@article {pmid41515895,
year = {2025},
author = {Strelnikova, PA and Kononikhin, AS and Zakharova, NV and Bugrova, AE and Indeykina, MI and Fedorova, YB and Kolykhalov, IV and Morozova, AY and Andryushchenko, AV and Fedoseeva, ED and Emelyanova, MA and Gryadunov, DA and Gavrilova, SI and Mitkevich, VA and Kostyuk, GP and Chaika, YA and Makarov, AA and Nikolaev, EN},
title = {Plasma Protein Panel for Assessing the Risk of Alzheimer's Disease by MRM-MS Analysis: The Study of Two Independent Clinical Cohorts.},
journal = {International journal of molecular sciences},
volume = {27},
number = {1},
pages = {},
pmid = {41515895},
issn = {1422-0067},
support = {grant agreement No. 075-15-2024-530//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; Male ; Female ; Biomarkers/blood ; Aged ; *Blood Proteins/analysis/metabolism ; Cognitive Dysfunction/blood/diagnosis ; *Proteomics/methods ; Cohort Studies ; Middle Aged ; *Mass Spectrometry/methods ; Aged, 80 and over ; ROC Curve ; Case-Control Studies ; },
abstract = {Early recognition of a risk of Alzheimer's disease (AD) remains a global challenge, and blood proteomic markers are of particular interest for wide-scale diagnostic use. Quantitative multiple reaction monitoring (MRM) approach demonstrates good reproducibility in the characteristic changes in the levels of reported candidate biomarkers (CBs) in different cohorts in AD. Following up on our previous study, we performed a joint analysis of 331 blood plasma samples from two different clinical cohorts of participants, comprising a total of 95 samples from patients with AD, 136 samples from patients with mild cognitive impairment (MCI), and 100 samples from controls. The obtained results confirm the significance of 37 CBs. A logistic regression-based algorithm was used to build protein classifiers, and a total of 21 important proteins were selected, 13 of which (ORM1, APOA4, LBP, HP, FN1, BCHE, APOE, PZP, A1BG, TF, SERPINA7, TTR, and F12) formed a universal panel that demonstrated strong classification performance in distinguishing AD patients from controls (ROC-AUC = 0.90) and in separating stable and progressing patients with MCI (ROC-AUC = 0.81). Overall, the analysis confirms the high potential of the MRM method for validating CBs in independent cohorts.},
}

Humans
*Alzheimer Disease/blood/diagnosis
Male
Female
Biomarkers/blood
Aged
*Blood Proteins/analysis/metabolism
Cognitive Dysfunction/blood/diagnosis
*Proteomics/methods
Cohort Studies
Middle Aged
*Mass Spectrometry/methods
Aged, 80 and over
ROC Curve
Case-Control Studies

@article {pmid41515556,
year = {2025},
author = {Kawakami, S and Jung, CG and Inoue, R and Nakamura, T and Sato, S and Michikawa, M},
title = {Elevated Flotillin-1 in Saliva and Salivary Glands: A Novel Non-Invasive Biomarker in an Alzheimer's Disease Mouse Model.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {1},
pages = {},
pmid = {41515556},
issn = {2075-4418},
support = {C25K13134//the Ministry of Education, Culture, Sports, Science and Technology, Japan./ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is currently diagnosed using established biomarkers, such as reduced cerebrospinal fluid (CSF) Aβ42, increased phosphorylated tau, and cerebral amyloid levels detected by PiB-PET. Because these methods are invasive or require specialized facilities, less invasive and easily detectable biomarkers are needed. Flotillin-1 concentrations are reduced in the CSF and serum of patients with AD. This study examined whether flotillin-1 in saliva, a less invasive specimen than blood, could serve as a biomarker. Methods: Wild-type (WT) and App[NL-G-F] (APP knock-in; APP-KI) mice were used to create four groups (2 and 9 months of age, six animals per group). Saliva and salivary glands were collected, and flotillin-1 levels were measured using Western blotting. Intracellular signaling pathways regulating flotillin-1 and salivary gland Aβ42 levels were analyzed using Western blotting and ELISA, respectively. Results: Flotillin-1 levels in the saliva and salivary glands were significantly higher in the 9-month-old APP-KI group than in all other groups, including age-matched WT mice. Phosphorylated extracellular signal-regulated kinase (p-ERK) levels were also significantly elevated in the 9-month-old APP-KI group, whereas phosphorylated c-Jun N-terminal kinase (p-JNK) levels did not differ significantly. Salivary gland Aβ42 levels were markedly increased only in the 9-month-old APP-KI group. Conclusions: Flotillin-1 levels in saliva and salivary glands were significantly elevated in the presence of AD pathology. Aβ accumulation in the salivary glands likely activates the ERK signaling cascade, promoting flotillin-1 expression and secretion. Thus, salivary flotillin-1 may serve as a promising noninvasive biomarker for the early diagnosis of Alzheimer's disease.},
}

