, suggesting propagation from retina to brain. Lysates from a Braak stage I PART case did not induce propagation but accelerated seeding in the retina. These findings suggest that human PReT, with its low levels of p-τ and lack of fibrillar p-τ lesions, is a separate entity from AD, especially in young individuals. However, propagation of p-τ pathology from retina to brain is possible. PReT's association with visual worsening in humans and reduced retinal ganglion cells in mice needs further exploration. PReT may also be a prerequisite for retinal involvement in AD and primary tauopathies, as indicated by its association with dementia symptoms. Funding: SAO/FRA 2020/017.},
}

Humans
Animals
*Tauopathies/pathology/metabolism
*tau Proteins/metabolism
*Retina/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Mice
Phosphorylation
Brain/pathology/metabolism
Mice, Transgenic
Disease Models, Animal

@article {pmid41436373,
year = {2025},
author = {Li, C and Leitner, D and Pang, H and Bruno, M and Wisniewski, T and Faustin, A and Zaim-Wadghiri, Y and Zhang, J and Ge, Y},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102276},
doi = {10.1002/alz70855_102276},
pmid = {41436373},
issn = {1552-5279},
mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Alzheimer Disease/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Male ; Female ; Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: White matter hyperintensities (WMHs), visible as increased signal intensity on T2-FLAIR MRI images, represents a key imaging biomarker in the Alzheimer's Disease and related dementias (AD/ADRD). Histopathology links WMHs to demyelination, axonal degeneration and loss, reactive astrogliosis and microglial activation. However, direct quantitative correlations between in vivo MRI signals and specific histopathological features are challenging due to differences in spatial resolution and the indirect nature of MRI. This study aims to bridge clinical MRI findings of WMHs with histopathological findings using multiparametric and multiscale MRI approaches in dementia brains.

METHOD: Two post-mortem brain specimens from pathologically confirmed AD cases were included in this study. The imaging protocol includes sequential MRI acquisitions at 3T. Whole-hemispheric imaging was initially performed using a 3T clinical system. The specimens were then sectioned into tissue blocks sized to fit histological cassettes. For high-resolution ex vivo imaging, each tissue block was imaged on a preclinical 3T MRI system, using the same imaging protocols as the hemispheric scans but with improved resolution.

RESULT: Postmortem hemisphere scans on a clinical scanner demonstrated that WMHs showed comparable contrast to in vivo imaging. Quantitative analysis of multimodal imaging data of WMHs from both preclinical and clinical 3T scanners, exhibited increased mean diffusivity (MD) and prolonged T1, T2, and T2* relaxation times compared to surrounding normal appearing white matter (NAWM). Histopathological staining confirmed spatial overlap between tissue block MRI and histological findings of WMHs, highlighting pathological features of white mater vacuolation, demyelination, astrogliosis and neuroinflammation.

CONCLUSION: In conclusion, the joint analysis of high-resolution postmortem MRI and histopathology revealed a complex signal origin of WMHs, characterized by elevated diffusivity and prolonged T1 and T2 relaxation times, which correlate with various histological findings. This preliminary study may provide insights into the signal composition of WMHs in vivo. Figure 1. Representative half hemisphere MRI data used to evaluate WMHs. Figure 2. High-resolution MRI of small tissue cassettes at 3T and (B) Histology of WMHs using LFB, MBP, GFAP, and IBA1 staining of WMHs. Figure 3. Spider plot of the multiparametric measurements between (A) NAWM and (B) WMHs from a single subject.},
}

Humans
*White Matter/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Alzheimer Disease/pathology/diagnostic imaging
*Brain/pathology/diagnostic imaging
Male
Female
Aged
Aged, 80 and over

@article {pmid41436372,
year = {2025},
author = {Faustin, A and Strobbe, A and Balcomb, K and Kanshin, E and Kavanagh, T and Genoud, S and Pires, G and Askenazi, M and Ueberheide, B and Wisniewski, T and Drummond, E},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102149},
doi = {10.1002/alz70855_102149},
pmid = {41436372},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/pathology/metabolism ; Male ; Female ; Proteomics ; *Cognitive Dysfunction/pathology/metabolism ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; Phosphorylation ; Temporal Lobe/pathology/metabolism ; Visual Cortex/pathology/metabolism ; },
abstract = {BACKGROUND: Emerging studies suggest that phosphorylation of specific tau residues may occur in a sequential manner in Alzheimer's disease (AD). This has important therapeutic and biomarker implications. While initial studies show promise, our understanding of which type of pTau that accumulates earliest in AD is still limited. Therefore, the aim of this study was to perform a detailed proteomic and neuropathological study of pTau accumulation in early AD.

METHOD: Localized proteomics was used to profile protein changes in human post-mortem brain tissue from early AD cases with pathology, but no cognitive impairment (preclinical AD cases; n = 20), cases with pathology and mild cognitive impairment (MCI; n = 20) and age-matched control cases (n = 20). Protein changes were assessed in the vulnerable inferior temporal cortex and the comparatively resistant primary visual cortex from each case. Validation studies were performed on the same tissue using immunofluorescence to assess abundance and localization of pTau181, pTau217, pTau231, and pTau202/205.

RESULT: >3,800 proteins were quantified using localized proteomics. Midkine emerged as the most significantly altered protein in early AD in both the temporal cortex and visual cortex. Proteomics also identified unique pTau species that correlated with vulnerability to disease. For example, pTau217 best correlated with disease vulnerability, with greater abundance in temporal cortex than visual cortex and in MCI > preclinical AD > controls, while pTau181 and pTau202 were more consistently observed in all groups, including controls. The minimal amount of pTau in the visual cortex in early AD allowed analysis of the sequential accumulation of specific pTau species using immunofluorescence. Neuritic pTau181 was the earliest tau accumulation we observed. As tau pathology accumulated, pTau217 and pTau202/205 pathology were next observed, followed by pTau231. Each type of pTau showed similar aggregate morphology, with neuritic pathology being most prevalent, followed by tangles and plaque-associated neurites as disease progressed.

CONCLUSION: Our results suggest that pTau accumulation in early AD may occur in a staged manner in AD, with pTau181 accumulation in neurites being observed before other pTau species. Additionally, our proteomics results highlight the potentially important role for midkine in early AD.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/pathology/metabolism
Male
Female
Proteomics
*Cognitive Dysfunction/pathology/metabolism
Aged
Aged, 80 and over
*Brain/pathology/metabolism
Phosphorylation
Temporal Lobe/pathology/metabolism
Visual Cortex/pathology/metabolism

@article {pmid41436371,
year = {2025},
author = {Fredriksen, K and Joshi, SS and Kim, M and Li, L},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102528},
doi = {10.1002/alz70855_102528},
pmid = {41436371},
issn = {1552-5279},
mesh = {Animals ; *Astrocytes/metabolism/drug effects ; Mice ; *Alzheimer Disease/genetics/metabolism ; Humans ; *Apolipoprotein E4/genetics/metabolism ; *Apolipoproteins E/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {BACKGROUND: Apolipoprotein E (APOE) is the greatest genetic risk factor for Alzheimer's disease (AD) and in humans has 3 isoforms; APOE4 (E4) increases risk, APOE3 (E3) is neutral and APOE2 (E2) decreases risk. APOE is mainly produced and secreted by astrocytes, where it binds lipids to form HDL-like particles. The lipidation state of APOE is crucial for maintaining lipid homeostasis and regulating Aβ aggregation and protein clearance. E4 is poorly lipidated compared to E2 and E3, contributing to cellular dysfunction. Emerging therapies aim to restore E4 lipidation levels to resemble E2 or E3. We previously showed that the HDL-mimetic peptide 4F increases APOE secretion and lipidation in primary mouse and human astrocytes. Furthermore, recent evidence suggests that the protective APOE Christchurch (APOEch) mutation alters APOE properties to resemble E2. However, the effects of HDL mimetic peptides and APOEch on APOE4 astrocytes remain unclear. We hypothesize that both pharmacological (4F) and genetic (APOEch) interventions enhance APOE secretion and lipidation, and rescue E4-related deficits.

METHOD: We generated APOE4 Christchurch (E4ch) induced pluripotent stem cells (iPSCs) and knock-in (KI) mice using CRISPR/Cas9. E3, E4 and E4ch isogenic iPSCs were differentiated into astrocytes. Primary astrocytes were isolated from E4 and E4ch KI mice. Astrocytes were incubated with aggregated Aβ42 and/or the HDL mimetic peptide 4F for 24 hours. Secreted media and cell lysates were subjected to non-denaturing gradient gel electrophoresis and immunoblot analyses.

RESULT: Compared to E4, E4ch primary and iPSC astrocytes enhanced APOE secretion and lipidation. Aβ42 inhibited APOE secretion in E4 astrocytes. Importantly, E4ch astrocytes were more resilient, maintaining elevated APOE secretion and lipidation levels in the presence of Aβ42. E4ch astrocytes also promoted lysosomal protein clearance more than E4 astrocytes. Remarkably, 4F treatment counteracted the inhibitory effects of Aβ42 and enhanced APOE secretion and lipidation in both primary and iPSC astrocytes.

CONCLUSION: HDL mimetic peptide 4F treatment resembles the protective effects of E4ch and mitigates E4-related deficits on APOE secretion and lipidation in astrocytes. These findings highlight the potential of targeting APOE secretion and lipidation as a therapeutic strategy for sporadic AD.},
}

Animals
*Astrocytes/metabolism/drug effects
Mice
*Alzheimer Disease/genetics/metabolism
Humans
*Apolipoprotein E4/genetics/metabolism
*Apolipoproteins E/metabolism/genetics
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Induced Pluripotent Stem Cells/metabolism

@article {pmid41436370,
year = {2025},
author = {Parithathvi, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102556},
doi = {10.1002/alz70855_102556},
pmid = {41436370},
issn = {1552-5279},
mesh = {Animals ; Female ; Rats, Sprague-Dawley ; Disulfides ; *Sulfinic Acids/pharmacology ; Rats ; *Brain/pathology/drug effects/metabolism ; Pregnancy ; Disease Models, Animal ; *Lead/toxicity ; tau Proteins/metabolism ; *Prenatal Exposure Delayed Effects/pathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders characterized by amyloid plaques and neurofibrillary tangles. The increasing prevalence of AD highlights the importance of comprehending the role of major factors in disease progression. heavy metals such as lead, along with age, are key drivers of neurodegeneration. Lead, a hazardous heavy metal is adequately available in the environment and its malleable and ductile properties, increased the lead consumption. As lead can pass through placenta and blood brain barrier it is very important to study the transgenerational neurodegenerative effects of lead. Allicin, naturally obtained from Allium sativum, is a strong neuroprotective agent, is involved in reducing tau hyperphosphorylation and also a natural chelator due to its sulfhydryl groups.

METHOD: In this study, Female Sprague-Dawley rats were exposed to lead nitrate of 2mg/Kg body weight from preconception to weaning period of F1 progeny and allicin treatment of 40μg/Kg body weight. The F1 progeny were studied after 6 months of observation for behavioural histopathological and molecular changes.

RESULT: The 6 months old F1 progeny showed significant behavioural changes attributing to anxiety and motor dysfunction between lead exposed and allicin treated groups. Similarly, histopathological studies like Nissl and H&E staining, immunohistochemistry using tau, tubulin and NeuN markers showed significant differences between lead exposed and allicin treated groups. mRNA studies of prominent AD-specific genes like APP, BACE1, APOE and PSEN1 showed significant differences between F1 progeny of lead exposed and allicin treated groups.

CONCLUSION: The results indicate the transgenerational effect of lead in inducing AD-like pathophysiology even at 6-month-old F1 progeny. Allicin treated groups showed a significant decrease in the effects indicating its chelating and neuroprotective effect. This study emphasises the transgenerational neurotoxic effect of lead, leading to early onset of major neurodegenerative disorders and its therapeutic interventions.},
}

Animals
Female
Rats, Sprague-Dawley
Disulfides
*Sulfinic Acids/pharmacology
Rats
*Brain/pathology/drug effects/metabolism
Pregnancy
Disease Models, Animal
*Lead/toxicity
tau Proteins/metabolism
*Prenatal Exposure Delayed Effects/pathology

@article {pmid41436369,
year = {2025},
author = {Lin, X and Blankers, SA and Go, K and Lee, BH and Galea, LA},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102174},
doi = {10.1002/alz70855_102174},
pmid = {41436369},
issn = {1552-5279},
mesh = {Animals ; Female ; Male ; *Neurogenesis/genetics/physiology ; Mice ; *Alzheimer Disease/genetics/pathology ; Hippocampus/pathology ; Mice, Transgenic ; Humans ; Apolipoprotein E4/genetics ; Disease Models, Animal ; Neural Stem Cells ; Brain/pathology ; Sex Factors ; },
abstract = {BACKGROUND: The three non-modifiable risk factors for Alzheimer's disease (AD) are advancing age, female sex and at least one APOEε4 allele. Females with AD experience more severe cognitive decline and pathological changes in the brain, including faster hippocampal atrophy, greater AD neuropathology, and steeper cognitive decline than males with AD. Notably, female APOEε4 carriers have an even higher risk of developing AD earlier, exhibiting greater cognitive decline and more severe neuropathological outcomes than male APOEε4 carriers at middle age. Hippocampal neurogenesis is altered in AD, and sex differences have been identified. However, the effect of advancing age, sex, and APOE genotype on neurogenesis remains unexplored. Therefore, the current study aims to identify how sex and APOE genotype differently affect the dynamics of neurogenesis, including the expression of neural progenitor cells and the maturation rate of new neurons.

METHOD: We used 2-month-old (young adulthood) and 12-month-old (middle age) male and female humanized (h) APOEε3 and hAPOEε4 mice. Newly proliferated cells were labeled with the thymidine analog bromodeoxyuridine (BrdU). Brains were collected either 24 hours, 2 weeks, or 4 weeks after BrdU injection to capture the various stages of neurogenesis. The extracted brains were sectioned and processed for immunohistochemistry to measure the neural progenitor cell pool (BrdU/Sox2), the maturation of new neurons (BrdU/NeuN), and potentially the pluripotency of newly formed putative neural stem cells (BrdU/Sox2-ir).

RESULT: Analyses are ongoing, but we expect that hAPOEε4 mice will display different temporal dynamics of neurogenesis compared to hAPOEε3 mice, which will result in different levels of hippocampal neurogenesis. Moreover, interactions between sex and genotype are anticipated, with hAPOEε4 females expected to exhibit a slower neuronal maturation rate compared to other groups.

CONCLUSION: Our research findings will reveal the role of sex and genotype in neurogenesis, neuronal maturation and factors influencing the pluripotency of neural stem cells in AD model, providing a better understanding of AD-related neuropathological changes.},
}

Animals
Female
Male
*Neurogenesis/genetics/physiology
Mice
*Alzheimer Disease/genetics/pathology
Hippocampus/pathology
Mice, Transgenic
Humans
Apolipoprotein E4/genetics
Disease Models, Animal
Neural Stem Cells
Brain/pathology
Sex Factors

@article {pmid41436368,
year = {2025},
author = {Gandy, SE and Castranio, EL and Varghese, M and Argyrousi, EK and Tripathi, K and Söderberg, L and Bresnahan, E and Lerner, D and Garretti, F and Zhang, H and de Loo, JV and Teunissen, B and Talty, R and Levy, E and Wang, M and Zhang, B and Lannfelt, L and Glabe, CG and Lubell, WD and Guerin, B and Rahimipour, S and Dickstein, D and Arancio, O and Ehrlich, ME},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102418},
doi = {10.1002/alz70855_102418},
pmid = {41436368},
issn = {1552-5279},
mesh = {Animals ; Mice, Transgenic ; *Alzheimer Disease/pathology/genetics/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; Disease Models, Animal ; *Brain/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Humans ; Hippocampus/metabolism/pathology ; Synapses/pathology ; },
abstract = {BACKGROUND: Studies of Alzheimer's disease have demonstrated that cognitive decline fails to correlate with fibrillar Aβ burden.

METHOD: We created a transgenic mouse overexpressing Dutch mutant hAPP (APPE693Q) driven by a pan-neuronal Thy1 promoter.

RESULT: Accumulation of oligomeric Aβ (oAβ) and alpha-CTFs (but not Aβ fibrils) was observed in the brains of Dutch mice which develop impaired learning behavior proportional to brain oAβ levels. Male & female Dutch mice & WT controls were compared using learning behavior, ICC, transmission electron microscopy (TEM), electrophysiology, epitomic assays & single cell RNA sequencing. Brain levels of nonfibrillar oAβ in Dutch mice increased during aging as revealed by A11 ICC and FITC-cyclic peptide (FITC-CP) fluorescence microscopy. Electrophysiology of hippocampal synapses in Dutch and WT mice at ∼7 & ∼11 months revealed no change in basal excitatory transmission consistent with normal density & morphology of synapses in hippocampal CA1. One exception was increased postsynaptic density area in Dutch mice. Functional characterization of presynaptic termini showed abnormal post-tetanic potentiation, synaptic fatigue & vesicle replenishment in Dutch mice. Single cell RNA-seq to elucidate cell-type specific transcriptional responses to oAβ revealed altered transcriptional profiles in multiple cell types. Unexpectedly, no obvious transcriptomic differences existed between Dutch vs WT microglia. Excitatory neurons showed the most altered profile which was associated with 'protein translation' & 'oxidative phosphorylation'. Mitochondrial complex I activity was reduced in 12- but not 7-mo-old Dutch vs WT mice. Ultrastructural analysis of excitatory presynaptic mitochondria revealed fewer mitochondria in Dutch mouse presynaptic termini. Nonfibrillar oAβ deposits were revealed by co-localization of A11 immunoreactivity with FITC-CP microscopy. Oligomer-detecting cyclic azaglycine PET tracer Lys(64Cu/NOTA)]-CP revealed robust PET signal from thalami and cerebral cortices of presymptomatic 5xFAD mice (10.1073/pnas.2210766119). Analysis using TEM and CP-gold nanoparticle labeling revealed that oAβ was concentrated around mitochondria & ER in Dutch mice.

CONCLUSION: Dutch oAβ accumulation associates with aging-related defects in learning behavior, presynaptic function & mitochondrial structure & function. Brain PET imaging with Lys(64Cu /NOTA)]-CP may enable development of an assay for monitoring oAβ levels & distribution for diagnosing living human subjects & patients.},
}

Animals
Mice, Transgenic
*Alzheimer Disease/pathology/genetics/metabolism
Mice
*Amyloid beta-Peptides/metabolism
Female
Male
Disease Models, Animal
*Brain/metabolism/pathology
Amyloid beta-Protein Precursor/genetics/metabolism
Humans
Hippocampus/metabolism/pathology
Synapses/pathology

@article {pmid41436365,
year = {2025},
author = {Jaisa-Aad, M and Aguero, C and Rabaneda-Lombarte, N and Bianco, CR and Melloni, AN and Hyman, BT and Gomez-Isla, T and Brugarolas, P and Serrano-Pozo, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102019},
doi = {10.1002/alz70855_102019},
pmid = {41436365},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Monoamine Oxidase/metabolism ; *Astrocytes/metabolism/pathology ; Male ; Female ; Aged ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/pathology/metabolism ; Biomarkers/metabolism ; Aged, 80 and over ; Middle Aged ; Gliosis/pathology/metabolism ; },
abstract = {BACKGROUND: Single nucleus RNA-sequencing has revealed the complexity and heterogeneity of reactive astrogliosis in Alzheimer's disease (AD) and AD-related dementias (ADRD). Our recent large snRNA-seq study comprising 5 brain regions and 32 brain donors representing the stereotypical hierarchical spatio-temporal progression of AD identified new markers of homeostatic and reactive astrocytes as well as subclusters with specialized functions, transcriptomic changes along AD-vulnerable neural networks and in parallel to Aβ plaque and pTau accrual, and potential signatures of regional vulnerability and resilience in the normal aging brain, overall supporting the idea that astrocytes contribute to the selective neuronal vulnerability that characterizes AD/ADRD. Here we focused on evaluating monoamine oxidase-B (MAO-B) as a reactive astrocyte marker in AD/ADRD given its implication in oxidative stress and GABA tonic inhibition and that MAO-B radioligands have been proposed for PET imaging of reactive astrogliosis.

METHOD: Quantitative immunohistochemical study of MAO-B, Aβ, pTau, pTDP43, GFAP, and YKL-40 in formalin-fixed paraffin-embedded sections from the frontal association cortex (BA8/9) of donors with no primary neuropathological diagnosis (controls, n = 20), AD (n = 30), Pick's disease (PiD, n = 20), progressive supranuclear palsy (PSP, n = 20), cortico-basal degeneration (CBD, n = 19), and frontotemporal lobar degeneration-TDP (FTLD-TDP, n = 20). Cortical thickness was also measured as a proxy for severity of atrophy. The cell type(s) expressing MAO-B was assessed with confocal microscopy and subcellular localization was investigated with super-resolution microscopy.

RESULT: Compared to controls, MAO-B immunoreactive area fraction was significantly increased in the frontal cortex and white matter of AD, CBD, and especially PiD and FTLD-TDP, but not PSP. MAO-B area fraction correlated positively with that of GFAP and YKL-40. MAO-B was primarily expressed by cortical astrocytes across AD/ADRD and, as expected, colocalized with their mitochondria. As reported for other reactive markers, tufted astrocytes in PSP tended to have low MAO-B levels. Importantly, multivariable linear regression analysis revealed a significant negative association between MAO-B area fraction and cortical thickness even after adjusting for Aβ, pTau or pTDP43 burdens.

CONCLUSION: MAO-B up-regulation may identify the subset of reactive neurotoxic astrocytes in AD/ADRD. Multimodal PET-MRI studies are needed to test the hypothesis that MAO-B radioligand binding predicts future neurodegeneration in individuals with AD/ADRD.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Monoamine Oxidase/metabolism
*Astrocytes/metabolism/pathology
Male
Female
Aged
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Brain/pathology/metabolism
Biomarkers/metabolism
Aged, 80 and over
Middle Aged
Gliosis/pathology/metabolism

@article {pmid41436364,
year = {2025},
author = {Cruz, LA and Liu, S and Miskimen, KL and Song, YE and Laux, RA and Lerner, AJ and Lynn, A and Fuzzell, SL and Hochstetler, SD and Konidari, I and McCauley, JL and Scott, WK and Pericak-Vance, M and Haines, JL and Crawford, DC},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102239},
doi = {10.1002/alz70855_102239},
pmid = {41436364},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/genetics/immunology ; *Cognitive Dysfunction/genetics/immunology ; Aged, 80 and over ; *Receptors, Antigen, T-Cell/genetics ; Saliva ; },
abstract = {BACKGROUND: Late-onset Alzheimer disease (LOAD) is the most common form of dementia among adults ≥65 years of age. Known risk factors include female sex, increased age, mild cognitive impairment (MCI), and LOAD-associated genetic risk alleles, most notably APOE e4. Recent evidence implicates the adaptive immune system as an important component of amyloid-β plaque clearance and suggests, in limited sample sizes, LOAD-associated immune profiles detectable in blood.

METHOD: We characterized somatic T-cell receptor (TCR) sequence diversity profiles from DNA extracted from blood (99%) and saliva (1%) in Ohio Amish participants with LOAD+MCI (n = 22), non-LOAD (n = 35), and an unclear diagnosis (n = 12). Sequencing was performed using Adaptive Biotechnologies immunoSEQ targeting the beta chain, resulting in >160,000 productive templates and >100,000 productive rearrangements. TCR beta chain sequences were characterized using Simpson's productive clonality, which ranges from 0 to 1 representing diverse and completely even sequences (e.g., 0) to monoclonal or single dominant clone (e.g., 1). We used productive Simpson clonality as a measure of TCR diversity in our supervised logistic regression. To assess the pairwise repertoire similarities, we focused on the Morisita-Horn index, which accounts for clonotype abundance while maintaining robustness against extreme values. We applied an unsupervised machine learning (ML) approach, fuzzy C-means clustering, to identify potential patterns specific to disease status.

RESULT: Participants did not differ significantly based on sex. LOAD+MCI participants were slightly older at last clinical exam than non-LOAD or unclear participants (83.9 vs 81.5 and 81.2 years, respectively; chi-square, p = 0.058). We observed significantly higher TCR sequence diversity in the non-LOAD group compared to the LOAD-MCI group (p = 0.027). However, the association was not significant after adjusting for age and sex. Clustering results showed moderate agreement with clinical diagnoses (adjusted rand index up to 0.4), and incorporating APOE genotypes enhanced the performance. The addition of age as a variable, which has been demonstrated to be related to both LOAD risk and TCR diversity, reduced the clustering agreement slightly.

CONCLUSION: Decreased TCR diversity is marginally associated with having LOAD or MCI. Our ongoing work focuses on applying ML approaches to TCR CD3 amino acid sequences to identify disease-associated clonotypes and develop predictive models for LOAD diagnosis.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/genetics/immunology
*Cognitive Dysfunction/genetics/immunology
Aged, 80 and over
*Receptors, Antigen, T-Cell/genetics
Saliva

@article {pmid41436362,
year = {2025},
author = {Meek, A and Neal, MP and Weaver, DF},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102284},
doi = {10.1002/alz70855_102284},
pmid = {41436362},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism/etiology ; Amyloid beta-Peptides/metabolism ; Animals ; Immunity, Innate ; tau Proteins/metabolism ; },
abstract = {BACKGROUND: Developing a comprehensive molecular pathogenesis model for Alzheimer's (AD) is a research priority; to-date, a range of different mechanistic proposals including proteopathy, immunopathy, gliopathy, synaptopathy, membranopathy, mitochondriopathy, oxidative stress, and metal dyshomeostasis have been proposed. Rather than unconditionally rejecting the role of any one specific disease mechanisms, the need for an innovative broadly-encompassing model of AD, which harmonizes multiple divergent theories into a single unified comprehensive explanation, emerges as a much-needed milestone on the road to a cure. Characterizing AD as an innate immunity mediated persistent neuroinflammatory disorder may provide such an all-encompassing model.

METHOD: We performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating multiple biochemical processes implicated in the pathogenesis of AD: Aβ/tau oligomerization, Aβ-mediated membrane rupture, pro-inflammatory cytokine release, mitochondrial damage, synaptotoxicity, and metal-catalyzed reactive oxygen species generation. These analyses were then systematically probed for unifying mechanistic commonalities.

RESULT: The following mechanistic model of AD was devised. Aβ has antimicrobial and immunomodulatory activities, functioning as a component of the innate immune system. In response to various stimuli (infection, trauma, ischemia, air pollution), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon 'self' neurons, arising from analogous electronegative surface topologies between bacteria and neurons (particularly within the synaptic region), rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides such as Aβ. In its role as an antimicrobial-immunomodulatory peptide, Aβ binds to monosialotetrahexosylganglioside (GM1) on the neuronal membrane surface to block viral entry, while intracellularly damaging mitochondria which are evolutionarily derived from endosymbiotic bacteria; concomitantly, Aβ binds to glial cells triggering release of neurotoxic pro-inflammatory cytokines. Following these self-directed attacks, the resulting neuronal breakdown products (particularly Aβ-GM1 co-aggregates) diffuse to adjacent neurons eliciting further release of Aβ, leading to chronic, persistent activation of innate immunity. AD thus emerges as a disorder of persistent innate immunity activation.

CONCLUSION: A new unifying, comprehensive model of AD as an innate immunity persistent activation disorder has been devised.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism/etiology
Amyloid beta-Peptides/metabolism
Animals
Immunity, Innate
tau Proteins/metabolism

@article {pmid41436360,
year = {2025},
author = {Imiruaye, OE and Perez, I and Carson, B and Crouzet, C and Garcia, J and Han, D and Bhattacharya, S},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102267},
doi = {10.1002/alz70855_102267},
pmid = {41436360},
issn = {1552-5279},
mesh = {Animals ; *Receptors, N-Methyl-D-Aspartate/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Neural Cell Adhesion Molecule L1/metabolism ; Mice ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Brain/metabolism/pathology ; Aging/metabolism ; Sialyltransferases/metabolism ; Disease Models, Animal ; Sialic Acids/metabolism ; },
abstract = {BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are critical for synaptic transmission, with GluN2B subunits playing key roles in synaptic plasticity. Extrasynaptic GluN2Bs (ES-GluN2Bs) activate long-term depression (LTD) pathways, potentially promoting dementia in Alzheimer's disease (AD). Polysialylation of neural cell adhesion molecule (NCAM) to PSA-NCAM by ST8-α-N-acetyl-neuraminide-α-2,8-sialyltransferase-4 (ST8Sia4) and UDP-N-acetylglucosamine-2-epimerase (UDP-E) regulates synaptic remodeling and inhibits ES-GluN2B activity physiologically. However, the spatiotemporal dynamics of ES-GluN2Bs and PSA-NCAM in brain aging versus AD and how Aβ, a pathological hallmark of AD, affects these proteins remain unclear.

METHOD: We examined expression levels of NMDAR subunits (GluN2A, GluN2B), ES-GluN2Bs, NCAM, and PSA-NCAM in young and old Tg2576 AD mice and wild-type (WT) controls across the cortex, prefrontal cortex, hippocampus, and midbrain using immunoblotting and pull-down assays. After this, we investigated the neurochemical effects of varying concentrations of Aβ treatment on ST8Sia4, PSA-NCAM, and UDP-E expression via protein and mRNA quantification in IMR-32 neuroblastoma cells.

RESULT: Aging reduced overall GluN2B expression in both WT and AD mice (47-51%, n≥4) while increasing GluN2A expression (up to 85%, n≥4). ES-GluN2B levels were significantly elevated in AD mice (2-3-fold, n≥4), but unchanged in WT mice. PSA-NCAM expression was downregulated in AD mice (by 43-58%, n≥4), particularly in the hippocampus and prefrontal cortex, while increasing with normal aging (up to 2-fold, n≥4). Analysis of protein and mRNA expression levels following Aβ treatment in IMR-32 cells revealed significant downregulation (up to 60%) in ST8Sia4, PSA-NCAM, and UDP-E across all concentrations.

CONCLUSION: Our findings demonstrate AD-specific increases in ES-GluN2B expression and a significant downregulation in PSA-NCAM levels, distinguishing AD from normal aging, potentially driven by Aβ-induced downregulation of biosynthetic enzymes ST8Sia4 and UDP-E. This underscores a potential link between PSA-NCAM expression and Aβ activity in AD, as well as possible therapeutic targets for AD intervention.},
}

Animals
*Receptors, N-Methyl-D-Aspartate/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Neural Cell Adhesion Molecule L1/metabolism
Mice
Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Brain/metabolism/pathology
Aging/metabolism
Sialyltransferases/metabolism
Disease Models, Animal
Sialic Acids/metabolism

@article {pmid41436357,
year = {2025},
author = {Santos, GAA and Junior, MR},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102095},
doi = {10.1002/alz70855_102095},
pmid = {41436357},
issn = {1552-5279},
mesh = {Humans ; *Neuroprotective Agents/pharmacology ; *Alzheimer Disease/prevention & control/metabolism ; *Fruit/chemistry ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/metabolism/drug effects ; Animals ; },
abstract = {BACKGROUND: bioactive compounds found in berries are capable of reducing brain inflammatory activity, in addition to exerting neuroprotective activity, as they contain substances such as Quercetin, Ellagic Acid, among others, which reduce oxidative stress, inhibit beta amyloid aggregation, TAU hyperphosphorylation, regulating synaptic function, activating the Transcription Factor Nrf2.

METHOD: This is a literature review carried out from August to December 2024, based on publications from the last 10 years that provided evidence regarding the neuroprotective results of bioactive compounds. The keywords used were: berries, TAU, Abeta, neuroprotection, anti-inflammatory; RESULT: The secondary metabolites of bioactive compounds demonstrate the ability to prevent neuronal death as they are capable of reducing the levels of Reactive oxygen species, blocking the activation of caspase-3; in addition to increasing redox activity.

CONCLUSION: The use of bioactive compounds in the diet, in a regulated manner, or even as a supplement can be a protective factor to avoid mild cognitive decline and consequently dementia, such as Alzheimer's.},
}

Humans
*Neuroprotective Agents/pharmacology
*Alzheimer Disease/prevention & control/metabolism
*Fruit/chemistry
Oxidative Stress/drug effects
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/metabolism/drug effects
Animals

@article {pmid41436356,
year = {2025},
author = {Serrano, GE and Aslam, S and Walker, J and Borja, C and Lorenzini, I and Mariner, M and Beach, TG},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101342},
doi = {10.1002/alz70855_101342},
pmid = {41436356},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Hispanic or Latino ; Aged ; *Brain/pathology ; *Alzheimer Disease/pathology/ethnology ; Aged, 80 and over ; Middle Aged ; United States/epidemiology ; Risk Factors ; White ; },
abstract = {BACKGROUND: Hispanics seem to be at higher risk of developing Alzheimer's disease dementia (ADD) but there are few neuropathologically validated studies.

METHOD: The National Alzheimer's Coordinating Center (NACC) functions as the centralized data repository for the National Institute of Aging's (NIA's) Alzheimer's Disease Research Centers (ADRC) Program and currently hosts data from over 2,100 Hispanic participants who have donated their brains to the study, and close to 60% of those have had full neuropathological evaluations done at 28 different ADRCs. The main goal of this study is to compare the neuropathological changes observed in these subjects to those reported as non-Hispanics.

RESULT: Hispanics in this study self-identified as Caucasians (72%), African American (4%), Native American (less than 2.5%), or "Other Races or unknown" (20%), as compared to the non-Hispanics, (82% Caucasian, 14% African American, 0.1% Other). The largest percentage of Hispanics were Mexican or of Mexican descent (64%), followed by 12% Puerto Rican, 6% Cuban, 5% Dominican, 6% South American, with the remainder from other central American countries or Spain. Sex distribution was similar in both groups with close to 49% of the participants identifying their biological sex as males. Hispanic participants died at younger ages (83 vs 84 years), had lower brain weights (1093 +/- 152g vs 1116 +/- 157g) and had a higher percentage of Intermediate to High levels of AD Neuropathological Changes (75% vs 67%). Vascular pathology was also more severe in Hispanics, both for moderate/severe cerebral amyloid angiopathy (45% to 29%) and moderate/severe cerebral white matter rarefaction (33% to 31%). Hispanics in this data set also had higher rates of heart attack, congestive heart failure, hypertension, and diabetes.

CONCLUSION: This also agrees with previous clinical studies suggesting that ethnic Hispanic people have greater white matter hyperintensity volumes and higher vascular risk factors, but additional studies are needed to also understand how race intersects ethnicity.},
}

Humans
Male
Female
Hispanic or Latino
Aged
*Brain/pathology
*Alzheimer Disease/pathology/ethnology
Aged, 80 and over
Middle Aged
United States/epidemiology
Risk Factors
White

@article {pmid41436355,
year = {2025},
author = {Zaragoza-Ballester, P and Nuscher, B and Alcolea, D and Fernández-León, Á and Rodríguez-Baz, Í and Bejanin, A and Vera, E and Vaqué-Alcázar, L and Sala, I and Gómez-Grande, A and Lleo, A and Fortea, J and Camacho, V and Haass, C and Morenas-Rodriguez, E},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102529},
doi = {10.1002/alz70855_102529},
pmid = {41436355},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Biomarkers/cerebrospinal fluid ; *Apolipoprotein E4/genetics ; *Alzheimer Disease/genetics/cerebrospinal fluid/pathology ; *Lewy Body Disease/genetics/cerebrospinal fluid/diagnostic imaging/pathology ; *Membrane Glycoproteins/cerebrospinal fluid ; *Receptors, Immunologic ; Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; tau Proteins/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: APOEε4 is a genetic risk factor for both Alzheimer's Disease (AD) and dementia with Lewy bodies (DLB). TREM2-dependent microglial activation is considered protective in AD and has been proposed to interact with APOE in this context. Since DLB often exhibits Alzheimer's copathology, we investigate the interplay between TREM2 response, APOEε4 carriage and Alzheimer's co-pathology, and its influence on disease evolution in DLB.

METHOD: We measured cerebrospinal fluid (CSF) cleaved soluble TREM2 (cTREM2), as a marker of TREM2-dependent microglial response, core AD biomarkers and determine APOEε4 carriage in 76 DLB patients (prodromal DLB [prodDLB], n = 39; DLB-dementia, n = 37). Forty one patients additionally underwent [[18]F]Florbetapir-PET (FBP-PET). We quantified cTREM2 by an in-house MSD-based immunoassay; core AD biomarkers (Aβ42, t-tau, p-tau181), by ELISA; and FBP-PET uptake, by standard uptake value ratio (SUVr). We stratified patients according to the A/T classification. Clinical follow-up (>1 year) was available for 69 patients.

RESULT: APOEε4 carriers had lower cTREM2 levels compared to non-carriers in prodDLB (3.72±1.79vs.6.83±2.25ng/mL, p-value=0.0005, Figure 1). Furthermore, APOEε4 carriage itself was associated with lower cTREM2 levels in prodDLB (β(carriers)=-0.42, p-value=0.025) independently of AD core biomarkers. Conversely, APOEe4 carriage did not impact cTREM2 levels in DLB-dementia. cTREM2 levels across A-/+ and T-/+ DLB groups are represented in Figure 1. In prodDLB, higher cTREM2 levels were associated with higher Aβ42 (β=0.77, p-value=0.0002) and p-tau181 levels (β=0.612, p-value=0.002). In DLB-dementia, cTREM2 levels were associated only with p-tau181 (β=0.58, p-value=0.0001). Additionally, higher cTREM2 levels were associated with lower FBP-PET SUVr in prodDLB (β=-1.71, p-value=0.04). Notably, higher sTREM2 levels at baseline in prodDLB were related to a smaller subsequent longitudinal decrease in MMSE scores (β=1.11, p-value=0.01). No significant relationship was observed between baseline cTREM2 at a DLB-dementia stage and subsequent cognitive decline (β=-0.3, p-value=0.5).

CONCLUSION: APOEε4 carriage attenuates the TREM2-dependent microglial response in prodromal DLB, as reflected by lower CSF cTREM2 levels. Elevated cTREM2 levels in the prodromal phase are associated with slower cognitive decline, suggesting a protective role of microglial activation during early disease stages. These findings suggest an early modulation of TREM2-driven microglial response by APOEε4 which influences DLB progression.},
}

Humans
Male
Female
Aged
Biomarkers/cerebrospinal fluid
*Apolipoprotein E4/genetics
*Alzheimer Disease/genetics/cerebrospinal fluid/pathology
*Lewy Body Disease/genetics/cerebrospinal fluid/diagnostic imaging/pathology
*Membrane Glycoproteins/cerebrospinal fluid
*Receptors, Immunologic
Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
tau Proteins/cerebrospinal fluid
Middle Aged
Aged, 80 and over

@article {pmid41436353,
year = {2025},
author = {Açık, MF and Alaylıoğlu, M},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102541},
doi = {10.1002/alz70855_102541},
pmid = {41436353},
issn = {1552-5279},
mesh = {Humans ; *ADAM10 Protein/genetics ; *Amyloid Precursor Protein Secretases/genetics ; *ADAM17 Protein/genetics ; *Alzheimer Disease/genetics ; *Polymorphism, Single Nucleotide/genetics ; *Membrane Proteins/genetics ; },
abstract = {BACKGROUND: Alpha-secretase, a member of the ADAM protein family, cleaves amyloid precursor protein (APP) within the amyloid-beta (Aβ) domain, preventing Aβ formation, a hallmark of Alzheimer's disease (AD). Alpha-secretase activity, primarily mediated by ADAM10 and ADAM17, has neuroprotective effects. ADAM10 and ADAM17 influence several proteins implicated in AD pathogenesis. For instance, ADAM10 facilitates the shedding of TREM2, which is critical for microglial activation, Aβ clearance, and inflammation control. ADAM17 modulates the release of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine linked to neuroinflammation and neuronal damage in AD. Dysregulation in these pathways due to genetic variations or altered enzymatic activity of ADAM10 and ADAM17 may exacerbate AD progression. Investigating genetic variations and their effects on enzyme activity is crucial for understanding the broader impact of ADAM10 and ADAM17 in AD pathogenesis and identifying potential therapeutic targets. Therefore, in this study, we aimed to identify non-synonymous single nucleotide polymorphisms (nsSNPs) in ADAM10 and ADAM17 and evaluate their potential pathogenicity in silico.

METHOD: SNPs and protein sequence data for ADAM10 and ADAM17 were retrieved from the dbSNP and Ensembl databases. Protein models were obtained from AlphaFold and modeled using Phyre2. The pathogenic potential of identified SNPs was assessed through SIFT, PolyPhen-2, PhD-SNP, PredictSNP1/2, Meta SNP, FATHMM, SNPs&GO, and CADD. Structural stability and disease relevance were evaluated with DynaMut2, MutPred, MUpro, mCSM, mCSM-Membrane, INPS-MD, and Missense3D, while protein region conservation was analyzed using PANTHER and Consurf.

RESULT: Initial findings suggest that rs1596019164, rs200737587 and rs1896150983 in ADAM10, as well as rs1339437801, and rs951262662 in ADAM17, may disrupt alpha-secretase activity, potentially altering Aβ production and contributing to AD progression. These variants could impact protein stability and enzymatic efficiency, further influencing disease mechanisms. Notably, some variants are located in conserved and functionally significant regions, suggesting a stronger pathogenic potential.

CONCLUSION: The analysis highlights the presence of variants with high pathogenicity scores, suggesting their significant role in disease mechanisms. This study identifies potentially pathogenic nsSNPs in ADAM10 and ADAM17 that may affect their alpha-secretase activity and contribute to AD pathogenesis. Further experimental validation is essential to confirm these results and clarify their roles in disease mechanisms.},
}

Humans
*ADAM10 Protein/genetics
*Amyloid Precursor Protein Secretases/genetics
*ADAM17 Protein/genetics
*Alzheimer Disease/genetics
*Polymorphism, Single Nucleotide/genetics
*Membrane Proteins/genetics

@article {pmid41436351,
year = {2025},
author = {Rodriguez, PR and Wang, W and Tsagkogianni, C and Feng, I and Morello-Megias, A and Jain, K and Vidal, N and Milosevic, A and Roussarie, JP},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102023},
doi = {10.1002/alz70855_102023},
pmid = {41436351},
issn = {1552-5279},
mesh = {Humans ; Reelin Protein ; *Alzheimer Disease/pathology/metabolism/genetics ; *Neurons/pathology/metabolism ; *Entorhinal Cortex/pathology/metabolism ; tau Proteins/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; Nerve Tissue Proteins/metabolism ; Male ; Female ; Cell Adhesion Molecules, Neuronal/metabolism ; Microglia/pathology/metabolism ; Aged ; Extracellular Matrix Proteins/metabolism ; },
abstract = {BACKGROUND: Stellate cells from layer II of entorhinal cortex (ECII) are one of the primary sites of pathological tau accumulation and neurodegeneration during preclinical stages of Alzheimer's disease (AD). Little is known about the pathological cascade taking place within these neurons or their neighbors, leading to neurofibrillary tangle formation. Exploring early transcriptional alterations in entorhinal cortex (EC) neurons is essential to find intervention points to curb the disease before symptom onset.

METHODS: Here we perform cell-type specific profiling of human EC at the onset of AD neuropathology, i.e. in postmortem tissue from individuals that were asymptomatic at death. We use single-nucleus RNAseq as well as fluorescence-activated neuron nucleus sorting, to determine the molecular changes that accompany pathological tau accumulation. We then use immunofluorescence and multiplex in situ hybridization, to follow up on specific pathways and neuron types.

RESULTS: We identify an expected early response to amyloid pathology by glial cells, in particular by disease-associated microglia. Importantly, we then provide the first insight into neuronal alterations that coincide with incipient tau pathology: we show evidence that the signaling pathway for Reelin, a putative AD resilience gene, is dysregulated in ECII neurons, while the secreted synaptic organizer molecules NPTX2 and CBLN4, emerging AD biomarkers, are downregulated in surrounding neurons. Investigation of the expression pattern of these genes in control EC, suggests a multicellular mechanism involving different types of neurons from layer II/III.

CONCLUSION: We highlight here the complex multicellular landscape of EC during the silent phase of AD, when the disease is still largely confined to this region. While the precise mechanisms of pathway dysregulation and the communication between the different highlighted cell types, remain to be discovered, our study paves the way for detailed characterization of the mechanisms governing NFT formation and opens long-needed novel therapeutic avenues.},
}

Humans
Reelin Protein
*Alzheimer Disease/pathology/metabolism/genetics
*Neurons/pathology/metabolism
*Entorhinal Cortex/pathology/metabolism
tau Proteins/metabolism
Neurofibrillary Tangles/pathology/metabolism
Nerve Tissue Proteins/metabolism
Male
Female
Cell Adhesion Molecules, Neuronal/metabolism
Microglia/pathology/metabolism
Aged
Extracellular Matrix Proteins/metabolism

@article {pmid41436338,
year = {2025},
author = {Silva, AMP and Gonçalves, OR and Tudella, GCN and Nascimento, MVS and Pereira, MAOM and Nantes, LAO and Fernandes, JVA and Quiroga, DG and Lima, DVS and Franco, ES and Maia, MBS},
title = {Intranasal insulin for mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2025.11.005},
pmid = {41436338},
issn = {0035-3787},
abstract = {BACKGROUND: Central insulin resistance has been implicated in the pathophysiology of Alzheimer's disease (AD), supporting the hypothesis that, in some individuals, AD may represent "type 3 diabetes." Intranasal insulin has been proposed as a non-invasive approach to enhance brain insulin signaling while minimizing peripheral metabolic effects, but clinical evidence remains inconsistent.

METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intranasal insulin with placebo in patients with mild cognitive impairment (MCI) or mild-to-moderate AD. Primary outcomes included changes in cognitive performance (ADAS-Cog13, CDR-SB, DSRS, delayed recall) and functional ability (ADCS-ADL). Secondary outcomes included cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau, phosphorylated tau) and safety endpoints. Literature searches were performed in PubMed, Embase, and Cochrane Central up to April 2025. Random-effects models were used to pool effect estimates, and risk of bias was assessed using the Cochrane RoB 2 tool.

RESULTS: Five RCTs enrolling 540 participants met the inclusion criteria. Pooled analyses showed no significant differences between intranasal insulin and placebo for ADAS-Cog13 (mean difference: -1.09 [95% CI: -4.89; 2.71]), ADCS-ADL (mean difference 0.06 [-0.33; 0.45]), CDR-SB, DSRS, or delayed recall. No significant effects were observed on CSF Aβ42, total tau, or p-tau181. Gastrointestinal adverse events were more frequent with insulin (risk ratio: 1.57; [95% CI: 1.15; 2.14]), whereas cardiovascular events were less frequent (risk ratio: 0.30 [0.12; 0.79]). No differences were found for other safety outcomes, and discontinuation rates were comparable between groups.

CONCLUSION: Intranasal insulin was generally well tolerated but did not produce meaningful improvements in cognitive, functional, or biomarker outcomes in patients with MCI or mild-to-moderate AD. Current evidence does not support its routine clinical use, and further trials with standardized dosing, longer follow-up, and biomarker-stratified designs are warranted to clarify its therapeutic potential.},
}

@article {pmid41436285,
year = {2025},
author = {Ribeiz, SRI and Caria, LB and Santos, W and Pasqualucci, CA and Nitrini, R and Ferrioli, E and Grinberg, LT and Leite, REP and Nunes, PV and Mantelli, CN and Suemoto, CK},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102228},
doi = {10.1002/alz70855_102228},
pmid = {41436285},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/pathology/psychology ; Aged ; Middle Aged ; Neurofibrillary Tangles/pathology ; *Brain/pathology ; *Adverse Childhood Experiences ; Plaque, Amyloid/pathology ; Aged, 80 and over ; Cohort Studies ; Surveys and Questionnaires ; },
abstract = {UNLABELLED: Relationship between childhood trauma and Alzheimer´s disease pathological changes in a psychiatric sample.

BACKGROUND: The stress resulting from traumatic events throughout life is often associated with an increased risk of developing mental disorders. The damaging effects of childhood trauma are widely presented in specific psychiatric conditions. Some studies suggest the potential occurrence of neurocognitive deficits in individuals exposed to adverse childhood experiences. To our knowledge there are no studies investigating neuropathological changes in individuals exposed to early trauma. This is an original study that aims to assess the possible association between the occurrence of childhood trauma and the development of Alzheimer´s disease anatomopathological (AP) changes.

METHODS: We included 68 participants of this study from Biobank for Aging Studies of the University of Sao Paulo (BAS-USP). Subjects were previously diagnosed with a psychiatric disorder using Structured Clinical Interview for DSM-IV Disorders (SCID) for Axis I, informant part. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ). AD-type neuropathology was evaluated using the Consortium to Establish a Registry for AD (CERAD) criteria for neuritic plaque burden, and the Braak and Braak staging for neurofibrillary tangle pathology. The cohort was dichotomized into 2 groups: Braak stage 0 vs. Braak stage >0 and CERAD stage 0 vs.CERAD >0. Demographic and clinical characteristics were compared between groups using the Student's t-test, Mann-Whitney U test, chi-square test, or Fisher's exact test. To investigate the association of childhood trauma (measured by the total score of CTQ) with AP neuropathology, we employed multivariable ordinal logistic regression models for both Braak and CERAD stages, adjusted for age, sex, education, and race.

RESULTS: Demographic analysis (Table 1) showed that younger age was associated with Braak=0 (p <0.001) and CERAD=0 (p <0.001). Braak=0 was also associated with a higher level of education (p = 0.025). The CTQ score did not show a significant effect on Braak and CERAD scores (Tables 2 and 3, respectively).

CONCLUSION: Our preliminary data does not support a relationship between AD-related pathology and childhood trauma in a psychiatric sample. Subsequent studies with greater sample size are encouraged to better investigate whether there is a link between AD-type neuropathology and childhood traumatic experiences.},
}

Humans
Male
Female
*Alzheimer Disease/pathology/psychology
Aged
Middle Aged
Neurofibrillary Tangles/pathology
*Brain/pathology
*Adverse Childhood Experiences
Plaque, Amyloid/pathology
Aged, 80 and over
Cohort Studies
Surveys and Questionnaires

@article {pmid41436281,
year = {2025},
author = {Agrawal, S and Leurgans, SE and Ayton, S and Wagner, M and Agarwal, P and Bennett, DAA and Bush, AI and Schneider, JA},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102215},
doi = {10.1002/alz70855_102215},
pmid = {41436281},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Iron/metabolism ; Aged, 80 and over ; *Cognitive Dysfunction/pathology/metabolism ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Brain/pathology/metabolism ; Aged ; *Alzheimer Disease/pathology/metabolism ; Neuropsychological Tests ; Longitudinal Studies ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is a common brain pathology associated with Alzheimer's Disease (AD) and cognitive decline. Iron is an essential micronutrient for brain health; elevated brain iron is associated with cognitive decline in our prior studies. This study aims to explore the association between CAA and brain iron and to examine whether the association between CAA and cognitive decline is modified by elevated iron levels. We hypothesized that persons with CAA would exhibit higher brain iron levels, and that higher iron levels would contribute to accelerated cognitive decline independently of AD neuropathologic changes (ADNC).

METHOD: Data came from the Rush Memory and Aging Project (N = 680, mean age at death 90 ± 6.1 years, 70% women). Participants completed baseline and longitudinal cognitive assessments and underwent detailed neuropathologic evaluation for CAA, ADNC, and other brain pathologies. Severity of CAA (none, mild, moderate and severe) was assessed from the four neocortical regions using immunohistochemistry against Aβ antibody. Brain iron level in the inferior temporal cortex was assessed using Inductively Coupled Plasma Mass Spectrophotometry and a composite mean z-score was generated. Linear regression and mixed-effects models, adjusted for age-at-death, sex, education, ADNC, and other pathologies, were used for analysis.