@article {pmid41515488,
year = {2026},
author = {Huang, Y and Li, X and Dai, L and Cheng, M and Zhao, L and Shen, Y and Xie, J and Luo, X},
title = {Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {1},
pages = {},
pmid = {41515488},
issn = {1420-3049},
support = {20232ACB2050009//Natural Science Foundation of Jiangxi Province, China/ ; 32060074//National Natural Science Foundation of China/ ; 20204BCJ22024//Major Academic and Technical Leader Training Project of Jiangxi Province/ ; },
mesh = {*Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Huperzia/chemistry ; Animals ; *Plant Extracts/chemistry/pharmacology ; Mice ; Sesquiterpenes/pharmacology/chemistry ; Alkaloids/pharmacology/chemistry ; RAW 264.7 Cells ; },
abstract = {Huperzine A is a preferred treatment option for Alzheimer's disease. Huperzia serrata (Thunb. ex Murray) Trev. (H. serrata) has garnered significant attention for its ability to produce Huperzine A (HupA). However, natural populations of wild H. serrata (WH) are rapidly declining. Fortunately, our group obtained two types of H. serrata thalli (OT and ST) capable of stably producing Huperzine A, which have the potential to serve as an alternative resource to WH. To evaluate the feasibility of this strategy, we conducted a comprehensive assessment of both WH and H. serrata thallus. The results indicated that compared to WH, ST and OT exhibited stronger anti-inflammatory and antioxidant activities, with lower cytotoxicity. Notably, ST demonstrated a strong radical scavenging activity, reaching 93.23% (DPPH at 0.2 μg/mL) and 99.87% (ABTS at 4 μg/mL), and reduced nitrite production from 10.29 μM to 6.51 μM at 50 µg/mL. GC-MS and widely targeted metabolomics analyses revealed that the higher antioxidant and anti-inflammatory activities for ST and OT were due to higher concentrations of phenolic acids and flavonoids compared to WH. In addition, the HupA content in ST reached 36.56% of that found in WH. KEGG enrichment analysis revealed that the flavonoid, phenylalanine, and phenylpropanoid biosynthesis pathways may be involved in regulating the antioxidant activity. P-coumaroyl quinic acid and caffeoyl quinic acid are the crucial metabolites for antioxidant activity. These findings suggested that the H. serrata thallus could serve as a sustainable alternative to WH.},
}

*Antioxidants/pharmacology/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry
*Huperzia/chemistry
Animals
*Plant Extracts/chemistry/pharmacology
Mice
Sesquiterpenes/pharmacology/chemistry
Alkaloids/pharmacology/chemistry
RAW 264.7 Cells