RESULT: The mean follow-up before death was 6.7 ± 3.8 years. Over one-third of participants (N = 243) had moderate-to-severe CAA, and mean brain iron was 52 (SD=14) μg/g. CAA was associated with higher iron levels (Est=0.018, SE=0.004, p = <0.001). When examining associations with cognitive change, both CAA and elevated iron level were independently associated with faster decline in global cognition and three cognitive domains (episodic, semantic, and perceptual speed) (all p <0.024). High iron was also associated with steeper decline in working memory (p = 0.001); CAA was associated with steeper decline in visuospatial orientation (p = 0.018). Furthermore, in participants with high iron levels, CAA was associated with steeper perceptual speed decline (Est=-0.125, SE=0.048, P=0.008). No other interactions were found between CAA and iron for cognitive decline.

CONCLUSION: Together, these findings demonstrate that the level of brain iron is associated with the clinical impact of CAA in older age.},
}

Humans
Female
Male
*Iron/metabolism
Aged, 80 and over
*Cognitive Dysfunction/pathology/metabolism
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Brain/pathology/metabolism
Aged
*Alzheimer Disease/pathology/metabolism
Neuropsychological Tests
Longitudinal Studies

@article {pmid41436276,
year = {2025},
author = {Coronel, I and Patel, H and Wallace, A and Soni, D and Martinez, P and Rangel-Barajas, C and Oblak, AL and Reeves, CAL and Landreth, GE and Moutinho, M},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102381},
doi = {10.1002/alz70855_102381},
pmid = {41436276},
issn = {1552-5279},
mesh = {Animals ; *Niacin/pharmacology/administration & dosage ; Microglia/metabolism/drug effects/pathology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism ; tau Proteins/metabolism ; *Receptors, G-Protein-Coupled/metabolism/genetics ; Hippocampus/metabolism/pathology/drug effects ; *Tauopathies/pathology/metabolism ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid-b plaques, intraneuronal neurofibrillary tangles, and a robust immune response. Dietary intake of niacin (nicotinic acid) has been correlated with decreased risk of AD and age-related cognitive decline. We have recently shown that niacin stimulates the receptor HCAR2 to induce a protective microglial phenotype and attenuated disease severity in an amyloid mouse model of AD. However, the therapeutic potential of HCAR2 in tauopathy remains unknown.

METHODS: To investigate the contribution of HCAR2 on tau pathology, we used the tauopathy mouse model PS19. We employed two different strategies of niacin treatment, daily oral gavage (100 mg/kg) for 30 days between 9-10 months of age, and a niacin-enriched diet between 6-9 months of age. To assess the effect of niacin on tau pathology, we analyzed motor phenotype, microglial and synaptic markers, as well as the levels of tau species in PS19 mice.

RESULTS: Our preliminary findings indicate that HCAR2 expression is significantly elevated in hippocampal microglia of PS19 mice. Oral niacin treatment ameliorates motor coordination deficits and prevents neuronal loss, suggesting a restoration of synaptic integrity. Furthermore, genetic deletion of the HCAR2 receptor in PS19 mice, accelerated the onset of motor deficits and exacerbated the accumulation of pathogenic species of tau. These results suggest that HCAR2 is protective in tau pathology and activating this receptor could serve as a promising pharmacological strategy to mitigate disease severity.

CONCLUSION: Our findings suggest that alterations in hippocampal HCAR2 expression may play a role in tau pathology. Niacin treatment improved motor coordination but did not affect the clasping reflex. In addition, niacin improved expression patterns of structural synaptic proteins. These results indicate that HCAR2 activation may help reduce disease severity. However, further studies are needed to clarify the underlying mechanisms. Overall, this research highlights a novel role for HCAR2 in tauopathies and supports the potential repurposing of existing niacin formulations as a therapeutic approach for Alzheimer's disease.},
}

Animals
*Niacin/pharmacology/administration & dosage
Microglia/metabolism/drug effects/pathology
Mice
Disease Models, Animal
Mice, Transgenic
*Alzheimer Disease/pathology/metabolism
tau Proteins/metabolism
*Receptors, G-Protein-Coupled/metabolism/genetics
Hippocampus/metabolism/pathology/drug effects
*Tauopathies/pathology/metabolism
Male

@article {pmid41436244,
year = {2025},
author = {Sheu, KM and Murdock, MH and Sun, N and Kellis, M and Tsai, LH},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102245},
doi = {10.1002/alz70855_102245},
pmid = {41436244},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/immunology/genetics/metabolism ; *Meninges/pathology/metabolism ; Male ; Female ; Aged ; Transcriptome ; Brain/pathology/metabolism ; tau Proteins/metabolism ; Endothelial Cells/metabolism ; },
abstract = {BACKGROUND: The meninges comprise several layers of connective tissue that regulate the influx and efflux of fluid, protein, and immune cells to and from the brain parenchyma. However, it remains unclear how different cell types within the meninges contribute to the increasing dysfunction of this neurovascular-immune interface during Alzheimer's Disease (AD) progression.

METHOD: Here, we profile single nuclei transcriptomes of leptomeninges from 51 individuals with varying degrees of Alzheimer's pathology.

RESULT: We identify fibroblasts, cell types of the meningeal vasculature, including endothelial cells and smooth muscle cells, and immune cells such as macrophages and lymphocytes. We find that increased global AD pathology is associated with endothelial cell and macrophage downregulation of gene programs associated with antigen presentation. Analysis of matched samples from the prefrontal cortex of a subset of 22 patients show a concordant pattern of decrease in antigen presentation programs in individuals with the greatest amyloid/tau burden.

CONCLUSION: Our findings point to a concomitant leptomeningeal and brain parenchymal dysfunction of humoral immunity associated with worsened AD pathology, suggesting a target for systemic immune therapy.},
}

Humans
*Alzheimer Disease/pathology/immunology/genetics/metabolism
*Meninges/pathology/metabolism
Male
Female
Aged
Transcriptome
Brain/pathology/metabolism
tau Proteins/metabolism
Endothelial Cells/metabolism

@article {pmid41436240,
year = {2025},
author = {Dzodic, I and Aleksić, P and Šarčević, M and Lazic, U and Vrlješ, A and Lešić, A and Salak-Djokic, B and Ilic, V and Stojmenovic, GM and Stefanova, E and Stojkovic, T},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102114},
doi = {10.1002/alz70855_102114},
pmid = {41436240},
issn = {1552-5279},
mesh = {Humans ; Female ; Middle Aged ; Adult ; Neuropsychological Tests ; *Apolipoprotein E4/genetics ; Aged ; *Alzheimer Disease/genetics ; Cognitive Reserve/physiology ; Risk Factors ; Heterozygote ; },
abstract = {BACKGROUND: Over 65% of people with late-onset Alzheimer's Disease (AD) are women. It is hypothesized that the higher rate of AD in women compared to men may be because women are more negatively affected by some of the known AD risk factors, particularly apolipoprotein E e4 allele (+APOE-e4).

METHOD: We recruited 114 healthy female volunteers aged 30-65 years among employes of the Belgrade University. The exclusion criteria were conditions affecting communicative ability and/or safe engagement in the interventions, as well as presence of any neurological, psychiatric, medical condition or iatrogenic cause known to affect the brain structure and/or function. All participants underwent a detailed assessment including basic demographic data, data on vascular risk factors, mood scales and comprehensive neuropsychological assessment as well as Cognitive Reserve Index Questionnaire (CRIq). Statistical analysis was done using SPSS20.

RESULT: Average age of all participants was 48,15±8,41 and average years of education was 19,02. In this cohort, which included 27 APOE4 heterozygotes, 2 homozygotes, and 85 non-carriers. Since there were only 2 homozygotes, we compared heterozygotes to non-carriers. Heterozygotes had a mean age of 46.27±7.91, and non-carriers had a mean age of 48,54±8.62. No significant differences were observed when compared neuropsychological measures by domain (i.e., attention, working memory, executive functions, verbal and visual memory, visuospatial and language functions).

CONCLUSION: We did not find differences in cognitive performance in healthy working-age females regarding their APOE4 carrier status. More research is needed on this kind off cohorts especially with APOE4 homozygous to better understand the onset of cognitive disturbances connected with APOE polymorphism.},
}

Humans
Female
Middle Aged
Adult
Neuropsychological Tests
*Apolipoprotein E4/genetics
Aged
*Alzheimer Disease/genetics
Cognitive Reserve/physiology
Risk Factors
Heterozygote

@article {pmid41436230,
year = {2025},
author = {Liew, YJ and Maclean, M and Howell, GR and Carter, GW and Uyar, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101659},
doi = {10.1002/alz70855_101659},
pmid = {41436230},
issn = {1552-5279},
mesh = {Animals ; *Aging/genetics ; Female ; Mice ; *Brain/metabolism/pathology ; Male ; *Alzheimer Disease/genetics/pathology ; Mice, Inbred C57BL ; Species Specificity ; },
abstract = {BACKGROUND: Age is a major risk factor for Alzheimer's disease (AD), with brain aging heterogeneity influencing individual susceptibility. Studying variability in aging trajectories due to genetic background can help distinguish normal brain aging from early pathological processes. We have previously showed that the profound impact of genetic variation in modulating phenotypes associated with Alzheimer's disease (AD). In this study, we aim to identify normal brain aging signatures across nine wild-type strains to capture biological variability often overlooked in single-strain studies, such as those limited to C57BL/6J.

METHOD: Brain hemispheres from female and male mice (n = 4 per sex) across three age timepoints (4, 12, and 24 months) from nine wild-type strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, WSB/EiJ and BALB/cJ) were processed for RNA-Seq. Strain-specific aging signatures were identified by comparing 12- and 24-month data to the 4-month timepoint. Differential expression (DE) and gene set enrichment analyses identified gene modules and pathways associated with brain aging. WGCNA was used to identify common aging signatures across strains. Strain-specific signatures were aligned with human AD-related modules using AD biodomains to examine brain aging in the context of AD.

RESULT: At 12 months, DE genes and enriched pathways were limited and highly variable across strains compared to 4 months. By 24 months, distinct strain-specific aging signatures emerged, alongside common disruptions in immune response and inflammation. Notably, the magnitude and rate of these disruptions varied across strains, suggesting that baseline genetic differences play a critical role in shaping aging trajectories. Aligning these signatures with Alzheimer's disease (AD) biodomains revealed strain-specific overlaps with AD-related processes: NOD mice showed synaptic downregulation, WSB, NZO, and 129 strains exhibited proteostasis disruptions, and CAST mice displayed elevated lipid metabolism.

CONCLUSION: These findings reveal both shared and strain-specific molecular mechanisms of brain aging, emphasizing genetic influences on neurodegeneration risk. Aging signatures become more pronounced over time, with significant pathway enrichment emerging at 24 months, suggesting an acceleration of aging-related molecular processes. Studying heterogeneous aging trajectories is crucial for capturing dynamic changes with age while also highlighting baseline genetic differences that shape these processes.},
}

Animals
*Aging/genetics
Female
Mice
*Brain/metabolism/pathology
Male
*Alzheimer Disease/genetics/pathology
Mice, Inbred C57BL
Species Specificity

@article {pmid41436228,
year = {2025},
author = {Budinger, D},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102361},
doi = {10.1002/alz70855_102361},
pmid = {41436228},
issn = {1552-5279},
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism/genetics ; *Neurons/pathology/metabolism ; Animals ; tau Proteins/metabolism ; *Cell Communication/physiology ; },
abstract = {BACKGROUND: Microglia are crucial for maintaining brain health and neuronal function. A novel mechanism of microglia-neuron interaction, mediated by direct intercellular connections, namely through tunnelling nanotubes (TNTs), has recently been described between these cell types (Scheiblich et al., 2024). Preliminary data in mice cells suggest that microglia can form TNTs with neurons and free those from pathological protein aggregates made of hyperphosphorylated tau or α-syn, and promoting protein degradation (Scheiblich et al., 2024). Additionally, microglia were shown to share their healthy mitochondria with burdened neurons through TNT, reducing oxidative stress and restoring neuronal health. Failure of such a neuroprotective mechanism may, in turn, be causative for neurodegeneration. Beyond supporting individual cells, TNT-mediated interactions enhance the collective function of microglial and neuronal populations, mitigating inflammation and neuronal dysfunction.

METHOD: We employ induced pluripotent stem cells (iPSCs) derived from Alzheimer's disease patients and healthy controls. These iPSCs are differentiated into cortical neurons and microglia, then cocultured to investigate TNT formation and the dynamics of aggregated protein transfer between these cell types, using high resolution microscopy techniques. Additionally, we evaluate how disease genotypes influence TNT formation parameters.

RESULT: Our findings confirm the presence of TNTs between iPSC-derived neurons and microglia. We show that the genetic background of these cells influences TNT morphology, including their length, diameter, and the number of TNTs per cell. Live imaging analyses further reveal that TNT dynamics-such as their formation speed, persistence over time, and the transfer kinetics of aggregated proteins and organelles-differ between control and patient-derived cultures.

CONCLUSION: In conclusion, this study confirms the formation of tunneling nanotubes (TNTs) between iPSC-derived neurons and microglia, revealing their role in clearing pathological protein aggregates and exchanging organelles. Genetic background significantly influences TNT morphology and dynamics, affecting neuroprotective processes. These findings deepen our understanding of microglia-neuron interactions and highlight TNTs as potential therapeutic targets in neurodegenerative diseases.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism/pathology
*Microglia/metabolism/pathology
*Alzheimer Disease/pathology/metabolism/genetics
*Neurons/pathology/metabolism
Animals
tau Proteins/metabolism
*Cell Communication/physiology

@article {pmid41436227,
year = {2025},
author = {Liu, S and Bush, WS and Kunkle, BW and Byrd, GS and Reitz, C and Tosto, G and Vance, JM and Pericak-Vance, M and Haines, JL and Crawford, DC and Williams, SM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102132},
doi = {10.1002/alz70855_102132},
pmid = {41436227},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/genetics/ethnology ; Female ; Aged ; Genome-Wide Association Study ; Pedigree ; *Genetic Predisposition to Disease ; Cohort Studies ; White People/genetics ; Apolipoprotein E4/genetics ; Aged, 80 and over ; White ; },
abstract = {BACKGROUND: Late-onset Alzheimer disease (LOAD) is highly heritable. Twin studies estimated up to 80% heritability in European populations. However, the range of narrow sense LOAD heritability estimates across multiple populations remains poorly understood, as does the relative contribution of factors, such as APOE, recorded race/ethnicity, and cohort effects.

METHOD: We computed family-based heritability leveraging Alzheimer's Disease Sequencing Project (ADSP) pedigrees and genome-wide data across five distinct groups identified by recorded race/ethnicity: non-Hispanic White (n = 7,024; 404 pedigrees), non-Hispanic Black (n = 286; 13 pedigrees), Dominican (n = 3,988; 101 pedigrees), Puerto Rican (n = 132; 3 pedigrees), and Dutch Isolate (n = 655; 10 pedigrees). Family-based heritability was estimated adjusting for 1) age and sex, 2) age, sex, and APOE ε4 carrier status, 3) age, sex, APOE ε4 carrier status, and cohort, using both Statistical Analysis for Genetic Epidemiology (S.A.G.E.) and Sequential Oligogenic Linkage Analysis Routines (SOLAR).

RESULT: Regardless of method or adjustment, the resulting heritability estimates were highly variable across populations. Using S.A.G.E. adjusted for age and sex (model 1), estimates were highest for the Dutch isolates (78.3%) followed by non-Hispanic Blacks (39.1%), Dominicans (31.7%), and non-Hispanic Whites (29.1%). The inclusion of APOE ε4 carrier status (model 2) reduced heritability estimates by an average of 4.9%, with the largest reductions observed in non-Hispanic Blacks (6.7%) and non-Hispanic Whites (6.2%). Cohort adjustment (models 3) primarily affected the estimates for the non-Hispanic Whites (2.4% decrease), reflecting their greater contributions to cohort diversity. The Puerto Rican dataset failed to converge in all models due to small sample size. In general, narrow sense heritability estimates were almost always higher (45.4% - 80.0%) using SOLAR compared with S.A.G.E. (20.4% - 81.9%), reflecting differences in modeling and handling of missing data, while relative patterns and trends remained consistent regardless of magnitude.

CONCLUSION: While family-based estimates complement previous twin-based and genome-wide studies, the wide range of narrow sense heritability estimated across populations reflects substantial variability in population-specific and unmeasured extrinsic factors, such as lifestyle and behaviors, environmental exposures, and social determinants of health. Work supported by AG074865 and AG072547 is ongoing to estimate SNP-based heritability in overlapping participants for direct comparisons with family-based heritability.},
}

Humans
Male
*Alzheimer Disease/genetics/ethnology
Female
Aged
Genome-Wide Association Study
Pedigree
*Genetic Predisposition to Disease
Cohort Studies
White People/genetics
Apolipoprotein E4/genetics
Aged, 80 and over
White

@article {pmid41436197,
year = {2025},
author = {Paxhia-Poppaw, Z and Mattam, U and Hemmelgarn, B and Talari, NK and Krishnan, KC},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102266},
doi = {10.1002/alz70855_102266},
pmid = {41436197},
issn = {1552-5279},
mesh = {Animals ; Female ; Male ; *Apolipoprotein E4/genetics ; Apolipoprotein E3/genetics ; Mice, Transgenic ; Humans ; *Hippocampus/metabolism/pathology ; Diet, Western/adverse effects ; *Alzheimer Disease/genetics/metabolism ; Mice ; Mitochondria/metabolism ; Gene Knock-In Techniques ; Disease Models, Animal ; Genotype ; Sex Factors ; Apolipoproteins E/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that affects 6.5 million Americans aged 65 or older. Of the 6.5 million Americans with AD, 4.2 million of them are female[,] demonstrating that females are at higher risk for AD than males. One genetic risk factor for AD is APOE genotype. Apolipoprotein E (APOE) has three predominant alleles in humans: APOE2, APOE3, and APOE4. Individuals that are homozygous for APOE4 have up to a 15-fold increase in AD risk compared to APOE3 homozygous individuals. A third, modifiable risk factor for AD is diet. A high fat, 'Western' style diet has been shown to be associated with AD.

METHOD: 12-week-old human APOE3 and APOE4 knock-in mice of both sexes were fed a standard chow or Western diet for 16 additional weeks (total 6 months old) to investigate the effects of diet, sex, and APOE genotype. Hippocampus were isolated and processed for mitochondrial frozen respirometry and immunoblotting.

RESULTS: When fed a chow diet, there were no differences in respiration capacities between the APOE3 and APOE4 genotypes within the sexes. Chow-fed females of both genotypes displayed significantly decreased mitochondrial complex I- and IV- dependent respiration capacities in the hippocampus compared to chow-fed males. On a Western diet, APOE4 males displayed significantly decreased mitochondrial complex I- and IV- dependent respiration capacities as well as significant decreases in all electron transport chain complex proteins compared to APOE3 males.

CONCLUSIONS: Our findings suggest that female APOE4 KI mice exhibit reduced mitochondrial function under chow-fed conditions compared to male APOE4 KI mice, while a Western diet leads to mitochondrial maladaptation in male APOE4 KI mice. A Western diet in female mice is likely to further exacerbate the observed sex differences in mitochondrial function, resulting in a more significant decrease in respiration capacities in APOE4 females compared to APOE3 females and/or APOE4 males. Further research is needed to examine the effects of a Western diet on mitochondrial function in APOE4 female mice.},
}

Animals
Female
Male
*Apolipoprotein E4/genetics
Apolipoprotein E3/genetics
Mice, Transgenic
Humans
*Hippocampus/metabolism/pathology
Diet, Western/adverse effects
*Alzheimer Disease/genetics/metabolism
Mice
Mitochondria/metabolism
Gene Knock-In Techniques
Disease Models, Animal
Genotype
Sex Factors
Apolipoproteins E/genetics

@article {pmid41436193,
year = {2025},
author = {Shukla, S and Kadam, A and Goyani, S and Tomar, D and Jadiya, P},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101755},
doi = {10.1002/alz70855_101755},
pmid = {41436193},
issn = {1552-5279},
mesh = {Humans ; *Mitochondria/metabolism/pathology ; *Calcium/metabolism ; *Neurons/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Astrocytes/metabolism ; Microglia/metabolism ; Calcium Channels/metabolism ; },
abstract = {BACKGROUND: We and others have demonstrated that mitochondrial dysfunction, particularly excessive mitochondrial calcium (mCa[2+]) accumulation in neurons, serves as an early hallmark of Alzheimer's disease (AD), driving neuronal cell death and metabolic dysregulation. While genetic modulation of mCa[2+] uptake and efflux in neurons shows promise in mitigating mitochondrial dysfunction. However, AD pathology involves disrupted coordination among neurons, microglia, and astrocytes. These cell-specific mechanisms remain poorly understood. Our study addresses this critical gap by investigating cell-type-specific differences in mCa[2+] flux and signaling under normal and AD conditions.

METHOD: To model AD, we generated stable human neuronal (SH-SY5Y), microglia (HMC3) and astrocyte (SVGp12) cell-line harboring AD-linked APP mutations (Swedish, Florida and London; APPswe/F/L). We analyzed the expression of the mitochondrial calcium uniporter (mtCU) using qRT-PCR and assessed mCa[2+] influx and efflux using ratiometric Ca[2+] reporter Fura-FF. We measured mitochondrial calcium retention capacity (CRC) to evaluate the Mitochondrial Permeability Transition Pore (MPTP) opening. Additional assays measured ATP, NADH, cell death, mitochondrial structure, membrane potential and mitochondrial ROS using a combination of imaging and biochemical approaches. Mitochondria isolated by sucrose-density gradient centrifugation were analyzed for lactylation, a novel post-translational modification, via western blotting.

RESULT: Our results reveal that mitochondrial dysfunction occurs in all brain cells, with neurons showing the highest susceptibility to cell death and reduced bioenergetics. Astrocytes and microglia exhibit elevated mCa[2+] signaling, higher uptake rates, and greater calcium retention capacity compared to neurons, reflecting cell-specific roles in energy demand and stress responses. Notably, cell-specific differences in lactylation were observed, with significantly higher expression in microglia and astrocytes, suggesting a role in mitochondrial functional regulation.

CONCLUSION: Cell-specific mCa[2+] signaling dynamics influence the metabolic and pathophysiological contributions of brain cells to AD. Identifying the regulatory mechanisms underlying mCa[2+] signaling dysregulation in each cell type offers potential therapeutic targets to restore cellular communication and function. Our findings provide insights into mitochondrial bioenergetics, cell death pathways, and AD progression, paving the way for novel therapeutic strategies targeting brain cell-specific mechanisms.},
}

Humans
*Mitochondria/metabolism/pathology
*Calcium/metabolism
*Neurons/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
Astrocytes/metabolism
Microglia/metabolism
Calcium Channels/metabolism

@article {pmid41436175,
year = {2025},
author = {Greenfest-Allen, E and Leung, YY and Lee, WP and Kuzma, A and Valladares, O and Bush, WS and Martin, ER and Naj, AC and Schellenberg, GD and Wang, LS},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101956},
doi = {10.1002/alz70855_101956},
pmid = {41436175},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics ; *Genomics ; Precision Medicine ; },
abstract = {BACKGROUND: In this introductory talk, we embark on a journey through the genomic frontiers of Alzheimer's disease (AD) research, illuminating the wide range of opportunities the pioneering Alzheimer's Disease Sequencing Project (ADSP) offers to AI/ML researchers. From predictive modeling to identifying novel biomarkers and therapeutic targets, we will explore the vast landscape of possibilities for ADSP data-driven discoveries that can help shape the future of Alzheimer's research and precision medicine.

METHOD: ADSP integrates numerous projects that collectively unravel the intricate genetic landscape of AD with the primary objective of advancing precision medicine for the millions affected globally by this devastating disease. Working toward the goal of sequencing and analyzing up to 150,000 complete genomes and associated clinical and functional data in the next five years, ADSP has amassed an unprecedented wealth of genomic data from diverse populations, providing a comprehensive and holistic understanding of the genetic underpinnings of AD.

RESULT: This presentation serves as a primer, exploring various components of the ADSP and discussing the unprecedented resources it presents AI/ML researchers: (1) Diversity Initiative: The ADSP places a paramount emphasis on diversity, ensuring the inclusion of a wide range of populations in its genomic dataset. The current (release 5) dataset includes whole genomes from 57,302 unique participants, including 6,875 with African ancestry, 5,523 with Asian, and 15,390 Hispanic/Latino individuals. (2) Phenotype Harmonization: Harmonizing phenotypic data across diverse cohorts is a critical aspect of the ADSP, facilitating meaningful comparisons and analyses. (3) Open Access Initiative: unrestricted access to harmonized summary statistics, curated genetic associations, and functional annotations enables generation of task- and domain-specific knowledge bases. (4) Functional Genomics: Moving beyond genetic variations, the ADSP incorporates functional genomics to discern the biological mechanisms at play.

CONCLUSION: The potential of AI/ML within the ADSP serves to emphasize the need for collaborative initiatives between AI/ML researchers and the broader Alzheimer's research community. The synergy between these fields holds the key to unlocking breakthroughs that can translate genomic insights into tangible clinical advancements.},
}

Humans
*Alzheimer Disease/genetics
*Genomics
Precision Medicine

@article {pmid41436171,
year = {2025},
author = {Marola, OJ and Kanyinda, JN and Liporace, EC and Howell, GR},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101963},
doi = {10.1002/alz70855_101963},
pmid = {41436171},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Alzheimer Disease/genetics/pathology ; *Cerebral Amyloid Angiopathy/genetics/pathology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Blood-Brain Barrier/metabolism/pathology ; Receptor, TIE-2/metabolism/genetics ; Male ; Female ; Angiopoietin-2/genetics/metabolism ; Humans ; Amyloid beta-Peptides/blood ; Brain/pathology/metabolism ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) co-occurs with neurodegeneration in Alzheimer's disease (AD). Here, genetic backgrounds with CAA susceptibility (WSB.APP/PS1) and resilience (B6.APP/PS1) are leveraged to map CAA-susceptibility loci. Furthermore, blood-brain barrier (BBB) compromise has been hypothesized to impair amyloid clearance and promote vascular deposition. Endothelial TIE2 deactivation has been shown to weaken BBB integrity in other models and may therefore drive CAA. TIE2 activation (pTIE2) is inhibited by endogenous ANGPT2, which can be genetically reduced to increase pTIE2. This study investigates the efficacy of pTIE2 elevation in preventing CAA in AD.

METHODS: To map CAA-susceptibility loci, B6.APP/PS1 and WSB mice were crossed, generating BXW.APP/PS1 (F1) offspring. To determine haplosufficiency of these alleles, CAA was evaluated in BXW.APP/PS1 mice (n =  6/sex). F1 mice were intercrossed to generate heterogeneous F2 progeny (n =  50/sex), which were evaluated for CAA. F1 mice were then bred to include Angpt2 heterozygosity (BXW.Angpt2[-/+]APP/PS1) to evaluate the effects of pTIE2 elevation on AD and CAA progression. Brain sections were evaluated for CAA (X34+ deposits within CD31+, COL4+, and/or αSMA+ vasculature) and neuronal cell (NEUN+) loss using immunohistochemistry, and plasma was analyzed for levels of Aβ42 and Aβ40.

RESULTS: CAA was significantly increased in BXW.APP/PS1 compared to founder strains at 8 months, and F2 mice exhibited varying CAA severity. BXW.APP/PS1 and BXW.Angpt2[-/+]APP/PS1 mice had significantly elevated plasma Aβ42 and Aβ40 levels compared to WSB.APP/PS1 and B6.APP/PS1 mice. However, Angpt2 heterozygosity did not alter plasma Aβ42 or Aβ40 levels, CAA severity, or NEUN+ cell counts within the cortex or hippocampus.

CONCLUSIONS: The robust CAA observed in BXW.APP/PS1 suggests that heterozygous loci promote CAA. The variability in CAA severity among F2 mice indicates that CAA-susceptibility loci are likely mappable. F2 SNP analysis and R/qtl2 software are being used to identify candidate loci associated with CAA. While pTIE2 elevation did not appear to affect CAA pathogenesis, candidate alleles from our F2 mapping study will be tested to determine whether CAA can be attenuated through genetic and pharmacological interventions.},
}

Animals
Mice
*Alzheimer Disease/genetics/pathology
*Cerebral Amyloid Angiopathy/genetics/pathology/metabolism
Mice, Transgenic
Disease Models, Animal
Blood-Brain Barrier/metabolism/pathology
Receptor, TIE-2/metabolism/genetics
Male
Female
Angiopoietin-2/genetics/metabolism
Humans
Amyloid beta-Peptides/blood
Brain/pathology/metabolism
Genetic Predisposition to Disease

@article {pmid41436170,
year = {2025},
author = {Augustinack, J and Rodríguez, JL and Chadha, S and Frosch, MP and van der Kouwe, AJW},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102022},
doi = {10.1002/alz70855_102022},
pmid = {41436170},
issn = {1552-5279},
mesh = {Humans ; *Entorhinal Cortex/pathology/metabolism ; *tau Proteins/metabolism ; Male ; Female ; Aged ; Aged, 80 and over ; *Alzheimer Disease/pathology/metabolism ; *Hippocampus/pathology/metabolism ; Middle Aged ; Phosphorylation ; },
abstract = {BACKGROUND: Healthy memory function relies on an intact entorhinal-hippocampal circuit. Hippocampal volume is and has been a staple in neuroimaging to structurally assess memory status. However, in Alzheimer's disease, the presence of phosphorylated tau (p-tau) in hippocampus occurs late in disease progression after memory impairment has begun. The entorhinal cortex (EC) represents an early target to evaluate, given that p-tau forms earlier in EC than hippocampus and EC is the site responsible for the conversion from healthy cognitive aging to AD. Evaluating the entorhinal cortex, as a whole, is not sensitive or early enough in disease pathogenesis. To study this, we evaluated p-tau in EC by substructure, as well as other neighboring neurodegenerative pathologies (e.g. TDP-43) and even tau's proximity to vasculature.

METHOD: We obtained 18 postmortem brain samples to assess the selective vulnerability of particular subfields within EC. Medial temporal lobe tissue blocks were fixed, excised, cryoprotected, sectioned, and immunostained for p-tau CP13. We applied a subfield framework dividing the entorhinal cortex into eight subfields. Multiple anterior-posterior sections were staged for tau severity. We evaluated tau burden semi-quantitatively by subfield, building on Braak's staging by adding tau burden density. The neuronal (EC II) cell type was also indexed. We acquired also postmortem MRI at 100 micron isotropic resolution on a subset of samples (n = 12), which enabled us to visualize intracortical vessels in 3D. We manually labeled intracortical vasculature on the high-resolution MRI were reconstructed to show vessel density in the entire EC.

RESULT: Our results show that the posterior subfields, ECs and ECL, represent the selectively vulnerable subfields at early stage (preclinical BBI and BBII) before cognitive impairment. Spearman's test showed a positive correlation between posterior EC and higher tau semi-quantitative score (Spearman's r = 0.956). We created multiple individual anterior to posterior matrices for the tau histopathology per subfield to show selective vulnerability at a precise level. The vessels in EC were most dense in regions/subfields that showed the highest tau burden.

CONCLUSION: The tau validated matrices, reconstructed vessel maps and particular neuronal populations provide perspective of the neuronal environment and the contribution to vulnerability.},
}

Humans
*Entorhinal Cortex/pathology/metabolism
*tau Proteins/metabolism
Male
Female
Aged
Aged, 80 and over
*Alzheimer Disease/pathology/metabolism
*Hippocampus/pathology/metabolism
Middle Aged
Phosphorylation

@article {pmid41436169,
year = {2025},
author = {Fereydouni-Forouzandeh, P and Doyon, N and Duchesne, S},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101224},
doi = {10.1002/alz70855_101224},
pmid = {41436169},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Brain/metabolism ; *Models, Theoretical ; Glucose/metabolism ; },
abstract = {BACKGROUND: Metabolism is progressively downregulated below healthy performance in Alzheimer's disease, at the same time as cellular and molecular damage demand increased energy. Understanding these findings will require a multifactorial causal framework, which we propose to test via mathematical modeling (Chamberland et al., 2024). Hence, we conducted a scoping review of mathematical models of human cerebral metabolism to guide our future implementation efforts.

METHOD: Our scoping review was conducted following the 2020 PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. We used the following keywords while searching the PubMed database for relevant entries, from inception date to March 2024: "mathematical", "model", "brain", and "glucose". Inclusion criteria required references to be in English, original works, targeting human cerebral metabolism in humans. Abstracts and full texts were screened by two independent reviewers (PFF and SD), with data extracted by PFF. Out of 299 screened studies, 25 remained for full-text screening, leading to 14 selected studies for data extraction and qualitative analysis (Figure 1).

RESULT: Model replicability was overall adequate, with the inclusion of equations, parameters and initial conditions, which contributed to internal validity, while attention to the model's external validity was neglected (Figure 2). Only half of the selected studies referred to human measures in parametrization, and none performed quantitative validation with real-life findings. In line with our desired computational approach, 12 models used ordinary differential equations. Most models focused on short timeframes, with the longer applicable window being 12 hours. The theoretical focus of the models ranged from metabolite flow between neurons and astrocytes, to depictions of glucose carriers, metabolite signaling, biophysical, and electrochemical behaviors.

CONCLUSION: There exist computational models that appear able to capture essential components of brain metabolism on a short timeframe. Overall, these models had high internal but poor external validity. To assess the trajectory of lifetime brain metabolism, adjustments will be required.},
}

Humans
*Alzheimer Disease/metabolism
*Brain/metabolism
*Models, Theoretical
Glucose/metabolism

@article {pmid41436166,
year = {2025},
author = {Lin, J and Shi, J},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101801},
doi = {10.1002/alz70855_101801},
pmid = {41436166},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/immunology/genetics/pathology ; Male ; Aged ; Female ; *T-Lymphocytes/immunology ; Single-Cell Analysis ; Microglia/immunology ; Macrophages/immunology ; Cohort Studies ; China ; Middle Aged ; Sequence Analysis, RNA ; Aged, 80 and over ; },
abstract = {BACKGROUND: Potential differences in immune characteristics between sporadic late-onset Alzheimer's disease (sLOAD) and sporadic late-onset AD (sEOAD) have not been well elucidate. Immune cells in the cerebrospinal fluid (CSF) can reflect the brain immune system dysregulation of patients.

METHOD: Here, we collected CSF of 9 sEOAD patients, 6 sLOAD patients, 11 age-matched controls for sEOAD, and 10 age-matched controls for sLOAD from patients in the China Aging and Neurodegenerative Initiative (CANDI) cohort, and performed single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq), obtaining a total of 52,719 single cells for further bioinformatics analysis.

RESULT: We found a reduction in the proportion of T cells and an increase in the proportion of microglia-like macrophages in the samples of AD patients. Microglia-like macrophages upregulate inflammation genes in AD patients. The proportion of clonally expanded CSF T cells in sLOAD patients was higher, indicating that antigen-specific T cells play a greater role in the disease process of sLOAD.

CONCLUSION: We revealed differences in the transcriptional signatures of immune cells in the CSF of sLOAD and sEOAD. In further studies, we plan to collect the publicly available scRNA-seq of brain from AD patients with age of disease onset information and combine these with our scRNA-seq data of CSF for integrated analysis to reveal the potential interactions between immune cells in CSF and brain parenchyma.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/immunology/genetics/pathology
Male
Aged
Female
*T-Lymphocytes/immunology
Single-Cell Analysis
Microglia/immunology
Macrophages/immunology
Cohort Studies
China
Middle Aged
Sequence Analysis, RNA
Aged, 80 and over

@article {pmid41436165,
year = {2025},
author = {Elyaman, W},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102122},
doi = {10.1002/alz70855_102122},
pmid = {41436165},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/immunology/genetics/pathology ; Male ; Aged ; Middle Aged ; Female ; Adult ; Aged, 80 and over ; *Aging/immunology ; Biomarkers/blood ; *Immunosenescence/immunology ; Transcriptome ; },
abstract = {BACKGROUND: Aging is the greatest risk factor for Alzheimer's disease (AD), with immunosenescence-the gradual decline in immune system function with age-playing a critical role in disease susceptibility. As individuals age, brain-resident microglia and circulating immune cells undergo functional changes that can compromise their ability to respond effectively to emerging pathology. Dysregulated immune responses, driven by immunosenescence, may exacerbate neuroinflammation and accelerate AD progression. Despite growing recognition of the link between aging, immune dysfunction, and neurodegeneration, no interventions specifically target the impact of immunosenescence during the prodromal stage of AD. Profiling immune changes associated with aging and their connection to early AD biomarkers could uncover druggable pathways, offering transformative opportunities to prevent or delay disease onset.

METHOD: To identify immune mechanisms underpinning preclinical AD, we performed single-cell RNA, and T cell and B cell receptor sequencing, capturing >439,000 transcriptomes from 205 participants (ages 29-81) in the Offspring Study of Racial and Ethnic Disparities in Alzheimer's Disease. Plasma proteomics data were also obtained from 86 participants. Immune cell phenotypes and gene expression were correlated with AD biomarkers, including plasma proteins, cortical thickness via MRI, cognitive performance, and parental AD diagnosis.

RESULT: Our analysis revealed distinct immune signatures associated with cortical integrity. B cell proportions positively correlated with left hemisphere cortical thickness, while CD8+ T cell proportions showed an inverse association. Within the CD8+ T cell population, naïve and mucosal-associated invariant T (MAIT) cells were enriched in individuals with preserved cortical structure, whereas effector memory cells were reduced. Transcriptomic profiling revealed downregulation of cytotoxicity, antigen processing, and antigen presentation pathways in T cells from individuals with greater cortical thickness and better cognitive function. Additionally, we identified an age-associated decline in T cell receptor (TCR) repertoire diversity and a reduction in MAIT cell proportions, highlighting the impact of immunosenescence on adaptive immune function and its potential link to neurodegenerative risk.

CONCLUSION: This study highlights the role of aging-related immunosenescence in shaping neuroimmune interactions linked to Alzheimer's disease risk. These findings underscore age-driven immune dysregulation as a key contributor to disease susceptibility and suggest potential targets for immune-based therapies to mitigate progression.},
}

Humans
*Alzheimer Disease/immunology/genetics/pathology
Male
Aged
Middle Aged
Female
Adult
Aged, 80 and over
*Aging/immunology
Biomarkers/blood
*Immunosenescence/immunology
Transcriptome

@article {pmid41436164,
year = {2025},
author = {Cheng, F and Hou, Y and Pieper, AA and Haines, JL and Cummings, JL},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101947},
doi = {10.1002/alz70855_101947},
pmid = {41436164},
issn = {1552-5279},
mesh = {Humans ; Genome-Wide Association Study ; *Alzheimer Disease/genetics/drug therapy ; Animals ; Mendelian Randomization Analysis ; *Machine Learning ; Quantitative Trait Loci/genetics ; *Artificial Intelligence ; Mice ; },
abstract = {BACKGROUND: Although high-throughput DNA/RNA sequencing technologies from the NIA-funded Alzheimer's disease sequencing project (ADSP) have generated massive genetic and genomic data in human disease, translation of these findings into new patient treatment has not materialized by lack of effective approaches, such as Artificial Intelligence (AL) and Machine Learning (ML) tools.

METHOD: To address this problem, we have developed and utilized AI/ML approaches, Mendelian randomization (MR), and large patient's genetic and functional genomic data to evaluate druggable targets using Alzheimer's disease (AD) as a prototypical example. We utilized the genomic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets across five human brain regions from three biobanks. We tested the outcome of Mendelian randomization across genome-wide association studies (GWAS) datasets with 275,540 AD cases and 1.55 million controls. We searched repurposable drugs using AI-assistant drugome-wide association studies from ∼80 million electronic health records.

RESULT: We identified ∼30 druggable genes supported by significant MR evidences. We pinpointed that an anti-inflammatory AD target of epoxide hydrolase 2 (EPHX2): (1) a pQTL lead SNP rs2741342 (PGWAS = 5.72×10[-13]; PpQTL = 1.19×10[-16]) located in an enhancer of EPHX2; and (2) a protein-coding variant of rs751141 (p.Arg287Gln) was associated with reduced EPHX2 protein expression (PpQTL = 5.50×10[-16]) from the AD knowledge portal. We experimentally validated that the EPHX2-p.Arg287Gln (a protective mutation) significantly reduced the level of phosphorylated-tau (ptau181) and increased neuron clumped size in AD patient iPSC-derived neurons. We demonstrated that EC5026 (a first-in-class, picomolar EPHX2 inhibitor) improves cognition in a 5xFAD mouse model. Wefurther identified that 12 drugs (i.e., trazodone [ADRA1A] and baclofen [GABBR1]) harboring MR-supported targets are significantly associated with reduced incidence of AD in 111,680 mild cognitive impairment (MCI) patients.

CONCLUSION: Combining genetics and real-world patient data via AI/ML technologies identifies potential therapeutic targets and medicines for AD. Further functional and clinical validation of candidate targets and drugs in ethnically diverse population are warranted.},
}

Humans
Genome-Wide Association Study
*Alzheimer Disease/genetics/drug therapy
Animals
Mendelian Randomization Analysis
*Machine Learning
Quantitative Trait Loci/genetics
*Artificial Intelligence
Mice

@article {pmid41436163,
year = {2025},
author = {Phuong, HT and Tomas, RF and Akamese, C and Mijares, A and Guo, S and Bell, LR and Yegorova, S and Ng, SK and Phillips, JL and Melloni, AN and Pletnikova, O and Clark, HB and Troncoso, JC and Hyman, BT and Ranum, LPW and Prokop, S and Nguyen, L},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101865},
doi = {10.1002/alz70855_101865},
pmid = {41436163},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; Male ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Female ; Aged ; Autophagy ; *Brain/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is prevalent in people ≥ 65-year-olds, which counts up to ∼75% dementia cases worldwide. AD patient is characterized by progressive cognitive impairment, the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary hyperphosphorylated tau (pTau) tangles. Molecular mechanisms of most AD cases are not fully understood. We recently identified poly-Glycine-Arginine containing (polyGR+) aggregates that frequently accumulate in AD autopsy brains. We also identified interrupted GGGAGA repeat expansions (exp) in CASP8 that produces polyGR+ protein accumulated in brain tissue from expansion AD carriers. Specific CASP8-GGGAGA[exp] variants are associated with increased AD risk. Previous studies suggested that impairment of autophagy-lysosomal pathway, which maintains cellular protein homeostasis, play important role in AD pathogenesis. In this study, we examine if polyGR+ aggregates are associated with known AD pathological hallmarks (Aβ, pTau). We also study if polyGR+ aggregates are linked with disruption of autophagy-lysosomal pathway.

METHOD: We performed immunohistochemical staining for polyGR, Aβ and pTau using the hippocampal sections from 133 AD cases, 30 controls, and 15 primary age-related tauopathy (PART) cases. We studied the levels of polyGR+ aggregate staining and Aβ and pTau deposition levels in the hippocampal regions. Double immunofluorescence (IF) staining of polyGR and autophagy-lysosomal markers (p62 and LC3B) was performed to study if polyGR co-aggregates with p62 and LC3B in AD autopsy brains.

RESULT: Consistent to our previous study, frequent a-polyGR positive aggregates are found in ∼50% AD autopsy brains but not in controls and PART cases (p <0.0001). PolyGR+ signal accumulates as cytoplasmic or nuclear puncta in CA regions, subiculum and presubiculum regions in the hippocampus of AD autopsy brains. We detect positive correlations of polyGR+ staining with Aβ (R[2]=0.2544, p = 0.0007) and pTau (R[2] =0.2822, p = 0.0003), which is stronger than the correlation of Aβ and pTau in the hippocampus (R[2]=0.1047, p = 0.0366). PolyGR+ aggregates co-localize with p62 and LC3B staining in polyGR+ AD brains.

CONCLUSION: Our data demonstrates that polyGR+ aggregates are an important proteinopathological feature in AD autopsy brains. Additionally, our data suggests that co-localization of autophagy and proteasome markers p62 and LC3B with polyGR+ aggregates could lead to dysregulation of autophagy-lysosomal pathway, which contributes to disease pathogenesis.},
}

Humans
*Alzheimer Disease/pathology/metabolism/genetics
Male
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Female
Aged
Autophagy
*Brain/pathology/metabolism
Neurofibrillary Tangles/pathology/metabolism
Aged, 80 and over

@article {pmid41436162,
year = {2025},
author = {Fu, H and Kim, TY and Acosta, DM and Sweeney, N and Vo, S and Wu, M and Hyman, BT and Nixon, RA},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102099},
doi = {10.1002/alz70855_102099},
pmid = {41436162},
issn = {1552-5279},
mesh = {Animals ; Humans ; *tau Proteins/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology/genetics ; Autophagy ; Male ; *Brain/metabolism/pathology ; Entorhinal Cortex/metabolism/pathology ; Female ; Neurons/metabolism ; },
abstract = {BACKGROUND: Higher ectodermal-neural cortex 1 (ENC1) RNA level is correlated with higher residual cognition in participants of the Religious Orders Study and the Rush Memory and Aging Project. Transcriptomic analyses show decreased overall ENC1 mRNA in human brains with Alzheimer's disease (AD) compared to control brains. We have previously identified ENC1 as one of the hub genes controlling tau homeostasis via the weighted gene co-expression network analysis of healthy donors. However, the relationship between ENC1 and tau remains unclear. We hypothesize that ENC1 interacts with tau and enhances tau clearance via the autophagy-lysosome pathway (ALP), inhibiting tau propagation.

METHODS: The co-immunoprecipitation and Duolink assay were used to measure the interaction between human ENC1 and tau in vitro and in human brains. The specific knockdown of ENC1 (mainly in the nucleus) in excitatory neurons (ENs) at the superficial layers of adult mouse entorhinal cortex (EC) was achieved by stereotaxic injection of AAV8-CaMKIIa-Cre in the EC of ENC1[flox/flox] mice. An autophagy reporter mouse (TRGL6) (mRFP-eGFP-LC3) and TRGL6;PS19 tau mice were used to measure the effect of ENC1 on autophagy dynamics. The tau propagation was measured by stereotaxic injection of a tau-propagation reporter virus (AAV8-hSyn-RFP-2A-V5-Tau) or TBS-soluble human tau seeds in the EC of ENC1[flox/flox] mice.

RESULTS: We found that ENC1 interacted with both total tau protein (TauC+) and pathological tau (TauY9+), and this interaction was significantly increased in human AD brains compared to controls. Conditional knockdown of ENC1 in ENs of TRGL6;ENC1[flox/flox] and TRGL6;PS19;ENC1[flox/flox] mice significantly reduced the number of single red puncta (autolysosomes) and increased the yellow puncta (autophagosome and poorly acidified autolysosomes), suggesting the ALP was impaired. Also, the knockdown of ENC1 specifically in ENs of the EC significantly increased the number of V5 only positive tau recipient neurons or MC1-positive (conformation-dependent tau) in the spreading areas such as deep layers of the EC and the hippocampal CA1. These results suggest that conditional knockdown of ENC1 in ENs could promote tau propagation in vivo.

CONCLUSIONS: We demonstrate that ENC1 is a novel modulator of tau protein homeostasis by regulating tau clearance and propagation probably via the regulation of ALP.},
}

Animals
Humans
*tau Proteins/metabolism
Mice
*Alzheimer Disease/metabolism/pathology/genetics
Autophagy
Male
*Brain/metabolism/pathology
Entorhinal Cortex/metabolism/pathology
Female
Neurons/metabolism

@article {pmid41436161,
year = {2025},
author = {Janve, VA and Seto, M and Klinger, HM and Brown, JA and Sperling, RA and Aisen, PS and Rissman, RA and Koran, MEI and Dumitrescu, L and Buckley, RF and Hohman, TJ and , },
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101170},
doi = {10.1002/alz70855_101170},
pmid = {41436161},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/genetics/blood ; Aged ; *tau Proteins/blood/genetics ; Biomarkers/blood ; Transcriptome ; Sequence Analysis, RNA ; Aged, 80 and over ; Amyloid beta-Peptides ; },
abstract = {BACKGROUND: pTau217 is a well validated plasma biomarker for Alzheimer's disease (AD), sensitive to the accumulation of amyloid pathology in the preclinical stages of disease. We leveraged whole blood RNA sequencing and plasma pTau217 measures of amyloid burden to identify blood transcriptomic gene-network changes that relate to plasma pTau217 levels in cognitively normal older adults. We then quantified the abundance of cell populations from the transcriptomic data to identify blood cell abundance alterations that correlate with plasma ptau217 levels.

METHOD: Whole blood RNA sequencing and plasma pTau217 data were obtained from 1739 participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. RNAseq data were aligned, sorted, counted, batch normalized, and iteratively adjusted for covariates. 20,718 genes were available for analysis following quality control. Plasma samples (n = 1597) were analyzed for pTau217 using the Eli Lilly and Company Diagnostics Laboratory immunoassay. Samples from 724 participants (63% females, mean age 71, 61% amyloid+) with RNA sequencing and biomarker data were used for analysis. Cell fractions were quantified using CIBERSORTx (LM22 used as reference) and WGCNA was used to calculate gene co-expression modules. Linear regression related gene module expression or cell fraction to mean pTau217 levels covarying for age, sex, education, APOE ε2 and ε4 status. Correction for multiple comparisons used the false discovery rate. Gene enrichment was performed using Gene Ontology.

RESULT: Five gene modules were associated with plasma pTau217. For the turquoise module (β=-0.81, p.fdr=0.005), higher expression was associated with higher p-tau217 while higher expression in the blue (β=-0.70, p.fdr=0.01), lightcyan (β=-0.68, p.fdr=0.01), grey60 (β=-0.64, p.fdr=0.02), and brown (β=-0.55, p.fdr=0.04) modules were associated with lower p-tau217. These modules were enriched for phagocytosis, ribonucleoprotein complex biogenesis, immunoglobulin mediated immune response, nucleosome assembly, and cytoplasmic translation pathway genes. In cell fraction analysis, higher predicted abundance of neutrophils related to ptau217 levels (β=0.33, p.fdr=0.03).

CONCLUSION: Our results demonstrate an association between immune response and epigenetic pathway genes with plasma pTau217 levels in preclinical AD. Future work will seek to clarify whether these signatures also relate to brain amyloid PET to evaluate blood transcription networks as complementary biomarkers to improve preclinical prediction.},
}

Humans
Female
Male
*Alzheimer Disease/genetics/blood
Aged
*tau Proteins/blood/genetics
Biomarkers/blood
Transcriptome
Sequence Analysis, RNA
Aged, 80 and over
Amyloid beta-Peptides

@article {pmid41436159,
year = {2025},
author = {Kayıklık, ZD and Çakır, B and Gülseren, İ and Bolat, ZB},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101906},
doi = {10.1002/alz70855_101906},
pmid = {41436159},
issn = {1552-5279},
mesh = {*Amyloid beta-Peptides/toxicity ; *Peptide Fragments/toxicity ; PC12 Cells ; Rats ; Animals ; Cell Survival/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Neuroprotective Agents/pharmacology ; Corylus/chemistry ; Humans ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease is associated with dementia and occurs due to the misfolding and extracellular accumulation of amyloid-beta (Aβ) protein in the brain. Aβ25-35 peptide is a toxic form of Aβ commonly used in in vitro models. Although no definitive cure exists, several FDA-approved drugs help patients maintain mental function. Bioactive peptides are specific protein fragments and are distinguished by their ability to promote positive effects on different neurodegenerative diseases. Bioactive peptides derived from hazelnuts (Corylus avellana L.) hold promise for neuroprotective effects against Alzheimer's disease.

METHOD: Alzheimer's disease model was established using PC-12 cell line treated with Aβ25-35. Toxic doses for the disease model were determined using resazurin-based cell viability assays. Subsequently, bioactive peptide derived from hazelnuts were applied to the Alzheimer's disease model, and the neuroprotective effect doses were identified through cell viability assays. Colony forming unit assay was performed to analyze the growth inhibition on Alzheimer's disease model. Cell cycle and Annexin V/PI assay was evaluated using flow cytometry. 2',7'-dichlorofluorescin diacetate (DCF-DA) reagent was used to detect intracellular ROS production by fluorescent microscopy.