@article {pmid41515483,
year = {2026},
author = {Georgieva, M and Sharkov, M and Mateev, E and Mateeva, A and Kondeva-Burdina, M},
title = {Evaluation of Pyrrole Heterocyclic Derivatives as Selective MAO-B Inhibitors and Neuroprotectors.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {1},
pages = {},
pmid = {41515483},
issn = {1420-3049},
support = {project № BG-RRP-2.004-0004-C01.//European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria/ ; },
mesh = {*Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Animals ; Rats ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Pyrroles/chemistry/pharmacology/chemical synthesis ; *Monoamine Oxidase/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; *Heterocyclic Compounds/chemistry/pharmacology/chemical synthesis ; Brain/drug effects/metabolism ; },
abstract = {Novel pyrrole-based derivatives were synthesized in high purity and yields (52-89%), with 17i and 17j displaying selective MAO-B inhibition (50-60%), comparable to Selegiline, and negligible MAO-A activity. In rat brain subcellular fractions, both compounds showed low intrinsic neurotoxicity at 100 μM while exerting significant neuroprotective and antioxidant effects under 6-OHDA, t-BuOOH, and Fe[2+]/ascorbate-induced stress. Mechanistic studies indicate dual protection via reactive oxygen species scavenging and preservation of reduced glutathione, with mitochondria and microsomes being the most responsive compartments. The performed in silico analysis revealed no general toxicity alerts, though hydrazine groups classify the compounds as contact allergens, and the furan ring in 17i poses hepatotoxic and carcinogenic risks. Metabolic predictions suggest ester hydrolysis at the pyrrole ring as the main biotransformation pathway. Overall, 17i and 17j are promising lead compounds for developing therapeutics targeting oxidative stress-related neurodegenerative diseases, such as Parkinson's and Alzheimer's, supporting further in vivo studies.},
}

*Neuroprotective Agents/pharmacology/chemistry/chemical synthesis
Animals
Rats
*Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis
*Pyrroles/chemistry/pharmacology/chemical synthesis
*Monoamine Oxidase/metabolism
Oxidative Stress/drug effects
Antioxidants/pharmacology/chemistry
Reactive Oxygen Species/metabolism
*Heterocyclic Compounds/chemistry/pharmacology/chemical synthesis
Brain/drug effects/metabolism

@article {pmid41515408,
year = {2025},
author = {Wu, X and Huang, G and Chen, L and Xie, Y and Ding, Q and Xi, E and Zhao, Y and Gao, N},
title = {D-Penicillamine/Dihydroquercetin Dual-Loaded Metal-Organic Framework as a Microenvironment Copper Regulator for Enhancing the Therapeutic Efficacy of Polyphenolic Antioxidant in Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {1},
pages = {},
pmid = {41515408},
issn = {1420-3049},
support = {2022YFB3805902//National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; 20210101353JC//National Natural Science Foundation of Jilin Province/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Quercetin/analogs & derivatives/chemistry/pharmacology ; *Copper/chemistry/metabolism ; *Metal-Organic Frameworks/chemistry/pharmacology ; *Antioxidants/pharmacology/chemistry ; Animals ; Mice ; *Polyphenols/chemistry/pharmacology ; *Penicillamine/chemistry/pharmacology ; Humans ; Disease Models, Animal ; Mice, Transgenic ; },
abstract = {Polyphenols like dihydroquercetin, rutin, and rifampicin show promise for Alzheimer's disease (AD) therapy due to their ability to inhibit amyloid-β (Aβ) aggregation and reduce reactive oxygen species (ROS), garnering significant recent interest. However, their efficacy is substantially diminished because excess metal ions present in amyloid plaques can chelate these compounds. Therefore, reshaping the metal microenvironment in the patient's brain is particularly important for the therapeutic effect of AD. To address the above issues, we have constructed a composite system formed by NH2-MIL-101(Fe) (MOF), dihydroquercetin (DHQ), and D-penicillamine (D-pen). Due to the lack of π-π interaction and the low adsorption energy between D-pen/MOF, the release order and speed of D-pen was much faster than DHQ, thus achieving metal microenvironment regulation and ensuring the therapeutic effect of DHQ. In a 5 × FAD transgenic mouse model, DD@MOF treated and improved spatial learning and memory deficits. Therefore, the DD@MOF based on polyphenolic compounds provides a potential research direction for intervention in Alzheimer's disease through chelating copper ions and antioxidant properties.},
}

*Alzheimer Disease/drug therapy/metabolism
*Quercetin/analogs & derivatives/chemistry/pharmacology
*Copper/chemistry/metabolism
*Metal-Organic Frameworks/chemistry/pharmacology
*Antioxidants/pharmacology/chemistry
Animals
Mice
*Polyphenols/chemistry/pharmacology
*Penicillamine/chemistry/pharmacology
Humans
Disease Models, Animal
Mice, Transgenic