RESULT: OC1 bioactive peptide from hazelnut ameliorated the cell viability of in vitro Alzheimer's model. OC1 peptide was further evaluated for their neuroprotective effects at the molecular level. Cell cycle analysis revealed that Alzheimer's model group (Aβ25-35 treated) showed G2/M phase arrest in cell cycle assay when compared to control. Conversely OC1 peptide treatment improved the G2/M arrest caused by Aβ25-35. Annexin V/PI results demonstrate that Aβ25-35 treated group induced late apoptosis, while OC1 peptide treatment reversed this effect. OC1 peptide exerted neuroprotective effect by reducing intracellular ROS formation compared to Aβ25-35 treated alone.

CONCLUSION: Our findings indicate that the newly synthesized bioactive peptide OC1 is promising as potential neuroprotective agents for neurodegenerative diseases and may offer encouraging results for the prevention of Alzheimer's disease. This study was supported by Türkiye Sağlık Enstitüleri Başkanlığı, grant number: 22740 TÜSEB. Attendance at this conference was supported by an AAIC 2025 Conference Fellowship.},
}

*Amyloid beta-Peptides/toxicity
*Peptide Fragments/toxicity
PC12 Cells
Rats
Animals
Cell Survival/drug effects
*Alzheimer Disease/drug therapy/pathology/metabolism
*Neuroprotective Agents/pharmacology
Corylus/chemistry
Humans
Reactive Oxygen Species/metabolism
Apoptosis/drug effects

@article {pmid41436158,
year = {2025},
author = {Sands, M and Benitez, BA and Wallace, CE and Patel, MP and Nykanen, NP and Yuede, CM and Eaton, SL and Pottier, CP and Cetin, A and Johnson, M and Bevan, M and Gardiner, W and Edwards, HM and Doherty, B and Harrigan, R and Kurian, D and Wishart, TM and Smith, C and Goodwin, N and Cirrito, JR},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101638},
doi = {10.1002/alz70855_101638},
pmid = {41436158},
issn = {1552-5279},
mesh = {Animals ; Humans ; *Alzheimer Disease/genetics/pathology/therapy ; Brain/pathology/metabolism ; Mice ; Lysosomes/enzymology/genetics ; Haploinsufficiency ; Genetic Therapy ; },
abstract = {BACKGROUND: Although lysosome dysfunction has been implicated in Alzheimer's disease (AD), it is unclear what level or type of dysfunction is pathogenic. We hypothesize that haploinsufficiency of lysosomal enzymes is associated with AD and that CNS-directed, AAV-mediated gene transfer can be an effective treatment.

METHOD: Although lysosome dysfunction has been implicated in Alzheimer's disease (AD), it is unclear what level or type of dysfunction is pathogenic. We hypothesize that haploinsufficiency of lysosomal enzymes is associated with AD and that CNS-directed, AAV-mediated gene transfer can be an effective treatment.

RESULT: Heterozygous protein-damaging mutations in several lysosomal enzyme genes are enriched in AD patients compared to matched controls. Proteomic analysis shows that the lysosomal storage disease pathway is activated in the brains of AD patients. There is a gene-dosage effect on Ab40 levels in brain ISF between WT, heterozygous, and homozygous PPT1 deficient mice. Although APP is not changed, the levels of a-, b-, and g-secretases are altered in PPT1 heterozygous mice in a pattern that favors an amyloidogenic pathway. Heterozygosity of PPT1 increases Ab plaques, insoluble Ab40 and Ab42 levels, and decreases the life span of 5xFAD mice. Consistent with the human genetic and murine data, the AD pathway is activated in heterozygous PPT1 sheep. AAV-mediated gene therapy in 5xFAD/PPT1+/- mice decreased the Ab burden, increased life span, and improved cognitive function. The effects of heterozygosity of the NAGLU, GALC, IDUA, and GUSB genes on Ab pathology were nearly identical to those observed for PPT1 heterozygosity.

CONCLUSION: These data strongly implicate heterozygosity of at least five, likely more, lysosomal enzyme genes in the development of AD and these genes might be effective therapeutic targets in certain genetically-defined forms of AD.},
}

Animals
Humans
*Alzheimer Disease/genetics/pathology/therapy
Brain/pathology/metabolism
Mice
Lysosomes/enzymology/genetics
Haploinsufficiency
Genetic Therapy

@article {pmid41436156,
year = {2025},
author = {Kim, J and Kim, K and Kum, J and Kim, Y and Kim, H},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101923},
doi = {10.1002/alz70855_101923},
pmid = {41436156},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/therapy/pathology ; Mice ; *Plaque, Amyloid/pathology ; Mice, Transgenic ; *Brain/pathology/metabolism ; Disease Models, Animal ; Peptide Fragments/blood ; *Ultrasonic Therapy/methods ; Humans ; },
abstract = {BACKGROUND: The accumulation of β-amyloid, the earliest pathological hallmark of Alzheimer's disease, contributes to neurodegenerative processes and cognitive decline. Recent studies highlight the potential of low-intensity ultrasound, characterized by its safety and neuromodulatory effects, to enhance existing neuromodulation approaches, offering an innovative therapeutic avenue for Alzheimer's disease.

METHOD: Focused ultrasound stimulation (FUS) was delivered to 5xFAD mice using implanted ultrasound transducers on their skulls. During a two-week period, five 5xFAD mice underwent low-intensity ultrasound stimulation while awake, with 30-minute sessions administered five days per week. Blood Aβ42 levels and brain amyloid plaque loads were subsequently assessed and compared with control mice.

RESULT: FUS treatment resulted in significant reductions in both the number and size of amyloid plaques, accompanied by an elevation in plasma Aβ42 levels. Importantly, no brain hemorrhages or significant alterations in GFAP levels were detected.

CONCLUSION: Transcranial Ultrasound Stimulation demonstrates safety and efficacy in reducing brain amyloid load, underscoring its potential as a promising therapeutic strategy for Alzheimer's disease.},
}

Animals
*Amyloid beta-Peptides/blood
*Alzheimer Disease/therapy/pathology
Mice
*Plaque, Amyloid/pathology
Mice, Transgenic
*Brain/pathology/metabolism
Disease Models, Animal
Peptide Fragments/blood
*Ultrasonic Therapy/methods
Humans

@article {pmid41436151,
year = {2025},
author = {Varma, S and Heath, LM and Malenfant, J and Leal, K and Britton, JS and Vu, M and Sieberts, SK and Suver, C and Pepe, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101428},
doi = {10.1002/alz70855_101428},
pmid = {41436151},
issn = {1552-5279},
mesh = {*Alzheimer Disease/genetics/etiology/pathology ; Humans ; Animals ; },
abstract = {BACKGROUND: To identify disease-modifying therapies and drug targets for Alzheimer's disease (AD), it is necessary to assess the impact of cellular and molecular dysfunction on disease aetiology. The AD Knowledge Portal (Portal) (https://adknowledgeportal.org), Exceptional Longevity Portal (ELITE) and Agora (https://agora.adknowledgeportal.org) are community-driven resources that support researchers as they: 1) identify new molecular hypotheses and mechanisms, 2) evaluate hypotheses via independent experimental assessments, and 3) prioritise new molecular mechanisms for therapeutic development.

METHOD: The Portals and Agora are free, open-access tools built to maximise therapeutic discovery by enabling researchers to re-use data from 41,000+ biospecimens collected from 12,000+ individuals across four species and browse or access analytical results related to putative drug targets. The Portals and Agora empower the research community with a trusted repository of data, computational and experimental tools and potential gene targets to test target hypotheses and therapeutics. The portals are also integrated with external Trusted Research Environments (TREs) like CAVATICA and integrate the portals with Terra and AD Workbench.

RESULT: The Portal supports research outputs from 55 grants (including the Accelerating Medicines Partnership-Alzheimer's Disease), each generating data and computational/experimental tools related to dementia and ageing. Utilizing samples from brain banks, longitudinal cohorts, and model systems, available data spans 55+ assays, including genomics, metabolomics, imaging, cognitive assessments, and more. Model systems in the Portal include iPSC-derived cell types and organoids and novel Late-Onset AD mouse models based on gene targets identified from human data. These mouse models are available with no limitation on use. The Portal also features a cloud-based analytical workspace providing access to preconfigured computational resources to process, integrate, and analyse data. A subset of the processed data is also presented in Agora, a visual results explorer that compiles evidence of genes' association with AD. Agora hosts a list of nominated targets and presents the results of omics analyses generated from Portal data. It also includes a catalogue of details and results from targeted validation studies.

CONCLUSION: The AD Knowledge Portal, the ELITE Portal and Agora offer the research community an accessible, rich data source, tools, and results.},
}

*Alzheimer Disease/genetics/etiology/pathology
Humans
Animals

@article {pmid41436150,
year = {2025},
author = {Malliou, G and Reus, LM and Pijnenburg, YAL and van der Flier, WM and Teunissen, CE and Visser, PJ and Ophoff, R and Tijms, BM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101527},
doi = {10.1002/alz70855_101527},
pmid = {41436150},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/classification/metabolism ; Aged ; Metabolomics ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is marked by molecular heterogeneity. We previously identified five distinct molecular AD subtypes based on CSF proteomics: neuronal hyperplasticity (S1), innate immune activation (S2), RNA dysregulation (S3), choroid plexus dysfunction (S4), and blood-brain barrier impairment (S5). These subtypes differ in proteins involved in metabolic processes, such as PKM and PYGL (S3) and ATP1A1 (S4), which suggests these subtypes also differ in affected metabolic processes. We investigated whether AD subtypes were associated with specific CSF metabolic signatures.

METHOD: We conducted untargeted metabolomics on the same CSF samples from 601 individuals in the Amsterdam Dementia Cohort, previously included in our CSF proteomic study (n = 416 AD, 185 controls|normal cognition/AD biomarkers; Table 1). Using HILIC-QTOF (metabolites) and GC-TOF (biogenic amines) platforms, we detected 2,011 metabolites, with 544 mapped to known classes. Metabolite levels were compared between subtypes and controls using linear regression models adjusted for age and sex (R v4.2.1). Metabolites with statistically different levels (p <0.05) underwent pathway enrichment analysis using MetaboAnalyst6.0.

RESULT: We found 993 metabolites with altered CSF levels between any of the AD subtypes compared to controls. The choroid plexus exhibited the most changes (S4:473, 47.6%) followed by innate immune activation (S2:339, 34.1%), RNA dysregulation (S3:315, 31.7%), blood-brain barrier (S5:287, 28,9%), and neuronal hyperplasticity (S1:242, 24.4%). These metabolites were mostly mapped to organic acids, carbohydrates, fatty acyls and alkaloids (Figure 1A). Organic acids were increased in S3/S5 but decreased in S1/S2/S4. Carbohydrates were elevated in S1/S2/S3/S5 but mainly reduced in S4 (Figure 1B). Fatty acyls increased in S1/S3/S5 and decreased in S4, while alkaloids increased in S3 and decreased in S1 (Figure 1B). While most metabolites were unique to each subtype (Figure 2), we observed common metabolites that were altered in the decreased categories of S4/S5, predominantly comprising organic acids and carbohydrates. Pathway analysis revealed enrichment for processes including compound trasport (S2/S4/S5), amino acid metabolism (S3/S1), tRNA aminoacylation (S2/S1), and glucose homeostasis (S3).

CONCLUSION: AD proteomic subtypes exhibit different CSF metabolomic alterations, reflecting heterogeneous pathophysiological mechanisms. This profiling could inform future subtype-specific therapies targeting metabolism. For example, therapies modulating glucose metabolism, typically tested in general AD populations, may be most effective for patients in S3.},
}

Humans
Male
Female
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/classification/metabolism
Aged
Metabolomics
Middle Aged
Cohort Studies

@article {pmid41436146,
year = {2025},
author = {Duff, KE and Bourdenx, M and Cauhy, PM and Prankerd, I},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102020},
doi = {10.1002/alz70855_102020},
pmid = {41436146},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Tauopathies/pathology/metabolism ; *Neurons/metabolism/pathology ; *Aging/pathology/metabolism ; tau Proteins/metabolism ; Disease Models, Animal ; *Alzheimer Disease/pathology/metabolism ; *Entorhinal Cortex/pathology/metabolism ; Humans ; Mice, Transgenic ; Male ; },
abstract = {BACKGROUND: Age is the greatest risk factor for Alzheimer's disease (AD) and aging is associated with decline in multiple pathways including cellular proteostasis efficiency, which has been shown to precipitate the accumulation of pathological proteins including tau. We are interested in whether there is an intersection between neuronal populations that are selectively vulnerable to age-related proteostasis deficits and those that are vulnerable to tauopathy. These data may help explain the phenomenon of primary age-related tauopathy (PART) (doi:10.1007/s00401-014-1349-0) and provide a framework to study the relationship between PART and AD.

METHOD: To test this, we have used a range of spatial biology and computational techniques, including spatial cell-typing and multi-plex imaging in aged mice, and compared vulnerable neuron populations to those affected by tauopathy in new, targeted mouse models of tauopathy (https://doi.org/10.1038/s41593-024-01829-7).

RESULT: During healthy aging, we have demonstrated that supragranular neurons from the entorhinal cortex uniquely accumulate the autophagy adaptor protein p62. Using a new spatial imaging technique, coppaFISH-3D, we identified that Layer2/3 intra-telencephalic projecting neurons of the entorhinal cortex (L2/3 IT ENT) are more likely to accumulate p62 than other L2/3 IT neurons. Those neurons are thought to be amongst the earliest ones affected by tau pathology. Building on a single-nuclei multiome dataset we showed that a gene network including synapse and calcium related genes was enriched in L2/3 IT ENT to be profoundly downregulated with aging, suggesting a functional impairment of those neurons. Such downregulation was not seen in neighbouring L2/3 IT neurons. 'Protected' neurons had higher expression of a proteostasis-related module, containing chaperone, lysosomal, and proteasome genes was observed. L2/3 IT ENT neurons fail to boost a proteostasis response potentially explaining p62 accumulation during ageing. We then assessed vulnerability to tau accumulation (including those phosphorylated at different epitopes) in the entorhinal cortex of a new MAPT KI mouse in situ, classifying affected neurons into fine transcriptomic subtypes. Affected neurons in the EC mapped to L2/3 IT ENT neurons.

CONCLUSION: These data strongly support the idea that neuronal populations that are vulnerable to declining proteostasis in older age are also vulnerable to accumulating tau.},
}

Animals
Mice
*Tauopathies/pathology/metabolism
*Neurons/metabolism/pathology
*Aging/pathology/metabolism
tau Proteins/metabolism
Disease Models, Animal
*Alzheimer Disease/pathology/metabolism
*Entorhinal Cortex/pathology/metabolism
Humans
Mice, Transgenic
Male

@article {pmid41436135,
year = {2025},
author = {Chen, J and Jiao, B and Shen, L},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101378},
doi = {10.1002/alz70855_101378},
pmid = {41436135},
issn = {1552-5279},
mesh = {Animals ; Humans ; *Alzheimer Disease/microbiology/pathology/cerebrospinal fluid ; Mice ; *Moraxella catarrhalis ; Male ; Female ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Aged ; Hippocampus/metabolism ; Mice, Transgenic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, has been linked to various hypotheses, including the Aβ cascade, tau protein hyperphosphorylation, and microbial inflammatory responses. However, the role of oral microbiota in AD pathogenesis remains unclear.

METHODS: Using the Illumina Novaseq 6000 platform for 16S rDNA sequencing and qPCR, the detection rate and expression of Moraxella catarrhalis were compared in the cerebrospinal fluid of 108 AD patients (based on the 2018 ATN framework) and 46 controls. To explore its role in AD pathogenesis, SY5Y-APPswe and SH-SY5Y cells were treated with varying concentrations of M. catarrhalis, pasteurized M. catarrhalis, outer membrane vesicles (OMVs), and UspA1 overexpression, with APP and Aβ expression analyzed via Western Blot and ELISA. In 5xFAD mouse models, M. catarrhalis and saline were administered intranasally, while PKH6-labeled OMVs and AAV-UspA1-EGFP were stereotactic injected into the hippocampus, followed by behavioral and pathological assessments.

RESULTS: The relative abundance of Moraxella species was significantly higher in the AD group, suggesting a potential association with AD pathogenesis. At the cellular level, we found that intervention with Moraxella catarrhalis and its extracellular vesicles, as well as overexpression of UspA1 protein, significantly upregulated APP and extracellular Aβ levels. In animal experiments, after Moraxella catarrhalis intervention or overexpression of UspA1 protein in the bilateral hippocampus of AD model mice, APP and Aβ protein levels in the cortical and hippocampal regions of the brain were significantly elevated, and learning, memory, and cognitive impairments were exacerbated.

CONCLUSIONS: This study suggests that Moraxella catarrhalis contributes to AD pathogenesis through its extracellular vesicles and the UspA1 outer membrane protein, which participate in the APP proteolytic pathway and Aβ generation.},
}

Animals
Humans
*Alzheimer Disease/microbiology/pathology/cerebrospinal fluid
Mice
*Moraxella catarrhalis
Male
Female
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Aged
Hippocampus/metabolism
Mice, Transgenic

@article {pmid41436133,
year = {2025},
author = {Taha, HB},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101454},
doi = {10.1002/alz70855_101454},
pmid = {41436133},
issn = {1552-5279},
mesh = {Animals ; Rats ; *Brain/metabolism ; Male ; *Physical Conditioning, Animal/physiology ; Female ; *Alzheimer Disease/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; },
abstract = {BACKGROUND: Exercise offers neuroprotective and cognitive benefits against neurodegeneration in Alzheimer's disease, hypothesized to be due to the secretion of signaling molecules known as brain-targeting exerkines. However, the responsiveness of these exerkines across multiple organs remains poorly understood.

METHOD: We leveraged the publicly available (MoTrPAC) dataset. Rats aged 6 months underwent a progressive treadmill training protocol. Blood (cells and plasma) and 18 solid tissues such as brain (cortex, hippocampus, hypothalamus) were collected, and multi-omics analyses were performed on them. We examined the protein and transcriptional expression of several brain-targeting exerkines across all collected tissues.

RESULT: Brain-targeting, tissue-specific exerkine responsiveness ranked as follows: prosaposin > cathepsin B > Clusterin = FNDC5/irisin > platelet factor 4 > brain-derived neurotrophic factor (BDNF) = Gpld1. However, both the protein and transcriptional expression of all these brain-targeting exerkines remained unchanged in the brain across males and females throughout all 8 weeks of treadmill training.

CONCLUSION: Contrary to previous studies, our analysis shows that brain-targeting exerkines remained unchanged in the brain after exercise, challenging the notion of a body-brain exerkine axis and questioning its role in neuroprotection and cognitive benefits.},
}

Animals
Rats
*Brain/metabolism
Male
*Physical Conditioning, Animal/physiology
Female
*Alzheimer Disease/metabolism
Brain-Derived Neurotrophic Factor/metabolism

@article {pmid41436132,
year = {2025},
author = {Ahmed, TF and Haque, Z and Ahmed, A and Us Salam, J and Bhatty, S and Hanif, F},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101481},
doi = {10.1002/alz70855_101481},
pmid = {41436132},
issn = {1552-5279},
mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Insulin Resistance/genetics ; Protein Interaction Maps/genetics ; Computational Biology ; Gene Regulatory Networks ; },
abstract = {BACKGROUND: The unclear pathophysiology of Alzheimer's disease complicates treatment development. Risk factors like diabetes, metabolic syndrome, and APOE4 allele are closely linked to insulin resistance (IR), but mechanisms connecting these conditions are unclear. Epigenetic regulation through microRNAs has been implicated in the regulation of both IR and AD, yet no studies have identified microRNAs simultaneously targeting both pathways. This study aims to bioinformatically identify such microRNAs and analyze functional annotation of their target genes to uncover shared regulatory mechanisms linking IR and AD.

METHOD: Using five prediction tools and two databases of experimentally validated microRNA-gene interactions we identified microRNAs targeting twenty key IR genes in humans (Table-1). We assigned a predicted score (P1) to each interaction, adding a point (E1) for experimental validation to calculate a cumulative score (C1) and its average (T1). We further analyzed microRNAs with T1 scores above 1.0 for interactions with AD pathway genes using KEGG analysis and constructed protein-protein interaction network with STRING to identify hub proteins. We re-evaluated the microRNAs for targeting these genes, calculating cumulative (C2) and total scores (T2). We performed functional annotation of target genes for microRNAs with the highest T2 scores using DAVID. Retrieving Gene Ontology terms for biological processes and molecular functions, we identified common terms to highlight shared regulatory mechanisms linking IR and AD.

RESULT: AKT3 had the most microRNA targets among insulin sensitivity regulators, and miR-15a-5p scored the highest among the selected microRNAs with high T1-scores. Altogether, these microRNAs targeted 299 AD-related genes, with miR-16-5p targeting the most. The top 10 hub genes in the AD protein-protein interaction network are shown in Figure 1. Rescoring based on AD targets revealed miR-7-5p, let-7a-5p, let-7b-5p, miR-15b-5p, miR-16-5p, miR-17-5p, and miR-424-5p as the highest-ranking microRNAs based on total scores (T2). Target genes of these microRNAs were found enriched in negative regulation of transcription by RNA polymerase II, chromatin remodeling, and G1/S transition of the mitotic cell cycle (Table-2). Molecular functions enriched included protein binding and protein serine/threonine kinase activity.

CONCLUSION: We recommend studying the identified microRNAs as a pathogenic link between AD and IR and as early biomarkers of AD in IR patients.},
}

Humans
*MicroRNAs/genetics/metabolism
*Alzheimer Disease/genetics/metabolism
*Insulin Resistance/genetics
Protein Interaction Maps/genetics
Computational Biology
Gene Regulatory Networks

@article {pmid41436130,
year = {2025},
author = {Shvetcov, A and Wilkins, HM and Burns, JM and Swerdlow, RH and Slawson, CM and Finney, CA and , },
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101734},
doi = {10.1002/alz70855_101734},
pmid = {41436130},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/cerebrospinal fluid/blood ; *Cognitive Dysfunction/genetics/cerebrospinal fluid/blood ; *Apolipoprotein E4/genetics/cerebrospinal fluid ; Male ; Female ; Aged ; Proteomics ; Biomarkers/cerebrospinal fluid/blood ; *Proteome ; },
abstract = {BACKGROUND: Apolipoprotein E ε4 (APOE4) is the single biggest genetic risk factor for mild cognitive impairment (MCI) and sporadic Alzheimer's disease (AD). Despite this, little is known about the mechanisms underlying APOE4 carriers' vulnerability to these diseases.

METHODS: We used the Global Neurodegeneration Proteomics Consortium dataset to obtain genetic and SomaScan 7k assay proteomic data from the plasma and cerebrospinal fluid (CSF) for 8965 non-impaired controls (NI), 1283 AD, and 505 MCI patients. To identify proteins that were predictive of APOE4 (features), we first performed feature selection using mutual information followed by supervised machine learning using classification and regression trees (CART). Biological pathways associated with APOE4-specific proteins were identified using functional network analyses.

RESULTS: Our CART models revealed that APOE4 carriers had a unique proteome signature across both the CSF and plasma. The proteome signature was independent of cognitive status and was found in NI, MCI, and AD patients. Functional enrichment analyses showed that these APOE4-specific proteins were associated with apoptosis and inflammation as well as dysregulation in immune system DNA/RNA processes, mitochondrion organization, and glycolysis.

CONCLUSION: Our findings demonstrate that APOE4 carriage defines both the CSF and plasma proteome irrespective of cognitive status. First, this suggests that APOE4 carriers have systemic biological alterations. Second, our findings suggest that the underlying biological changes in APOE4 carriers are essential but not sufficient for developing MCI and AD. It may be the case that these biological changes make APOE4 carriers more vulnerable to environmental insults, such as viral infections, and together these factors drive MCI and AD pathogenesis.},
}

Humans
*Alzheimer Disease/genetics/cerebrospinal fluid/blood
*Cognitive Dysfunction/genetics/cerebrospinal fluid/blood
*Apolipoprotein E4/genetics/cerebrospinal fluid
Male
Female
Aged
Proteomics
Biomarkers/cerebrospinal fluid/blood
*Proteome

@article {pmid41436129,
year = {2025},
author = {Barth, C},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101658},
doi = {10.1002/alz70855_101658},
pmid = {41436129},
issn = {1552-5279},
mesh = {Humans ; Female ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Male ; *Estradiol/blood/metabolism/genetics ; *Alzheimer Disease/genetics ; Polymorphism, Single Nucleotide ; Sex Factors ; Risk Factors ; Middle Aged ; Aged ; },
abstract = {BACKGROUND: Estradiol - the most potent estrogen in females - has been implicated in the development of Alzheimer's disease (AD) - a sex-biased brain disorder with a female preponderance. Yet, while some studies suggest protective effects of estradiol on AD risk, results are inconsistent partly due to methodological challenges of observational studies such as confounding and reverse causation. Mendelian randomization (MR) can overcome these limitations by using genetic variants to test for causal associations. Here, we examined whether genetically predicted estradiol-related factors (exposures) are causally linked to AD risk (outcome) in females, by conducting two-sample MR analyses.

METHOD: Two-sample MR analyses were conducted using female-specific summary statistics from previously conducted and newly run genome-wide association studies (GWAS). We ran and annotated GWAS on sex-specific estradiol levels, both in females and males, using data from the UK Biobank. Exposure variables included estradiol levels as well as factors related to lifetime estradiol exposure (i.e., reproductive span, age at menarche, age at menopause, and number of childbirths). For the univariable MR analyses, we applied the inverse-variance weighted method and robust estimation methods including MR-Egger, weighted median, simple mode, and weighted mode. To ensure the robustness of results, we run several sensitivity analyses such as including BMI as confounder in multivariable MR analyses and replicated our estradiol findings in a stratified pre-and postmenopausal UK Biobank sample, an independent sample of females from the LIFE-Adult and LIFE-Heart study as well as in a male-only UK Biobank sample.

RESULT: Across all female-only samples, we consistently did not find any significant associations between estradiol-related factors and AD risk. These results were robust throughout sensitivity analyses and using a male-only sample.

CONCLUSION: The results do not support a causal link of estradiol-related factors and AD risk in females as well as males. Future studies should assess other influencing factors, as well as implement sex-specific, causal frameworks to examine potential time-varying effects of hormonal fluctuations and periods of increased susceptibility to sex steroids such as the perimenopausal period.},
}

Humans
Female
Genome-Wide Association Study
Mendelian Randomization Analysis
Male
*Estradiol/blood/metabolism/genetics
*Alzheimer Disease/genetics
Polymorphism, Single Nucleotide
Sex Factors
Risk Factors
Middle Aged
Aged

@article {pmid41436128,
year = {2025},
author = {Li, W},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100962},
doi = {10.1002/alz70855_100962},
pmid = {41436128},
issn = {1552-5279},
mesh = {Humans ; Animals ; *Alzheimer Disease/genetics/pathology ; Mice ; Male ; Female ; Pedigree ; *Acyltransferases/genetics ; Disease Models, Animal ; Middle Aged ; Amyloid beta-Protein Precursor/genetics/metabolism ; Exome Sequencing ; Mutation/genetics ; Amyloid beta-Peptides/metabolism ; Aged ; },
abstract = {BACKGROUND: The identification of pathogenic mutations in Alzheimer's disease (AD) causal genes led to a better understanding of the pathobiology of AD. Familial Alzheimer's disease (FAD) is known to be associated with mutations in the APP, PSEN1, and PSEN2 genes involved in Aβ production; however, these genetic defects occur in only about 10-20% of FAD cases, and more genes and new mechanism causing FAD remain largely obscure.

METHOD: We performed exome sequencing on family members with a FAD pedigree and identified gene variant ZDHHC21 p.T209S. A ZDHHC21T209S/T209S knock-in mouse model was then generated using CRISPR/Cas9. The Morris water navigation task was then used to examine spatial learning and memory. The involvement of aberrant palmitoylation of FYN tyrosine kinase and APP in AD pathology was evaluated using biochemical methods and immunostaining. Aβ and tau pathophysiology was evaluated using ELISA, biochemical methods, and immunostaining. Field recordings of synaptic long-term potentiation were obtained to examine synaptic plasticity. The density of synapses and dendritic branches was quantified using electron microscopy and Golgi staining.

RESULT: We identified a variant (c.999A > T, p.T209S) of ZDHHC21 gene in a Han Chinese family. The proband presented marked cognitive impairment at 55 years of age (Mini-Mental State Examination score = 5, Clinical Dementia Rating = 3). Considerable Aβ retention was observed in the bilateral frontal, parietal, and lateral temporal cortices. The novel heterozygous missense mutation (p.T209S) was detected in all family members with AD and was not present in those unaffected, indicating cosegregation. ZDHHC21T209S/T209S mice exhibited cognitive impairment and synaptic dysfunction, suggesting the strong pathogenicity of the mutation. The ZDHHC21 p.T209S mutation significantly enhanced FYN palmitoylation, causing overactivation of NMDAR2B, inducing increased neuronal sensitivity to excitotoxicity leading to further synaptic dysfunction and neuronal loss. The palmitoylation of APP was also increased in ZDHHC21T209S/T209S mice, possibly contributing to Aβ production. Palmitoyltransferase inhibitors reversed synaptic function impairment.

CONCLUSION: ZDHHC21 p.T209S is a novel, candidate causal gene mutation in a Chinese FAD pedigree. Our discoveries strongly suggest that aberrant protein palmitoylation mediated by ZDHHC21 mutations is a new pathogenic mechanism of AD, warranting further investigations for the development of therapeutic interventions.},
}

Humans
Animals
*Alzheimer Disease/genetics/pathology
Mice
Male
Female
Pedigree
*Acyltransferases/genetics
Disease Models, Animal
Middle Aged
Amyloid beta-Protein Precursor/genetics/metabolism
Exome Sequencing
Mutation/genetics
Amyloid beta-Peptides/metabolism
Aged

@article {pmid41436098,
year = {2025},
author = {Fournier, JL and Arrar, A and Longmuir, MR and Schmitz, TW and Saksida, LM and Bussey, TJ and Prado, VF and Prado, MA},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101626},
doi = {10.1002/alz70855_101626},
pmid = {41436098},
issn = {1552-5279},
mesh = {Animals ; *tau Proteins/metabolism/genetics ; Female ; Male ; Mice, Transgenic ; Phosphorylation ; Disease Models, Animal ; Mice ; Apolipoprotein E4/genetics/metabolism ; Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Gene Knock-In Techniques ; Mice, Inbred C57BL ; Aging ; Brain/pathology/metabolism ; },
abstract = {BACKGROUND: Tau is a microtubule stabilizing protein that becomes dysfunctional during the course of Alzheimer's Disease. Previous research has shown that individually amyloid and APOE4 have the potential to increase tau phosphorylation and worsen tau pathology in tau mutant models of tauopathy. However, whether both amyloid and APOE4 can further contribute to tau dysfunction in mouse models that more faithfully reflect the levels of tau in humans is unknown. We developed mouse models with a combination of incorporated humanized knock-in variants of hMAPT, App[NL] and App[NL-F] and APOE 3 or APOE 4 genotypes.

METHOD: Biochemical and imaging techniques including immunofluorescence microscopy and Western Blots were performed for phosphorylated tau at the Serine 202/Threonine 205 sites (AT8) and total tau. Visuospatial learning and memory were assessed using the Paired Associates Learning (PAL) task, an automated touchscreen task.

RESULT: Our preliminary results indicated that tau protein phosphorylated at the Serine 202/Threonine 205 phosphorylation site is detected in in both male and female mice in a genotype dependent manner. Aging, expression of App [NL-F] and APOE4 increased tau phosphorylation. Insoluble total tau was found predominantly in aged mice (18 months) and was worse in APOE4 expressing individuals. All the antibodies used detected no signal in tissue from tau knockout mice confirming the results are a consequence of changes in tau. Preliminary results indicate that 12-month old App [NL] and App [NL-F] mice (ApoE3 and ApoE4) were able to learn the PAL task to 70% accuracy. There were no genotype-dependent differences in performance.

CONCLUSION: The results of this project demonstrate that tau pathology markers appear to increase as a function of age, APOE4 and the ability to accumulate insoluble Abeta and plaques[.] These results agree with the notion that amyloid and APOE4 can increase tau markers even in less aggressive animal models without tau overexpression or mutations. Our findings also suggest that there are no genotype-dependent differences in learning and memory in the PAL task at early ages, despite these mice presenting other cognitive deficits at that stage.},
}

Animals
*tau Proteins/metabolism/genetics
Female
Male
Mice, Transgenic
Phosphorylation
Disease Models, Animal
Mice
Apolipoprotein E4/genetics/metabolism
Humans
*Alzheimer Disease/genetics/pathology/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
Gene Knock-In Techniques
Mice, Inbred C57BL
Aging
Brain/pathology/metabolism

@article {pmid41436095,
year = {2025},
author = {Snitchler, K and Waring, AL and Hartness, E and Mortimer, N},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101820},
doi = {10.1002/alz70855_101820},
pmid = {41436095},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/genetics/immunology ; Drosophila ; *Alzheimer Disease/immunology ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Drosophila Proteins/genetics/metabolism ; Disease Models, Animal ; Humans ; Animals, Genetically Modified ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death in the United States; as the population continues expanding, so will the number of cases. New drugs targeting amyloid oligomers have been approved to treat AD, but some patients experience serious adverse effects such as swelling and bleeding in the brain, or limited reversal of cognitive impairments. To limit these, must improve our understanding of amyloid β (Aβ) in healthy individuals. We hypothesize that amyloid β acts as an opsonin to direct immune activity to sites of infection or injury.

METHOD: To test the contribution of Aβ the amyloid precursor protein (APPL) to the Drosophila immune response, we used the GAL4/UAS system to develop dAβ and APPL mutants with altered activity. We developed additional Drosophila lines to overexpress Drosophila amyloid β (dAβ), and a control line with no amyloid expression (Figure 1). Parasitoid wasps infect the developing larvae, and eggs develop to specific time points relating to infection (Figure 3). At each time point, the wasp egg is dissected from the fly larva to assess immune function and stained with Congo-red to visualize amyloids. Under polarized light, the stain reacts via birefringence when amyloids are present. We can then detect the localization of dAβ over the course of the infection.

RESULT: We found that dAβ and sAPPL mutant flies exhibit an impaired immune response and capsule formation in response to infection, with the expression of dAβ and sAPPL rescuing this response (Figure 2). While sampling different time points during infection, we detected birefringence on the surface of the developing wasp egg from our dAβ lines prior to the encapsulation. This same signal was absent from our control samples, indicating that dAβ and immune cell activity co-localize.

CONCLUSION: Our data suggests a natural function of Aβ is to act as an opsonin and that its aggregation may activate immune cells responsible for inflammation seen in AD.},
}

Animals
*Amyloid beta-Peptides/metabolism/genetics/immunology
Drosophila
*Alzheimer Disease/immunology
*Amyloid beta-Protein Precursor/genetics/metabolism
Drosophila Proteins/genetics/metabolism
Disease Models, Animal
Humans
Animals, Genetically Modified

@article {pmid41436094,
year = {2025},
author = {Hwang, D and Lee, K and Park, S and Yim, S and Kim, K and Dunn, AR and Gatti, DM and Chesler, EJ and O'Connell, KM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100708},
doi = {10.1002/alz70855_100708},
pmid = {41436094},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/genetics ; Polymorphism, Single Nucleotide/genetics ; Mice ; Disease Models, Animal ; Phenotype ; Mice, Transgenic ; Humans ; Fear ; *Cognition/physiology ; },
abstract = {BACKGROUND: The AD-BXD mouse panel consists of genetically diverse lines that carry human familial Alzheimer's disease (FAD) transgenes, making it a valuable model for studying cognitive function and genetic factors associated with Alzheimer's disease (AD). The dataset includes single-nucleotide polymorphism (SNP) data, cognitive phenotypes, and non-cognitive phenotypes such as metabolic and sensory-motor features. Cognitive phenotypes such as contextual fear acquisition (CFA; learning of fear-related stimuli) and contextual fear memory (CFM; recall of fear-related stimuli) are key measures of cognitive function. Challenges include sparse non-cognitive features, requiring imputation, and the high dimensionality of SNP data relative to the limited sample size, necessitating robust dimensionality reduction. Our goal is to build a cognitive phenotype prediction model, and find biomarkers based on feature importance analysis with the model, despite above challenges.

METHOD: We developed a predictive model for cognitive function using data generated from AD-BXD mice at the Jackson Laboratory. The model uses SNP and non-cognitive phenotype features before 7 months as input, and targets cognitive phenotype after 14 months. Step 1, we applied bootstrapped k-NN imputation to address missing non-cognitive data. Step 2, an autoencoder was trained to reduce SNP dimensionality by encoding essential reconstruction information. The latent vectors from the autoencoder were concatenated with imputed non-cognitive features. Step 3, a multi-layer perceptron (MLP) model was trained to predict cognitive labels, optimizing both the encoder and predictor iteratively to minimize mean squared error between predictions and ground truth. Step 2 and 3 are iterated.

RESULT: Bootstrapped k-NN imputation with non-cognitive phenotypes produced 300 instances. MLP predictor using all features concatenated produced PCC(Pearson Correlation Coefficient) of 0.587 for CFM and 0.504 for CFA as predictive performance. SNP dimension produced PCC 0.69 for CFM and 0.606 for CFA. The feature importance analysis revealed biomarkers that are consistent with previously reported findings in the literature.

CONCLUSION: The proposed model effectively utilized the genetically diverse AD-BXD population for cognitive function prediction. Bootstrapped k-NN imputation addressed missing data challenges, and SNP dimensionality reduction significantly enhanced predictive performance. Findings from feature importance analysis demonstrate the potential for identifying meaningful patterns and biomarkers to further AD-related research.},
}

Animals
*Alzheimer Disease/genetics
Polymorphism, Single Nucleotide/genetics
Mice
Disease Models, Animal
Phenotype
Mice, Transgenic
Humans
Fear
*Cognition/physiology

@article {pmid41436093,
year = {2025},
author = {Gamez, N and Eid, AM and Pascual, B and Masdeu, JC and Appel, SH and Faridar, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101037},
doi = {10.1002/alz70855_101037},
pmid = {41436093},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Aged ; Leukocytes, Mononuclear/metabolism/immunology ; Cytokines/blood ; Middle Aged ; *Aphasia, Primary Progressive/immunology/blood ; Monocytes/metabolism/immunology ; Inflammation/immunology ; *Frontotemporal Dementia/immunology ; },
abstract = {BACKGROUND: Despite growing evidence supporting the role of inflammation in neurodegenerative processes, a detailed molecular understanding of the peripheral immune system's status and its mechanistic implications in the pathology of frontotemporal dementia (FTD) remains limited. In this study, we investigate (a) the suppressive function of regulatory T cells (Tregs), (b) the inflammatory profile of peripheral monocytes, and (c) the levels of inflammatory markers in the plasma of individuals with non-fluent variant primary progressive aphasia (nfvPPA), a subtype of FTD.

METHOD: Plasma and peripheral blood mononuclear cells (PBMCs) were obtained from 17 nfvPPA and 34 age-matched HC recruited by the Houston Methodist Nantz National Alzheimer's Center. The suppressive function of Tregs was assessed using proliferation assays. RNA from peripheral monocytes was analyzed via Nanostring chips and qRT-PCR to determine the inflammatory profiles. Plasma cytokine levels were measured using the Olink® Target 48 Cytokine panel. Time-of-flight mass cytometry (CyTOF) was employed to evaluate PBMCs immunoprofiles and the activation of signaling pathways at single-cell resolution.

RESULT: Tregs from nfvPPA individuals demonstrated a compromised ability to suppress responder T cell proliferation compared to HC. Additionally, peripheral monocytes in the nfvPPA cohort exhibited significantly increased expression of pro-inflammatory genes, including C1q, NLRP3, PRG3, and CXCL10. Elevated levels of CXCL10 were also detected in the plasma of nfvPPA patients. By integrating both transcriptomic and proteomic data, we identified the activation of the CXCL10/CXCR3 cascade in nfvPPA individuals. Proteomic analysis by CyTOF revealed that CXCL10 was predominantly expressed by CD14 monocytes, while its receptor, CXCR3, was highly expressed on CD4 and CD8T cells. Our in vitro studies demonstrated that CXCL10 exerted pro-inflammatory effects on CXCR3-positive T cells, effects that were mitigated by the addition of the selective CXCR3 blocker AMG487.

CONCLUSION: Individuals with nfvPPA exhibit impaired immunosuppressive function of Tregs, accompanied by systemic activation of the CXCL10/CXCR3 pathway, which is involved in the homing of T cells into the brain. Our findings highlight the potential clinical impact of (i) restoring Treg suppressive function and (ii) targeting the CXCL10/CXCR3 axis to mitigate neurodegeneration by limiting neuroinflammation and the infiltration of cytotoxic T cells to the brain.},
}

Humans
Male
Female
*T-Lymphocytes, Regulatory/immunology/metabolism
Aged
Leukocytes, Mononuclear/metabolism/immunology
Cytokines/blood
Middle Aged
*Aphasia, Primary Progressive/immunology/blood
Monocytes/metabolism/immunology
Inflammation/immunology
*Frontotemporal Dementia/immunology

@article {pmid41436091,
year = {2025},
author = {Edwards, AJ and Camp, L and Forsyth, AV and Kuruvilla, J and Simonton, B and Jamshidi, P and Castellani, RJ and Nicoll, JA and Boche, D and van Olst, L and Gate, D},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100543},
doi = {10.1002/alz70855_100543},
pmid = {41436091},
issn = {1552-5279},
mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism/immunology ; *Amyloid beta-Peptides/immunology/metabolism ; Microglia/metabolism/pathology ; *Brain/pathology/metabolism ; Male ; Plaque, Amyloid/pathology/metabolism ; Female ; Aged ; Transcriptome ; },
abstract = {BACKGROUND: Recently approved Alzheimer's disease (AD) therapies leverage immunization strategies targeting amyloid-β (Aβ). While most studies focus on microglial responses to these treatments, evidence suggests that sustained immune activity and Aβ clearance drive broader cellular changes. Astrocytes, which accumulate at microglia-targeted Aβ plaques, may play a complementary role in clearance. This study examines how astrocyte phenotypes are altered by Aβ immunization and their contribution to Aβ clearance.

METHODS: We performed single-cell RNA sequencing and spatial transcriptomics on post-mortem brain tissue from 16 AD patients-10 immunized (9 with AN1792 from the first active Aβ immunotherapy trial, 1 with lecanemab) and 6 non-immunized controls. We identified astrocyte states enriched in immunized brains and analyzed their transcriptomic profiles. Additionally, we mapped astrocyte states localized at microglia-targeted Aβ plaques.

RESULTS: A distinct astrocyte population emerged following immunization with both AN1792 and lecanemab, characterized by upregulated CHI3L1 and other reactive astrocyte markers. Spatial analysis revealed these astrocytes preferentially localize at microglia-targeted Aβ plaques post-lecanemab treatment. Ongoing analyses aim to further define astrocyte phenotypes in terms of morphology, protein expression, Aβ uptake, and spatial relationships with Aβ pathology and microglia.

CONCLUSION: We identify a unique astrocyte phenotype induced by Aβ immunization in AD, marked by high CHI3L1 expression. This astrocyte state may be driven by microglia at Aβ plaques and contribute to plaque clearance. Our findings highlight distinct astrocyte responses to Aβ immunization, shedding light on their role in therapeutic outcomes.},
}

Humans
*Astrocytes/metabolism/pathology
*Alzheimer Disease/pathology/metabolism/immunology
*Amyloid beta-Peptides/immunology/metabolism
Microglia/metabolism/pathology
*Brain/pathology/metabolism
Male
Plaque, Amyloid/pathology/metabolism
Female
Aged
Transcriptome

@article {pmid41436086,
year = {2025},
author = {Cui, Y and Srinivasan, D and Yang, Z and Wen, J and Erus, G and Hohman, TJ and Saykin, AJ and Thompson, PM and Shen, L and Davatzikos, C},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101581},
doi = {10.1002/alz70855_101581},
pmid = {41436086},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Genome-Wide Association Study ; Atrophy/pathology/genetics ; *Brain/pathology/diagnostic imaging ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Aging/pathology/genetics ; *Cognitive Dysfunction/genetics/pathology/diagnostic imaging ; Neuroimaging ; Whole Genome Sequencing ; },
abstract = {BACKGROUND: Deep learning methods help to disentangle heterogeneity of brain aging and find distinct neuroimaging patterns of neurodegeneration. However, the relationship between aging-related brain atrophy patterns and genetics is complex and requires further exploration.

METHOD: Patterns of regional bran volumes extracted from T1 scans and Whole-genome sequencing (WGS) data in The Alzheimer's Disease Sequencing Project (ADSP) were analyzed (2401 subjects, age = 72.75 ± 9.08; 54.07% female). We investigated 5 recently published brain aging patterns (R-indices) (Yang et al., 2024), and evaluated out-of-sample reproducibility of previously reported associations between R-indices and diagnostic groups (CN vs MCI/AD). We conducted genome-wide association analysis to investigate genetic associations of R-indices controlling for confounders (e.g., age).

RESULT: Linear regression models identified significant group differences with large effect size in diagnostic groups in R2 (Cohen's d=1.05, p = 1.66e-105; this is a typical AD pattern of atrophy) and R3 (d=0.81, p = 2.16e-66), and moderate effect size in R5 (d=0.44, p = 9.59e-22; this pattern was previously associated with a variety of cardiovascular risk factors and immune system markers). Genetic analyses identified 5 genes significantly associated with R1, R2, R3 and R5 indices (Figure 1). R1, characterized with subcortical atrophy, had associations with A1CF (chr10), which has been associated with urate levels, gout and colorectal cancer. R2, with focal medial temporal lobe atrophy, was associated with EXT1 (chr8), which has been associated with BMI, general cognitive ability, cortical thickness and insomnia. R3, with parieto-temporal atrophy patterns, was associated with CUL4A (chr13), which has been linked to blood cell volume/distribution, bipolar disorder, HDL cholesterol, corpuscular hemoglobin and atrial fibrillation. R5, with primarily perisylvian atrophy, was associated with DDX39B and ATP6V1G2-DDX39B (chr6), which have been associated with insomnia, general cognitive ability and blood cell measures.

CONCLUSION: We evaluated 5 recently established brain aging indices, which capture the heterogeneity of structural brain aging, in ADSP participants. R-indices replicated previously reported associations with AD groups (Yang et al., 2024), indicating the generalizability of the model. We identified different associations with genes that were previously linked to various traits. These findings provide new insights into the exploration of heterogeneity of neurodegeneration and related genetic risk factors.},
}

Humans
Female
Male
Aged
Genome-Wide Association Study
Atrophy/pathology/genetics
*Brain/pathology/diagnostic imaging
*Alzheimer Disease/genetics/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Aging/pathology/genetics
*Cognitive Dysfunction/genetics/pathology/diagnostic imaging
Neuroimaging
Whole Genome Sequencing

@article {pmid41436084,
year = {2025},
author = {Sheng, Z and Chen, M and Zhang, J and Wang, LY and Yu, W and Lü, Y},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101030},
doi = {10.1002/alz70855_101030},
pmid = {41436084},
issn = {1552-5279},
mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/cerebrospinal fluid/genetics ; Female ; Male ; *Alzheimer Disease/pathology/cerebrospinal fluid/genetics ; Aged ; Biomarkers/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Disease Progression ; Aged, 80 and over ; },
abstract = {BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is expressed in neurons and glial cells, but the potential role of LRRK2 in the progression of Alzheimer's disease (AD) and its impact on neuroinflammatory pathways remains unclear.

METHOD: Respectively, 716 and 87 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Parkinson's Progression Markers Initiative (PPMI) cohorts were included. Participants had cerebrospinal fluid (CSF) LRRK2 or LRRK2 (rs34637584 and rs76904798) genotypes, CSF biomarkers for AD core pathology, microglial activation and axonal injury, and underwent cognitive assessments. Statistical models, including one-way analysis of covariance, multiple linear regression models and Spearman partial correlation analyses, linear mixed-effects models, mediation analyses, and least squares structural equation modeling were used to explore the role of LRRK2 in the AD pathology, neuroinflammation, and neurodegeneration.

RESULT: Among participants, the positive tau pathology group had higher CSF LRRK2 levels than the negative group both in ADNI (p = 0.017) and PPMI (p < 0.001). Moreover, CSF LRRK2 level was significantly correlated with the levels of CSF phosphorylated tau181 (p-Tau181) (ADNI: β= 0.106, p =  0.007; PPMI: β= 0.351, p =  0.004), total Tau (t-Tau) (ADNI: β= 0.105, p =  0.009; PPMI: β= 0.362, p =  0.003), and NfL (ADNI: β= 0.221, p < 0.001; PPMI: β= 0.308, p =  0.002). Further, significant indirect effects were found in the TREM2-dependent mediation pathway in ADNI, CSF LRRK2 → CSF T-tau or p-Tau → CSF TREM2 → CSF sTREM2→ CSF NfL (IE = 0.013, p = 0.036 or 0.032). In PPMI, CSF p-Tau partially mediated the correlation between CSF LRRK2 and CSF NfL (proportion = 40.1%, IE= 0.125, p =  0.004).

CONCLUSION: This study suggests that CSF LRRK2 promotes Tau-associated synaptic neurodegeneration, and TREM2-related microglial activation may play an important role in this process.},
}

Humans
*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/cerebrospinal fluid/genetics
Female
Male
*Alzheimer Disease/pathology/cerebrospinal fluid/genetics
Aged
Biomarkers/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Disease Progression
Aged, 80 and over

@article {pmid41436083,
year = {2025},
author = {Hervé, V and KaAli, OB and Benali, H and Brouillette, J},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101022},
doi = {10.1002/alz70855_101022},
pmid = {41436083},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity/administration & dosage ; *Hippocampus/metabolism/drug effects/pathology/physiopathology ; Microdialysis ; Disease Models, Animal ; Rats ; Male ; *Alzheimer Disease/pathology/metabolism/physiopathology ; *Neurons/drug effects/metabolism ; Neurotransmitter Agents/metabolism ; Rats, Sprague-Dawley ; },
abstract = {BACKGROUND: One of the main neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid-beta oligomers (Aβo), which begins in the brain approximately 15 years prior to the onset of clinical symptoms. Aβo-induced neuronal hyperactivity has emerged as an early functional characteristic of AD, contributing to synaptic deficits, memory impairment, and neurodegeneration. Several studies suggest that Aβo reduce the inhibitory activity of the GABAergic system, leading to excessive activation of the glutamatergic system. The aim of this study is to investigate the impact of Aβo on neuronal activity and neurotransmitter release within the same animal model.

METHOD: A microdialysis probe is implanted in the right hippocampus of a rat model to deliver Aβ oligomers over five consecutive days and to collect interstitial fluid (ISF) samples before, during, and after the injections. In addition, five electrodes are implanted within the hippocampi and default mode network of the rats to record neuronal activity.

RESULT: Firstly, we demonstrated through immunohistochemistry that our Aβo injections are successfully delivered into the hippocampus. Our initial results demonstrate the ability to record local field potential (LFP) signals in five distinct brain areas and to detect several neurotransmitters (glutamate, GABA, serine, taurine, glutamine, and glycine) in ISF samples. Chronic Aβo injections resulted in a clear time-dependent increase in delta power and a progressive decrease in higher frequency bands (theta, alpha, beta, gamma) in the injected hippocampus. In the non-injected (left) hippocampus, stable trends were observed initially, with a late onset increase in delta power and reduction in higher frequency power by day 5 in the Aβo group. Preliminary results on the quantification of neurotransmitters, including glutamate and GABA, are currently being analyzed but have already been detected by mass spectrometry in the ISF fractions.