@article {pmid41515344,
year = {2025},
author = {Kobori, Y and Abe, T},
title = {First Total Synthesis of Pestasulfamides A and B Through Iminoketene Dimerization of Anthranilic Acid in One-Pot Manner.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {1},
pages = {},
pmid = {41515344},
issn = {1420-3049},
support = {JPJS00420230010//JSPS Program for Forming Japan's Peak Research Universities (J-PEAKS)/ ; },
mesh = {*ortho-Aminobenzoates/chemistry ; Dimerization ; Molecular Structure ; *Sulfonamides/chemical synthesis/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; },
abstract = {Pestasulfamides A and B are phenylbenzene-sulfonamides with an eight-membered dilactam, produced by mangrove endophytic fungus Pestalotiopsis sp. HNY36-1D. In bioassay, pestasulfamide A (1) exhibited potent anti-acetylcholine esterase (AChE) activities with an IC50 value of 11.94 μM, offering new pharmacophores with relevance to anti-Alzheimer's disease drug discovery. Although the dimerization reaction of anthranilic acid derivatives forges an dibenzodiazocin-2,6-dione framework, the application of the dimerization to total synthesis of pestasulfamides A (1) and B (2) has not yet been realized. Herein, the first total synthesis of pestasulfamides A and B was achieved through one-pot protocol. The key step features a sulfonylation-induced iminoketene dimerization of anthranilic acid in a pyridine/THF system.},
}

*ortho-Aminobenzoates/chemistry
Dimerization
Molecular Structure
*Sulfonamides/chemical synthesis/chemistry/pharmacology
*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology

@article {pmid41515287,
year = {2026},
author = {Guidotti, L and Lapi, D and Lucchesi, M and Valori, S and Corsi, F and Giambastiani, L and Vornoli, A and Gargini, C and Cammalleri, M and Dal Monte, M},
title = {An Acebuche Oil-Enriched Diet Prevents Early-Stage Cerebrovascular Alterations in the 5xFAD Mouse Model of Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {1},
pages = {},
pmid = {41515287},
issn = {2072-6643},
support = {European Union - Next Generation EU, NRRP Mission 4 Component 2 Investment 1.4, CUP B93D21010860004, CN_00000041 - National Center for Gene Therapy and Drugs based on RNA Technology//Italian Ministry of University and Research/ ; Department of Excellence 2023-2027 initiative//Italian Ministry of University and Research/ ; },
mesh = {Animals ; *Alzheimer Disease/prevention & control/diet therapy ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Blood-Brain Barrier/drug effects/metabolism ; *Plant Oils/pharmacology/administration & dosage ; Amyloid beta-Peptides/metabolism ; Male ; Antioxidants/pharmacology ; *Diet ; Olive Oil ; Brain/blood supply/metabolism ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder in which altered microvascular circulation participates in the pathogenesis. The lack of therapeutic treatments for AD makes the development of strategies aimed at preventing or delaying the disease onset urgent. In recent years, several studies have highlighted that a diet rich in antioxidants and anti-inflammatory compounds may positively impact AD development. In this study, we assessed the impact of a diet enriched with Acebuche (ACE) oil, an extra-virgin olive oil particularly rich in antioxidants and anti-inflammatory compounds, on AD progression in the 5xFAD mouse model. Methods: After weaning, wild-type (WT) and 5xFAD mice received the standard or the ACE oil-enriched diet. At 2, 4 and 6 months, the effects of the diet were evaluated on AD-related microvascular aberrancies, beta-amyloid (Aβ) formation, hypoxic state, blood-brain barrier (BBB) alterations, neuroinflammation and cognitive impairment. Metabolic parameters were also evaluated. Results: In 5xFAD mice, the ACE oil-enriched diet prevented alterations in cerebral microcirculation. Moreover, Aβ accumulation, downregulation of Aβ-degrading enzymes, hypoxia, BBB breakdown, neuroinflammation, and cognitive deficits were delayed by the ACE oil-enriched diet. However, some of these effects were reduced at 6 months, in concomitance with systemic metabolic changes, such as hepatic steatosis, evidenced in both WT and 5xFAD mice receiving the ACE oil-enriched diet. Conclusions: Overall, the present results represent proof of concept for the validity of early dietary interventions in AD prevention.},
}