CONCLUSION: This study will provide novel insights into the relationship between Aβo-induced changes in neuronal activity and neurotransmitter release, contributing to a better understanding of the neurodegenerative processes involved in early AD.},
}

Animals
*Amyloid beta-Peptides/metabolism/toxicity/administration & dosage
*Hippocampus/metabolism/drug effects/pathology/physiopathology
Microdialysis
Disease Models, Animal
Rats
Male
*Alzheimer Disease/pathology/metabolism/physiopathology
*Neurons/drug effects/metabolism
Neurotransmitter Agents/metabolism
Rats, Sprague-Dawley

@article {pmid41436082,
year = {2025},
author = {Wagner, B and Chauvet, M and Ferreira, ST and Isaac, A and Lourenco, MV},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101647},
doi = {10.1002/alz70855_101647},
pmid = {41436082},
issn = {1552-5279},
mesh = {Animals ; Mice, Inbred C57BL ; Mice ; Male ; Female ; Disease Models, Animal ; Lipopolysaccharides ; *Fatty Acids, Unsaturated/administration & dosage/pharmacology ; *Neuroinflammatory Diseases ; },
abstract = {BACKGROUND: Neuroinflammation, oxidative stress and lipid peroxidation comprise key events in neurodegenerative diseases, such as Alzheimer's disease, and are associated with neuronal damage, synaptic loss and cognitive decline. Recent studies have demonstrated that deuterated polyunsaturated fatty acids (D-PUFA) are able to favor resolvin pathways (e.g. lipoxins) in detriment of the prostaglandin pathway, and therefore promote anti-inflammatory effects. Our group has shown that lipoxin A4 protects against cognitive decline in animal models and is reduced in the liquor of patients with dementia. Here we investigate whether a diet enriched with D-PUFAs is neuroprotective against neuroinflammation induced by LPS.

METHOD: Three month-old C57BL/6 male and female mice were fed with deuterated polyunsaturated fatty acid enriched diet (D-PUFA) or control diet (H-PUFA) for two months. Then, mice received intraperitoneal injections of LPS or vehicle. Behavior was tested by novel object recognition (NOR), displaced object recognition (DOR) and open field tasks.

RESULT: All groups gained weight at the same rate during treatment and no gross difference in diet consumption was observed. Our results demonstrated that, whereas animals fed with control diet that received LPS presented deficits in NOR and DOR test, animals fed with D-PUFA diet that received LPS did not present memory impairment. Brain tissues and plasma were collected for biochemistry analysis.

CONCLUSION: Our findings suggest that D-PUFA diet might be an interesting nutritional approach to mitigate neuroinflammation and cognitive decline.},
}

Animals
Mice, Inbred C57BL
Mice
Male
Female
Disease Models, Animal
Lipopolysaccharides
*Fatty Acids, Unsaturated/administration & dosage/pharmacology
*Neuroinflammatory Diseases

@article {pmid41436081,
year = {2025},
author = {Grau-Perales, AB and Yerapathi, S and Ferreira, AC and Philippi, SM and Hemmer, BM and Rosenstadt, JL and Sanctis, C and Crary, JF and Castellano, JM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101110},
doi = {10.1002/alz70855_101110},
pmid = {41436081},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism ; *Tissue Inhibitor of Metalloproteinase-2/metabolism/genetics ; Humans ; *Hippocampus/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Matrix Metalloproteinase 2/metabolism ; Disease Models, Animal ; Mice ; Extracellular Matrix/metabolism/pathology ; Mice, Transgenic ; Male ; *Brain/pathology/metabolism ; Astrocytes/metabolism/pathology ; Plaque, Amyloid/pathology/metabolism ; Female ; Mice, Inbred C57BL ; Aged ; Cerebral Cortex/pathology/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by several pathological processes, including amyloid-beta (Aβ) accumulation and neuroinflammation, both of which have been linked to extracellular matrix (ECM) dyshomeostasis. We previously reported that the youth-associated factor TIMP2 revitalizes brain function in the context of aging and regulates ECM accumulation through its essential role in matrix metalloproteinase-2 (MMP2) activation, an enzyme predominantly released by reactive astrocytes in response to injury. How TIMP2 may regulate AD pathology through its roles in ECM remodeling remains unexplored.

METHOD: We characterized TIMP2 expression using immunohistochemistry in human AD and mouse brain tissue. Mouse hippocampus and cortex from two mouse models of Aβ pathology in which TIMP2 has been targeted was assessed for Aβ pathology, astrogliosis, accumulation of ECM components, as well as MMP2 expression. The impact of ECM accumulation on Aβ metabolism was evaluated through intrahippocampal injections of Chondroitinase ABC (ChABC). We also investigated the impact of TIMP2 rescue on AD pathology and behavioral performance using a vrial-mediated overexpression approach.

RESULT: TIMP2 expression differs significantly in human AD tissue and amyloid-expressing mice relative to their respective controls. Mice in which TIMP2 had been targeted exhibit exacerbated amyloid pathology and astrogliosis in several brain regions, with increased expression of MMP2 and CSPGs, indicative of altered ECM homeostasis. Despite showing increased astrocyte recruitment around plaques, mice lacking TIMP2 have larger, more numerous plaques and greater astrocyte-to-plaque distance. Further analyses revealed more CSPG-Aβ overlap but less MMP2-Aβ overlap in mice lacking TIMP2. APP processing remained unchanged between TIMP2 genotypes, suggesting impaired Aβ clearance when modulating TIMP2. Intrahippocampal targeting of the ECM appears to increase astrocyte recruitment around plaques in amyloid-bearing mice with coincident reductions in plaque size and number and enhanced MMP2-Aβ overlap. TIMP2 overexpression in aged mice exhibiting beta-amyloidosis improves cognitive performance, decreases Aβ plaque load, and reduces ECM accumulation.

CONCLUSION: TIMP2 deficiency exacerbates amyloid pathology by affecting MMP2-associated astrocyte modulation of ECM. Restoring TIMP2 improves cognitive and pathological outcomes, highlighting its therapeutic potential in AD. These findings suggest that TIMP2-targeted strategies may represent a novel approach for addressing amyloid accumulation and downstream effects in AD. Funded by: NHI/NIA 1RF1AG072300, R01AG061382, Alzheimer's Association 24AARF-1201458.},
}

Animals
*Alzheimer Disease/pathology/metabolism
*Tissue Inhibitor of Metalloproteinase-2/metabolism/genetics
Humans
*Hippocampus/pathology/metabolism
Amyloid beta-Peptides/metabolism
Matrix Metalloproteinase 2/metabolism
Disease Models, Animal
Mice
Extracellular Matrix/metabolism/pathology
Mice, Transgenic
Male
*Brain/pathology/metabolism
Astrocytes/metabolism/pathology
Plaque, Amyloid/pathology/metabolism
Female
Mice, Inbred C57BL
Aged
Cerebral Cortex/pathology/metabolism

@article {pmid41436080,
year = {2025},
author = {de Souza, RB and Limberger, C and Martins, GC and Hoffmeister, GL and Schmaedek, MR and de Oliveira, RDS and Baldasso, GM and Bastiani, MA and Zimmer, ER},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101393},
doi = {10.1002/alz70855_101393},
pmid = {41436080},
issn = {1552-5279},
mesh = {Animals ; *Astrocytes/metabolism ; *Alzheimer Disease/genetics/pathology/metabolism ; Mice ; Disease Models, Animal ; Glutamic Acid/metabolism ; Mice, Transgenic ; *Hippocampus/metabolism/pathology ; Neurons/metabolism ; Humans ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {BACKGROUND: Astrocytes, the most abundant glial cells in the brain, exhibit remarkable heterogeneity and play critical roles in maintaining brain homeostasis. Their responses to Alzheimer's disease (AD) pathology are diverse, particularly in the context of glutamate excitotoxicity - a hallmark of AD characterized by impaired astrocytic glutamate uptake. Recently, de Ceglia et al. (2023) identified a astrocyte subtype involved in glutamatergic gliotransmission, defined by the expression of genes linked to glutamate exocytosis. Here we investigate whether the transcriptional profile of this specific astrocyte subtype is altered across various AD mouse models.

METHOD: We conducted differential gene expression analysis and cellular deconvolution using population-specific expression analysis (PSEA) on bulk RNA-seq data from the hippocampus of three amyloidosis models: APP/PS1 (n = 18), 5xFAD (n = 49), and hAβKi (n = 41). Cell type-specific gene expression signatures for astrocytes, neurons, oligodendrocytes, endothelial cells, and microglia were assigned using the BRETIGEA R package. The transcriptional signature for glutamatergic gliotransmission-specialized astrocytes consisted of 15 genes associated with synaptic-like glutamate release machinery. We analyzed cellular enrichment proportions and identified differentially expressed genes (DEGs) within the glutamatergic astrocyte signature across the three models (p < 0.05).

RESULT: The APP/PS1 model showed the highest glutamatergic astrocyte enrichment (24.8%), similar to hAβKI (23.8%), while 5xFAD had minimal enrichment (2.2%) (Figure 1). From these astrocytic genes, DEGs analysis revealed 52 upregulated and 547 downregulated genes in the APP/PS1 model, 24 upregulated and 36 downregulated genes in the hAβKI model, and 10 upregulated and 8 downregulated genes in the 5xFAD model. Notably, genes like KIF5B and GRASP were significantly downregulated, indicating impairment in vesicle homeostasis. The most significantly up- or downregulated genes differed across the three models (Figure 2).

CONCLUSION: Our results show that the glutamatergic astrocyte signature varies in AD mouse models, with significant differences in their enrichment and gene expression profiles. The APP/PS1 and hAβKI models showed substantial enrichment of this astrocyte subtype, whereas the 5xFAD model exhibited minimal representation. The significant downregulation of genes related to vesicle trafficking suggests potential impairments in glutamatergic astrocyte function. Our findings highlight the role of a specific astrocyte subtype in AD pathogenesis. Further single-cell analysis will provide more information at the cellular level.},
}

Animals
*Astrocytes/metabolism
*Alzheimer Disease/genetics/pathology/metabolism
Mice
Disease Models, Animal
Glutamic Acid/metabolism
Mice, Transgenic
*Hippocampus/metabolism/pathology
Neurons/metabolism
Humans
Amyloid beta-Protein Precursor/genetics

@article {pmid41436078,
year = {2025},
author = {Shen, KR and Shum, GC and Woods, AC and Belton, TB and Leisten, ED and Wong, YC},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101226},
doi = {10.1002/alz70855_101226},
pmid = {41436078},
issn = {1552-5279},
mesh = {Humans ; *Cholesterol/metabolism ; *Endoplasmic Reticulum/metabolism/ultrastructure ; tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Microtubules/metabolism ; *Alzheimer Disease/metabolism/pathology ; Acetyl-CoA C-Acetyltransferase/metabolism ; Sterol O-Acyltransferase ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the pathological accumulation of both amyloid-beta (Aβ) and cytoplasmic tau, but their mechanistic crosstalk remains to be further investigated. Moreover, while cholesterol dyshomeostasis has been implicated in AD, its role is still not completely understood. Cholesterol homeostasis is tightly regulated at the endoplasmic reticulum (ER), a highly dynamic and structurally complex organelle, where the enzyme ACAT1 turns over cholesterol into cholesteryl esters. Importantly, the ER also dynamically tethers to microtubules via ER-microtubules contact sites, and are implicated in dendritic spine stability and memory. However, whether ACAT1 functionally interacts with Aβ to regulate ER cholesterol and ER structure, and its downstream regulation of ER-microtubule contact sites and tau dynamics have never been studied.

METHOD: We utilized super-resolution live Lattice SIM2 microscopy to uncover a new mechanistic pathway connecting cholesterol turnover, Aβ function, and tau aggregation in AD. We examined the role of ER cholesterol in modulating ER ultrastructure and dynamics over time, and a converging role for Aβ production and Aβ42 versus Aβ40 in regulating this pathway. We further conducted in silico structural multimer modeling of Aβ42 and Aβ40's structural interactions with ACAT1's catalytic pocket. Finally, we investigated cholesterol's role in modulating ER-microtubule contact site tethering via STIM1-EB binding, and its impact on downstream tau microtubule dynamics and aggregation.

RESULT: We found that accumulation of ER cholesterol resulted in the dynamic formation of ER spheres as a novel structural component of the ER network. Remarkably, inhibition of Aβ generation also induced ER sphere formation, supporting a role for Aβ regulation of ER cholesterol's turnover. Mechanistically, Aβ42 but not Aβ40 structurally interacted with key catalytic residues of ACAT1 to promote ACAT1's turnover of cholesterol, which was supported by reduced ER sphere formation in AD-associated mutant APP with increased Aβ42 production. Functionally, ER cholesterol resulted in the downstream untethering of ER-microtubule contact sites mediated by STIM1 and EB, ultimately leading to tau dissociation from microtubules and oligomerization.

CONCLUSION: Our work provides evidence for a unifying mechanism linking Aβ function with tau dynamics through cholesterol-mediated ER dynamics, and identifies a novel cellular pathway underlying AD pathogenesis.},
}

Humans
*Cholesterol/metabolism
*Endoplasmic Reticulum/metabolism/ultrastructure
tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Microtubules/metabolism
*Alzheimer Disease/metabolism/pathology
Acetyl-CoA C-Acetyltransferase/metabolism
Sterol O-Acyltransferase

@article {pmid41436074,
year = {2025},
author = {Prakapenka, AV},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101073},
doi = {10.1002/alz70855_101073},
pmid = {41436074},
issn = {1552-5279},
mesh = {Animals ; Female ; Pregnancy ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; *Alzheimer Disease/physiopathology/genetics ; Mice, Transgenic ; *Perimenopause ; Mice ; *Maternal Behavior/physiology ; Maze Learning/physiology ; },
abstract = {BACKGROUND: Pregnancy and perimenopause are female-specific reproductive events that are accompanied by drastic shifts to circulating ovarian hormone milieu. Ovarian hormones modulate female physiology, biology, and behaviors, and may, at least in part, contribute to increased Alzheimer's disease (AD) risk in females compared to males. We utilized translational mouse models to investigate the relationship between age, pregnancy, and perimenopause on cognitive and behavioral health in healthy and AD females.

METHODS: Wildtype (WT; C57BL/6J) and 3xTg-AD mice were purchased from Jackson laboratories. Virgin females were paired with WT males for first pregnancy and birth to occur at 2-m-o, 5-6-m-o, or 9-m-o. A subset of virgin females was not paired with a male to serve as virgin controls. Postnatal maternal behaviors were assessed on the maternal pup retrieval task and with home cage maternal care evaluations. At 10-m-o, females received intraperitoneal 160 mg/kg/day VCD for 10 days to model perimenopause. Perimenopausal maternal behaviors were evaluated on the water radial arm maze for spatial working memory, open field task for locomotor activity, elevated plus maze for anxiety-like behaviors, and forced swim task for depressive-like behaviors.

RESULTS: Number of successful first pregnancies and size of the first litter decreased as maternal age increased. Maternal pup retrieval time was similar between the 2-m-o WT and AD dams. When compared to the 2-m-o WT dams, age at first birth did not impact maternal pup retrieval time for the 5-6-m-o WT dams. However, the 5-6-m-o AD dams took longer to retrieve pups to the nest than the 2-m-o AD dams and the 5-6-m-o WT dams. Of note, at the end of the task, all 5-6-m-o AD dams had two or more pups outside of the nest. When maternal care behaviors were scored in the home cage environment, WT and AD dams exhibited similar behaviors across the 2-hr period.

CONCLUSIONS: AD genotype and maternal age at first birth modulate maternal behaviors during the postnatal period, an effect that may be influenced by behavioral changes associated with AD progression. Additional analyses address the relationship between postnatal and perimenopausal maternal behaviors in the context of healthy and AD female aging trajectories.},
}

Animals
Female
Pregnancy
Male
Disease Models, Animal
Mice, Inbred C57BL
*Alzheimer Disease/physiopathology/genetics
Mice, Transgenic
*Perimenopause
Mice
*Maternal Behavior/physiology
Maze Learning/physiology

@article {pmid41436073,
year = {2025},
author = {Park, S and Lee, K and Yim, S and Hwang, D and Kim, K and Dunn, AR and Gatti, DM and Chesler, EJ and O'Connell, KM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100741},
doi = {10.1002/alz70855_100741},
pmid = {41436073},
issn = {1552-5279},
mesh = {*Alzheimer Disease/diagnosis/genetics/metabolism ; Humans ; Biomarkers ; *Machine Learning ; Databases, Factual ; },
abstract = {BACKGROUND: Multi-omics data from large-scale consortium databases, such as the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), combined with advanced AI technologies, hold significant promise for identifying biological mechanisms and biomarkers for diagnosis and treatment. However, two major challenges hinder effective multi-omics integration: modality collapse, where prediction models overly rely on a single modality, and data incompleteness, which limits the potential of machine learning approaches to fully utilize these rich resources. To address these issues, we developed an Alzheimer's disease (AD) prediction method capable of utilizing incomplete modalities while identifying key biomarkers through feature importance analysis.

METHOD: The proposed model is designed to ensure that each modality contributes meaningfully to phenotype prediction, even in the absence of some modalities. It comprises three modules: Encoder, Aggregator, and Predictor. Each omics data type is independently encoded into an embedding vector, which is then aggregated into a unified representation to facilitate the integration of diverse data types for AD prediction. This unified vector, along with other modality-specific embedding vectors, is fed to a shared predictor. To align the heterogeneous omics embeddings, the model computes a collective loss that integrates both the unified and modality-specific vectors, akin to main and auxiliary tasks in multi-task learning. For missing modalities, the embedding vectors of other available modalities are amplified to compensate for the loss of information.

RESULT: Trained on multi-omics samples with both complete and incomplete modalities, the model achieved an accuracy of 0.890 in classifying CogDX labels, outperforming existing state-of-the-art models. Ablation studies showed that all omics data contributed to the prediction, effectively preventing modality collapse. Including samples with missing modalities significantly boosted performance, emphasizing the importance of leveraging incomplete data. The model's performance was also evaluated across varying numbers of available modalities to present its practicality. Feature importance analysis identified biomarkers consistent with findings in existing literature.

CONCLUSION: The proposed method effectively integrates multi-omics data, even with incomplete modalities. By rediscovering biomarkers aligned with other studies, it demonstrates the potential of deep learning approaches in multi-omics research for AD.},
}

*Alzheimer Disease/diagnosis/genetics/metabolism
Humans
Biomarkers
*Machine Learning
Databases, Factual

@article {pmid41436072,
year = {2025},
author = {Owens, JP and Castora, FJ},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101455},
doi = {10.1002/alz70855_101455},
pmid = {41436072},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Brain/metabolism ; *DNA, Mitochondrial/genetics ; Mutation/genetics ; },
abstract = {BACKGROUND: A mutation in mitochondrial DNA (mtDNA) that is associated with Alzheimer's disease (AD) has been reported by us. We compared human brain RNA expression data from PCR array and bulk RNA seq analyses to understand effects of the T9861C mutation on gene expression and to help identify potential therapeutic targets for AD and AD+ patients.

METHOD: Qiagen Ingenuity Pathway Analysis (IPA) software was used to compare each gene as three expression log ratios: AD/control brains, AD+/control brains, and AD+/AD brains. The two analyses were compared. Regulator effects were grown to connect with other molecules, and the downstream and upstream effects of activating and inhibiting molecules were observed using the molecule activity predictor (MAP). We created a pathway using regulators and molecules directly related to AD and used MAP to identify potential therapeutic targets.

RESULT: Our analysis identified the top canonical pathways, the most expressed regulators, the top diseases and functions affected by the expression of the genes, and the downstream and upstream effects of the changing expression of genes in our datasets. The RNA bulk sequencing provided more data, resulting in IPA returning more canonical pathways, regulators, regulator effects, diseases and functions related to the genes in the datasets. These results were less statistically significant than those returned by the PCR array analysis. The AD/Control ratio was the most statistically significant for PCR array analysis while AD+/Control was the most statistically significant for RNA bulk sequencing analysis.

CONCLUSION: The difference in the amount of data and statistical significance provided by the RNA bulk sequencing and the PCR array analyses provides evidence that the focused number of genes in the PCR array analysis results in greater statistical significance while sacrificing breadth. Through manipulating the expression of regulators, molecules, and diseases for the two datasets, we identified activating brain derived neurotrophic factor (BDNF) as the most effective therapeutic approach for inhibiting Alzheimer's disease. BDNF will be added to a mathematical model for AD that we are constructing to evaluate and optimize the therapeutic potential of activating BDNF to significantly inhibit AD in AD or AD+ patients.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Brain/metabolism
*DNA, Mitochondrial/genetics
Mutation/genetics

@article {pmid41436070,
year = {2025},
author = {McLean, JW and Wang, T and Shang, Y and Brinton, RD},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101089},
doi = {10.1002/alz70855_101089},
pmid = {41436070},
issn = {1552-5279},
mesh = {Animals ; Female ; Rats, Sprague-Dawley ; *Hippocampus/metabolism/pathology ; Rats ; Ovariectomy ; *Estrogens/deficiency ; *Estradiol/pharmacology ; Neurons/metabolism ; *Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Estrogen is a master regulator of systems biology in the female brain, coordinating metabolic, immune, and neuronal homeostasis. Loss of estrogen during menopausal transition is associated with declining brain glucose metabolism and increasing neuroinflammation, which may contribute to neuronal vulnerability and a doubled lifetime risk of Alzheimer's disease (AD) in women. However, neuronal and glial cell type-specific responses to estrogen deficiency in the hippocampus, a brain region critically affected in AD, is incompletely understood.

METHOD: To identify hippocampal cells and pathways affected by estrogen loss, 5-month-old female Sprague Dawley rats were randomly assigned to sham ovariectomized (SHAM), ovariectomized plus vehicle (OVX), or OVX with 17β-estradiol (OVX+E2) and sacrificed 5 weeks post-surgery. Nuclei isolated from dorsal hippocampus were pooled from two biological replicates per treatment group. A 10X Genomics Chromium Single Cell 3' kit was used to generate a single-nuclei cDNA library for each condition. Libraries were sequenced on an Illumina NovaSeq6000, and demultiplexed FASTQ files were analyzed using CellRanger 7.1.0 and Loupe Browser 8.0. After a quality-control step filtering out nuclei with >5% mitochondrial reads, established cell type-specific marker genes allowed annotation of distinct clusters of major brain cell types including excitatory and inhibitory neurons, astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPCs), microglia, and endothelial cells.

RESULT: Single-nuclei transcriptomics identified reduced cell percentage of a neuron cluster (Exc1) expressing Slc17a6 (vGlut2) in OVX hippocampus (10%), which was partially rescued in OVX+E2 (17%), relative to SHAM (37%). Additional subpopulations affected included other inhibitory and excitatory neuron clusters, as well as oligodendrocytes. Bulk analysis identified KEGG pathways altered in OVX condition, including antigen processing, cholesterol metabolism, insulin resistance, and glutamatergic synapse pathways. Gene Set Enrichment Analysis of differentially expressed genes within estrogen-sensitive neuronal subpopulations indicated a reduction in oxidative phosphorylation pathways in OVX compared to both SHAM and OVX+E2.

CONCLUSION: These findings extend previous reports of estrogen loss affecting bioenergetics, specifically oxidative phosphorylation, as well as neuroinflammation and synaptic function. Ongoing studies aim to identify further cell-type specific pathway contributions. Outcomes will advance an understanding of brain cell-specific responses to estrogen loss and help identify specific drivers of brain vulnerability in the estrogen-deficient female brain.},
}

Animals
Female
Rats, Sprague-Dawley
*Hippocampus/metabolism/pathology
Rats
Ovariectomy
*Estrogens/deficiency
*Estradiol/pharmacology
Neurons/metabolism
*Alzheimer Disease/metabolism

@article {pmid41436069,
year = {2025},
author = {Iliyasu, MO and Ajayi, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101337},
doi = {10.1002/alz70855_101337},
pmid = {41436069},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; *Blood-Brain Barrier/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Apolipoproteins E/metabolism/genetics ; Apolipoprotein E4/metabolism ; Brain/metabolism/pathology ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), a progressive neurodegenerative disease, is the most common type of dementia affecting people over 65 years of age. The prevalence of AD is rising quickly because of extended lifespans, and by 2050, there will be roughly 115 million AD patients worldwide. Apolipoprotein E (APOE), the major genetic risk factor of AD, has been reported to mediate blood-brain barrier (BBB) integrity and influence amyloid beta aggregation. Findings have initiated the future development of APOE-targeted AD therapeutics. The present study aimed to review the latest developments in APOE, BBB and amyloid beta mechanisms, mediating AD pathogenesis.

METHOD: The literature for this review was collected from PubMed, Scopus, Research Gate and Google Scholar.

RESULT: The three APOE isoforms are APOE4, APOE3, and APOE2. APOE4 raises the risk of AD by causing earlier and more abundant amyloid pathology and impairs BBB integrity and several aspects of normal brain functions. APOE4 affects the production, clearance, and aggregation of Aβ, leading to amyloid plaque formation. It also has other effects, like increasing tau hyperphosphorylation to neurofibrillary tangle, neuroinflammation, and mitochondrial and synaptic dysfunctions.

CONCLUSION: APOE4 contributes to AD pathogenesis, mainly through BBB integrity and pathways dependent on amyloid beta. Therefore, APOE4-targeted therapy could be useful for Alzheimer's disease treatment.},
}

Humans
*Alzheimer Disease/pathology/metabolism/genetics
*Blood-Brain Barrier/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Apolipoproteins E/metabolism/genetics
Apolipoprotein E4/metabolism
Brain/metabolism/pathology
Animals

@article {pmid41436068,
year = {2025},
author = {Yang, CY and Jalsrai, A and Hsieh, HM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101570},
doi = {10.1002/alz70855_101570},
pmid = {41436068},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Alzheimer Disease/drug therapy/pathology ; Mice, Inbred C57BL ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Mice, Transgenic ; *Polysaccharides/pharmacology ; Male ; Maze Learning/drug effects ; *Plant Extracts/pharmacology ; RAW 264.7 Cells ; *Anti-Inflammatory Agents/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by a progressive decline in cognitive functions. Key pathological features of AD include the accumulation of Aβ plaques, the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau, and significant neuronal loss. Neuroinflammation is critical to the pathogenesis of AD, closely linked to the development of these pathological hallmarks and the progression of neuronal damage. Hedysarum, a traditional herbal medicine and dietary supplement with a long history of clinical application, is widely recognized for its health-promoting and disease-managing properties.

METHODS: In this study, we investigated the neuroprotective and anti-inflammatory potential of Hedysarum alpinum L. polysaccharide extracts (HAP) using two models, in vivo 5xFAD mice and in vitro LPS-induced RAW264.7 macrophages. The 4-month-old 5xFAD and wild-type (C57BL/6J) mice were orally administered with HAP (20 mg/kg) or saline vehicle daily for six weeks, respectively. Behavioral tests were conducted during the last two-week treatment to evaluate cognitive functions.

RESULTS: In the Barnes maze, the TG+HAP group exhibited a significantly shorter latency to locate the escape hole during the training phase compared to the TG+saline group. During the probe phase, the HAP-treated group also spent considerably more time in the target quadrant, indicating improved spatial learning and memory. Moreover, in the Y-maze test, 5xFAD mice showed a significantly reduced spontaneous alternation rate compared to wild-type mice, reflecting impaired short-term memory. However, HAP administration significantly improved the spontaneous alternation rate in 5xFAD mice. Furthermore, HAP effectively attenuated LPS-induced activation of the NLRP3 inflammasome in RAW264.7 macrophages by inhibiting the NFκB signaling pathway. HAP significantly reduced LDH release and gene expression levels of pro-inflammatory mediators, including IL-1β, IL-6, TNF-α, and iNOS.

CONCLUSIONS: Our findings demonstrate that HAP significantly reduces inflammation and improves cognitive function in 5xFAD mice. These beneficial effects could be mediated through the modulation of the microbiota-gut-brain axis, which will be further elucidate through analyzing of the gut microbiome composition.},
}

Animals
Mice
*Alzheimer Disease/drug therapy/pathology
Mice, Inbred C57BL
*Neuroprotective Agents/pharmacology
Disease Models, Animal
Mice, Transgenic
*Polysaccharides/pharmacology
Male
Maze Learning/drug effects
*Plant Extracts/pharmacology
RAW 264.7 Cells
*Anti-Inflammatory Agents/pharmacology

@article {pmid41436040,
year = {2025},
author = {Huhmer, A and Zhang, Z and Budamagunta, V and Joly, J and Guha, SK and Wang, R and Tan, S and Juneau, K and Mallick, P},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101345},
doi = {10.1002/alz70855_101345},
pmid = {41436040},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Brain/metabolism/pathology ; Protein Processing, Post-Translational ; Phosphorylation ; Male ; Protein Isoforms/metabolism ; Female ; Aged ; Proteomics ; },
abstract = {BACKGROUND: The microtubule-associated protein Tau (MAPT) is implicated in various progressive neurodegenerative diseases, including Alzheimer's Disease (AD). With six primary splicing isoforms and over 70 different post-translational modifications (PTMs) identified on Tau, its proteoform diversity is extensive. However, a significant knowledge gap remains regarding the prevalence of specific proteoforms and their role in the progression of neurodegenerative diseases.

METHOD: We employed a novel single-molecule assay utilizing the Nautilus proteome analysis platform to investigate the Tau proteoform landscape in human brain samples. This platform immobilizes individual protein molecules on a hyper-dense flow cell, which are then probed iteratively with splice-variant specific or PTM-specific antibodies. Each Tau molecule's proteoform is estimated based on the pattern of antibody binding, with the overall abundance of each proteoform quantified by advanced data-processing software that corrects for potential binding errors and off-target interactions.

RESULT: We analyzed brain samples from seven individuals, five diagnosed with Alzheimer's and two controls, assessing the diversity and abundance of Tau proteoforms. Our findings reveal a complex proteoform landscape with distinct differences in the maturity and phosphorylation patterns of Tau isoforms between affected individuals and controls. Notably, hyperphosphorylation was prevalent in samples from Alzheimer's patients, with clear differentiation between proteoforms with minimal phosphorylation and those with extensive modifications.

CONCLUSIONS: The single molecule platform has proven effective in quantifying the molecular heterogeneity of Tau proteoforms in human brain tissue. This analysis begins to enhance our understanding of Tau's role in Alzheimer's disease, highlighting its potential for developing more sensitive diagnostic approaches based on proteoform heterogeneity. This study sets the stage for future research on the impact of specific Tau proteoforms on neurodegenerative disease progression and their utility as biomarkers for AD.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/pathology
*Brain/metabolism/pathology
Protein Processing, Post-Translational
Phosphorylation
Male
Protein Isoforms/metabolism
Female
Aged
Proteomics

@article {pmid41436039,
year = {2025},
author = {Reid, K},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101257},
doi = {10.1002/alz70855_101257},
pmid = {41436039},
issn = {1552-5279},
mesh = {Humans ; *Electronic Health Records/statistics & numerical data ; *Alzheimer Disease/diagnosis/epidemiology ; *Machine Learning ; United States/epidemiology ; Medicare/statistics & numerical data ; Aged ; Male ; Female ; *Dementia/epidemiology ; },
abstract = {BACKGROUND: There are more than 5.8 million Americans who suffer from Alzheimer's disease 1. By 2060 13.8 million Americans will be living with Alzheimer's Dementia 2. As of 2022, the financial burden of Alzheimer's Dementia is $321 billion and is expected to reach $1 trillion. 2 Detection and prediction of Alzheimer's and related dementia using widely available data such as electronic health record and electronic claim data could help identify populations at risk for development the disease.

METHOD: We used electronic health record and claim data to predict Alzheimer's and Related Dementias (ADRD) up to 10 years in advance using electronic health record data from the Mimic-IV dataset, and electronic claim data form a 5% sample of medicare data from various care settings. For this modeling effort, we used machine learning methods. We also explored techniques to ascertain that models are explainable and work effectively across demographic gorups.

RESULT: Using the Mimic-IV dataset, we achieved an AUC of 0.92 predict ADRD up to 10 years in advance. Using a 5% sample of Medicare claim data from diverse healthcare settings, we have achieved an Area Under the Curve (AUC) of 0.86, 0.85, and 0.83 respectively for predicting ADRD 1,3, and 5 years in advance respectively.

CONCLUSION: Machine learning methods can be utilized to predict ADRD using widely available administrative data such as electronic health record and electronic claim data.},
}

Humans
*Electronic Health Records/statistics & numerical data
*Alzheimer Disease/diagnosis/epidemiology
*Machine Learning
United States/epidemiology
Medicare/statistics & numerical data
Aged
Male
Female
*Dementia/epidemiology

@article {pmid41436038,
year = {2025},
author = {Zhang, T and Peng, G},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101496},
doi = {10.1002/alz70855_101496},
pmid = {41436038},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/pathology/metabolism ; *Cognitive Dysfunction/pathology/metabolism ; Aged ; *Gastrointestinal Microbiome/physiology ; *Bile Acids and Salts/blood ; *Basal Forebrain/pathology/diagnostic imaging ; Cognition/physiology ; Magnetic Resonance Imaging ; Aged, 80 and over ; },
abstract = {BACKGROUND: Emerging research highlights the role of the gut microbiome in the progress of Alzheimer's disease (AD). Alterations in serum bile acid (BA) profiles, reflecting gut microbial activity, have been observed in AD patients; however, the connection to cognitive decline is still poorly understood. This research aims to deepen our understanding of the complex mechanisms through which the gut microbiome and its metabolites influence cognitive function in AD patients.

METHOD: We analyzed data from 1,414 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 389 cognitively unimpaired controls, 754 mild cognitive impairment (MCI) individuals, and 271 AD patients. We examined 15 BA metabolites and 8 BA ratios to explore their correlations with volumes of the basal forebrain cholinergic system (BFCS) and cognitive performance. We also conducted mediation analyses to assess the role of BFCS in the impact of BA profiles on cognitive function, as well as the role of AD pathology in the effect of BA profiles on BFCS.

RESULT: Associations were observed between serum BA profiles, BFCS volumes, and cognitive performance, even after adjusting for demographic factors. The mediation analysis suggested the mediating role of the BFCS in the relationship between gut microbiota metabolism-related secondary-to-primary BA ratios and cognitive function. Furthermore, the influence of secondary-to-primary BA ratios on BFCS was modulated by tau pathology.

CONCLUSION: Our findings suggest that BFCS may modulate the relationship between BAs and cognitive function, with tau pathology potentially mediating the influence of BAs on BFCS. These results enhance our understanding of the intricate mechanisms through which the brain-gut axis modulates cognitive function in AD.},
}

Humans
Male
Female
*Alzheimer Disease/pathology/metabolism
*Cognitive Dysfunction/pathology/metabolism
Aged
*Gastrointestinal Microbiome/physiology
*Bile Acids and Salts/blood
*Basal Forebrain/pathology/diagnostic imaging
Cognition/physiology
Magnetic Resonance Imaging
Aged, 80 and over

@article {pmid41436035,
year = {2025},
author = {D'Oliveira, R and Bertucci, T and Yilmaz, E and Aladyeva, E and Benitez, BA and Kizil, C and Sutherland, GT and Karch, CM and Temple, S and Harari, O},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101122},
doi = {10.1002/alz70855_101122},
pmid = {41436035},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Brain/pathology/metabolism/blood supply ; *Cerebral Amyloid Angiopathy/genetics/pathology ; Male ; Female ; Aged ; Transcriptome ; *Cerebrovascular Disorders/genetics/pathology ; },
abstract = {BACKGROUND: Cerebrovascular disorders are associated with an increased risk for neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration are poorly understood. We aim to dissect the complex interplay between vascular dysfunction and AD to molecular features in cerebrovascular cells (CVCs) through deep multi-omic profiling of human brains.

METHOD: We have previously performed single-nucleus transcriptomic profiles (snRNA-seq) and chromatin accessibility (snATAC-seq) of parietal cortex from healthy and AD donors from the Australian Brain Bank Network (ABBN; n = 72 brains), which are richly annotated for cerebrovascular phenotypes, including cerebral amyloid angiopathy (CAA). In parallel, we generated spatially resolved transcriptomic profiles for a subset of these samples. We integrated this data with seven public snRNA-seq datasets to create a comprehensive multi-omic cerebrovascular atlas.

RESULT: Our cerebrovascular atlas encompassed >133K nuclei across major CVC types. This high resolution identified perturbed CVC transcriptional programs between cases and controls, including changes specific to rare AD risk variants. We identified perturbed regulatory programs associated with CAA in large-diameter endothelial cells and capillary-specific changes related to late-onset AD, including up-regulation of metallothionein genes. We validated these findings in human brains using immunohistochemistry. In addition, we identified an age-associated CVC transcriptional signature linked to APOE4 detectable before disease onset, suggesting that APOE4 associates with accelerated vascular aging. Lastly, we used snATAC-seq to prioritize multiple independent AD risk loci, including APP and APOE, where at least one fine-mapped risk variant (95% credible set) overlapped a regulatory element active in vascular cells. Finally, we observed extensive transcriptional changes in putative AD-risk genes in all CVCs subtypes, supporting a shared genetic risk between AD and cerebrovascular disease but suggesting the shared risk is mediated in a cell type-specific manner.

CONCLUSION: Our work provides novel insights into the links between cerebrovascular dysfunction and AD and identifies genes and regulatory elements mediating AD genetic risk through CVCs.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Brain/pathology/metabolism/blood supply
*Cerebral Amyloid Angiopathy/genetics/pathology
Male
Female
Aged
Transcriptome
*Cerebrovascular Disorders/genetics/pathology

@article {pmid41436033,
year = {2025},
author = {Ma, L and Qu, Q},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101510},
doi = {10.1002/alz70855_101510},
pmid = {41436033},
issn = {1552-5279},
mesh = {Animals ; *Hippocampus/metabolism/ultrastructure/pathology ; Rats ; *Diabetes Mellitus, Experimental/metabolism/pathology/complications ; Autophagy/physiology ; Male ; Lysosomes/metabolism ; Humans ; Rats, Sprague-Dawley ; Amyloid beta-Peptides/metabolism ; rab7 GTP-Binding Proteins ; rab GTP-Binding Proteins/metabolism ; Autophagosomes/metabolism ; Apoptosis ; Cell Line, Tumor ; *Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Diabetes has been regarded as an independent risk factor for Alzheimer's disease(AD). This study investigates the effect of diabetes on autophagosome-lysosome fusion using STZ-induced diabetic rats and SH-SY5Y cells, aiming to clarify the molecular mechanisms linking diabetes to Aβ deposition and AD pathogenesis.

METHOD: In vivo, STZ-induced diabetic rats were tested using the Open-field and Morris water maze tests to assess cognitive function. Hippocampal ultrastructural changes were observed via electron microscopy, while Western blot and qRT-PCR were used to measure Aβ, CTSD, CTSL, and Rab7 expression. In vitro, SH-SY5Y cells were cultured under high glucose (HG) conditions with or without rapamycin (Rap) or 3MA. Autophagy was analyzed using electron microscopy and mRFP-GFP-LC3 adenovirus transfection. Lysosomal activity (ACP2) was measured via ELISA, and apoptosis was assessed using flow cytometry.

RESULT: Diabetic rats showed impaired spatial memory in the Morris water maze test and increased hippocampal Aβ expression, with decreased CTSD and CTSL levels. SH-SY5Y cells in the HG group exhibited increased autophagosomes and enhanced autophagic flux but reduced lysosomal ACP2 activity. Rab7, Cath L, and Cath D levels were lower in the HG group, impairing autophagosome-lysosome fusion and Aβ clearance. Rapamycin improved lysosomal function, reduced apoptosis, and restored Rab7, Cath L, and Cath D levels, while 3MA exacerbated these impairments.

CONCLUSION: Diabetes disrupts autophagosome-lysosome fusion, impairing Aβ clearance and lysosomal function, leading to increased apoptosis and cognitive dysfunction. These findings provide insights into the mechanisms of diabetes-related AD and suggest potential therapeutic targets.},
}

Animals
*Hippocampus/metabolism/ultrastructure/pathology
Rats
*Diabetes Mellitus, Experimental/metabolism/pathology/complications
Autophagy/physiology
Male
Lysosomes/metabolism
Humans
Rats, Sprague-Dawley
Amyloid beta-Peptides/metabolism
rab7 GTP-Binding Proteins
rab GTP-Binding Proteins/metabolism
Autophagosomes/metabolism
Apoptosis
Cell Line, Tumor
*Alzheimer Disease/metabolism

@article {pmid41436032,
year = {2025},
author = {Gao, H and Jensen, K and Nesbitt, J and Ostroot, M and Baloni, P and Funk, CC and Wiley, JC and Watzlawik, JO and Springer, W and Galkin, A and Trushina, E},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101111},
doi = {10.1002/alz70855_101111},
pmid = {41436032},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; Mice, Knockout ; *Electron Transport Complex I/metabolism/genetics ; Female ; Mice ; Male ; *Brain/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; Oxidative Phosphorylation ; Disease Models, Animal ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Early mechanisms of neuronal damage in Alzheimer's Disease (AD) include mitochondrial dysfunction and abnormal energy homeostasis. AD-associated mitochondrial signaling was shown to occur upstream of amyloid precursor protein processing, Ab production, apolipoprotein E (APOE) expression, and tau pathology. However, whether alterations in mitochondrial function are sufficient to instigate AD remains unclear. Mitochondrial complex I (mtCI) is a rate-limiting enzyme in the oxidative phosphorylation (OXPHOS) machinery. Changes in mtCI activity influence ATP and ROS production, cellular energy and redox homeostasis. We examined how reduced activity of mtCI due to a knockout of one of its accessory subunits Ndufs4 in mice affects transcriptional networks in the brain. We also determined whether reduced activity of mtCI abrogates neuroprotective properties of a small molecule CP2.

METHOD: RNA-sequencing of the brain tissue was performed using Ndufs4[-/-] and control mice (n = 3-5 per group). The co-expression modules of differentially expressed genes were compared to the AMP-AD patient cohort data. Key mechanisms, including mitophagy signaling, were confirmed using ELISA and western blot analyses; the effect on mtCI activity was confirmed using functional assays.

RESULTS: In Ndufs4[-/-] mice, a residual activity of mtCI was ∼50% of the control. This loss of function led to a global disruption of mitochondrial homeostasis, energy metabolism, synaptic function, significant increase in mitophagy and a reduction in biogenesis. Transcriptomic signatures in brain tissue of male and female Ndufs4[-/-] mice overlapped with changer reported for AD patients and AD mouse models with Ab and p-tau pathologies. These changes were partially rescued by a neuroprotective mitochondria-targeting small molecule CP2. Consistent with studies in AD mice, CP2 treatment in Ndufs4[-/-] mice augmented the expression of genes associated with mitochondrial biogenesis and turnover, synaptic activity, autophagy, redox balance, and reduced expression of genes related to inflammation. Sex-specific differences included better adaptation to a reduced activity of mtCI and to CP2 treatment in female mice.

CONCLUSION: Reduced mtCI activity was sufficient to induce the AD-like transcriptomic changes in brain. Residual mtCI function was sufficient to mediate neuroprotective effect of CP2, emphasizing a key role of mitochondria in AD development and treatment.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
Mice, Knockout
*Electron Transport Complex I/metabolism/genetics
Female
Mice
Male
*Brain/metabolism/pathology
Humans
*Mitochondria/metabolism
Oxidative Phosphorylation
Disease Models, Animal
Mice, Inbred C57BL

@article {pmid41436031,
year = {2025},
author = {Talbot, A and Trevino, CE and Seyfried, NT and Dammer, EB and Johnson, ECB and Lah, JJ and Wingo, AP and Wingo, TS and Imam, F and Levey, AI and Kotlar, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100509},
doi = {10.1002/alz70855_100509},
pmid = {41436031},
issn = {1552-5279},
mesh = {Humans ; *Proteomics/methods ; *Alzheimer Disease/genetics/metabolism ; Female ; Male ; *Genomics/methods ; Genome-Wide Association Study ; },
abstract = {BACKGROUND: With the growing availability of large genetic and proteomic datasets there is unprecedented need for simplified, scalable methods for integrated omics analysis of Alzheimer's disease (AD). We have built 8 distinct genomic and proteomic analysis tools for AD community use in the Global Research and Imaging Platform (GRIP), which improve accuracy and interpretability in diverse cases. Included are methods for network discovery, removing the influence of confounders, ancestry inference, variant annotation, natural language filtering, ancestry-corrected polygenic risk scores, and data harmonization. Here we highlight two methods: generative PCR (gPCR) for detecting phenotypically relevant networks, and FairPCA for removing the influence of confounders.

METHOD: Latent variable models struggle in ensuring that the latent space is relevant to low-variance phenotypes. We developed gPCR, which improves on supervised variational autoencoders (SVAEs) to generate phenotypically relevant latent components. We demonstrate its performance by learning a proteomic network associated with AD in a balanced cohort of 300 samples with proteomic data from SomaScan and Tandem Mass Tag mass spectrometry (TMT-MS). For evaluation, we used a 70/30 train/test split. To deal with the corresponding problem of removing confounder effects we created FairPCA, an adversarial learning algorithm that ensures principal components are orthogonal to the undesired confounders and utilizes randomization to scale to large datasets. We evaluate FairPCA by removing the influence of sex from protein isoform abundance in 300 TMT-MS samples, and in removing confounders in a simulated genome wide association study.

RESULT: gPCR had better predictive performance (AUC=0.94) than traditional PCR (AUC=0.62) and comparable to elastic net regression (AUC=0.94) while also creating relevant protein networks. FairPCA trained to remove the influence of sex outperformed traditional PCA in predicting AD status (FairPCA AUC=0.83, PCA AUC=0.64), while in GWAS simulations the method improved cosine similarity between the inferred betas and the unconfounded true effects (before=0.71, after=.99).

CONCLUSION: gPCR maintains the predictive power of regularized regression while improving on the generative abilities of SVAEs, and our FairPCA solution simplifies the removal of confounding factors. These and the other 6 tools we have developed for the AD community and made available through GRIP will dramatically accelerate scientific discovery.},
}

Humans
*Proteomics/methods
*Alzheimer Disease/genetics/metabolism
Female
Male
*Genomics/methods
Genome-Wide Association Study

@article {pmid41436029,
year = {2025},
author = {Huang, Z and Sekhon, VK and Guo, O and Newman, M and Sadeghian, R and Vaida, ML and Jo, C and Ward, D and Bucci, V and Haran, JP},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100530},
doi = {10.1002/alz70855_100530},
pmid = {41436029},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Gastrointestinal Microbiome ; Female ; Male ; Aged ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complicated neurodegenerative disorder influenced by dynamic interactions among clinical, microbial, and other complex underlying mechanisms. The Alzheimer's Disease Analysis Model Generation 1 (ADAM-1) is an innovative multi-agent large language model (LLM) framework proposed to deal with the complications of analyzing diverse and multi-modal datasets. ADAM-1 integrates clinical datasets, microbiome profiles, and existing Alzheimer's publications using retrieval-augmented generation (RAG) techniques supporting AI agents to enhance diagnostic and analytical capabilities offering unified and comprehensive insights into Alzheimer's disease prognosis.

METHOD: The study incorporates a multi-modal dataset with paired clinical and gut microbiome data from 102 nursing home residents, including 64 healthy controls (HC) and 38 individuals with AD, collected across four facilities in central Massachusetts as part of one of our previous studies. ADAM-1, built on the GPT-4o-mini-2024-07-18 model, integrates three AI agents designed for Alzheimer's binary classification: a computational agent for generating descriptive statistics, a summarization agent for synthesizing insights from the data and knowledge database, and a classification agent for performing binary predictions based on prior outputs. The knowledge database comprises 80,909 Alzheimer's-focused publications from PubMed. Classification performance was assessed using F1 scores across 15 randomized seeds, with comparisons to XGBoost as the baseline model. The study was conducted using Python 3.10.14 on an Ubuntu 24.04.1 LTS workstation with four 3090 GPUs.

RESULT: For Alzheimer's classification, ADAM-1 achieved a mean F1 score comparable to that of XGBoost (p = 0.0967, t-test) while demonstrating significantly reduced F1 score variance (p = 0.0083, F-test), indicating more stable performance across evaluations using 15 randomized seeds. The reduced variance in F1 scores emphasizes the reliability of ADAM-1 in handling relatively small sample data, a common scenario in clinical translational research.

CONCLUSION: ADAM-1 offers a robust and consistent platform for multi-modal data analysis in Alzheimer's research. The system's human-machine interaction through natural language queries enhances data interpretability, expanding and broadening researchers' insights in analyzing such complex datasets. Future versions of ADAM will include blood biomarkers and neuroimaging thus enabling more comprehensive and precise diagnostics, advancing the understanding of the complicated and dynamic underlying mechanisms of Alzheimer's disease progression.},
}

Humans
*Alzheimer Disease/diagnosis
*Gastrointestinal Microbiome
Female
Male
Aged

@article {pmid41436025,
year = {2025},
author = {Pickles, SR and Gaiani, L and Lin, L and Jansen-West, K and Tong, J and Rosso, GD and Daughrity, L and Zhang, Y and Petrucelli, L},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e101194},
doi = {10.1002/alz70855_101194},
pmid = {41436025},
issn = {1552-5279},
mesh = {Animals ; Disease Models, Animal ; Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Mice ; *Stathmin/genetics/metabolism ; *Alzheimer Disease/genetics/pathology/metabolism ; Brain/metabolism/pathology ; Mice, Transgenic ; },
abstract = {BACKGROUND: Some cases of Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) feature the mislocalization of the normally nuclear TAR DNA binding protein (TDP-43) to the cytoplasm where it is incorporated into inclusions in affected brain regions. TDP-43 plays a crucial role in the suppression of cryptic exons in the mature RNA of many targets in both AD and FTD. One such target, Stathmin-2 (STMN2), is misspliced in the absence of TDP-43 leading to a reduction of STMN2 RNA and protein while the levels of the cryptic splice variant is increased. Cryptic exons are not conserved across species, meaning previous Tdp-43 models did not capture Stmn2 processing defects and Stmn2 loss of function (LOF). We hypothesize that STMN2 LOF contributes to cognitive phenotypes observed in AD and FTD.

METHOD: We have generated a novel mouse that more accurately models human disease mechanisms by expressing short-hairpin (shRNA) via adeno associated virus in the central nervous system of a recently described humanized Stmn2 mouse model in which Stmn2 splicing is dependent on Tdp-43. In this mouse we will simultaneously model Tdp-43 loss of function and aberrant Stmn2 splicing.

RESULT: Our preliminary experiments demonstrate that humanized Stmn2 mice expressing shRNA against Tardbp have a reduction of Tardbp RNA and TDP-43 protein compared to mice expressing a non-targeting shRNA. Tdp-43 knock-down is accompanied by cryptic splicing of endogenous mouse targets, Sortilin 1 and Translin. As anticipated, we also detected cryptic Stmn2 splicing, suggesting that correct Stmn2 splicing is dependent on Tdp-43 in this model. We will further characterize motor and cognitive functions in addition to neurodegeneration and gliosis in these animals.

CONCLUSION: We anticipate this novel model, and our subsequent studies will identify relevant disease mechanisms and provide an invaluable tool with which to investigate therapies for AD and FTD.},
}

Animals
Disease Models, Animal
Humans
*DNA-Binding Proteins/genetics/metabolism
*Frontotemporal Dementia/genetics/pathology/metabolism
Mice
*Stathmin/genetics/metabolism
*Alzheimer Disease/genetics/pathology/metabolism
Brain/metabolism/pathology
Mice, Transgenic

@article {pmid41435973,
year = {2025},
author = {Cho, S and Zhu, R and Kuncewicz, K and Duan, H and Gabr, M},
title = {AI-guided design of cyclic peptide binders targeting TREM2 using CycleRFdiffusion and experimental validation.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130512},
doi = {10.1016/j.bmcl.2025.130512},
pmid = {41435973},
issn = {1464-3405},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimer's disease. Despite advances in antibody-based therapeutics, small molecules and peptides capable of modulating TREM2 remain limited. Here, we present a cyclic peptide design pipeline that integrates CycleRFdiffusion, ProteinMPNN for sequence design, and HighFold for structural prediction and screening. Using the TREM2 structure as input, we generated and screened 1500 peptide-target complexes, prioritizing four candidates that met structural and energetic criteria. Subsequent biophysical evaluation identified TP4 as a weak but reproducible TREM2 binder, demonstrating consistent binding in spectral shift, microscale thermophoresis, and surface plasmon resonance. Pharmacokinetic profiling indicated that TP4 possesses favorable plasma stability and moderate metabolic stability, supporting its potential for further optimization. This study establishes a generalizable framework for AI-driven cyclic peptide discovery and provides the first proof-of-concept demonstration of TREM2-targeted cyclic peptide binders.},
}