Animals
*Alzheimer Disease/prevention & control/diet therapy
Disease Models, Animal
Mice
Mice, Transgenic
Blood-Brain Barrier/drug effects/metabolism
*Plant Oils/pharmacology/administration & dosage
Amyloid beta-Peptides/metabolism
Male
Antioxidants/pharmacology
*Diet
Olive Oil
Brain/blood supply/metabolism

@article {pmid41515140,
year = {2025},
author = {D'Errico, A and Nasso, R and Ruggiero, M and Rullo, R and De Vendittis, E and Masullo, M and Mazzeo, F and Arcone, R},
title = {Polyphenol-Enriched Extracts from Leaves of Mediterranean Plants as Natural Inhibitors of Monoamine Oxidase (MAO)-A and MAO-B Enzymes.},
journal = {Nutrients},
volume = {18},
number = {1},
pages = {},
pmid = {41515140},
issn = {2072-6643},
support = {CUP I53D23004270006 (M.M.)//This research work was supported by grants from Next Generation EU in the framework of PRIN 2022,/ ; },
mesh = {*Polyphenols/pharmacology/isolation & purification ; *Monoamine Oxidase Inhibitors/pharmacology/isolation & purification ; *Monoamine Oxidase/metabolism ; *Plant Leaves/chemistry ; *Plant Extracts/pharmacology/chemistry ; Humans ; Diet, Mediterranean ; Cell Line, Tumor ; },
abstract = {Background: Alzheimer's disease and Parkinson's disease are multifactorial disorders causing severe disability, rising with the increase in life expectancy. Currently, the identification of natural compounds useful against these disorders is becoming an urgent necessity. In this study, we used polyphenol-enriched extracts obtained from leaves of Mediterranean plants, which are important in animal feeding (Lotus ornithopodioides, Hedysarum coronarium, Medicago sativa) and in the human Mediterranean diet (Cichorium intybus). Objectives: The aims of this study were as follows: (i) tentative identification of the organic compounds present in the extracts; (ii) determination of their effect on the activity of monoamine oxidase (MAO)-A and MAO-B, key enzymes involved in the metabolism of aminergic neurotransmitters, as well as on protein expression level of these enzymes in cell lines expressing basal MAO-A and MAO-B. Methods: The ability of plant polyphenol extracts to inhibit MAO-A and MAO-B activity was assessed by in vitro enzyme assays. The protein expression level was analyzed by Western blotting. Results: Our data demonstrate that all the extracts behaved as MAO-A and MAO-B inhibitors, although to a different extent and enzyme inhibition mechanism; among them, the extract from L. ornithopodioides induced a decrease in MAO-A protein level in human AGS gastric adenocarcinoma and SH-SY5Y neuroblastoma cell lines. Conclusions: These data reinforce the hypothesis that a plant-based diet and/or integrative supplementation of pharmacological treatments can be considered for preventing and relieving symptoms of neurodegenerative diseases.},
}

*Polyphenols/pharmacology/isolation & purification
*Monoamine Oxidase Inhibitors/pharmacology/isolation & purification
*Monoamine Oxidase/metabolism
*Plant Leaves/chemistry
*Plant Extracts/pharmacology/chemistry
Humans
Diet, Mediterranean
Cell Line, Tumor

@article {pmid41515125,
year = {2025},
author = {Jo, H and Shin, J and Lee, H and Bae, GS and Kim, S},
title = {Network Pharmacology-Based Characterization of Mecasin (KCHO-1) as a Multi-Target Modulator of Neuroinflammatory Pathways in Alzheimer's Disease.},
journal = {Nutrients},
volume = {18},
number = {1},
pages = {},
pmid = {41515125},
issn = {2072-6643},
support = {2025-03-25-338//Wonkwang University/ ; },
mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism ; Humans ; *Network Pharmacology ; Molecular Docking Simulation ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Proto-Oncogene Proteins c-akt/metabolism ; *Plant Extracts/pharmacology ; *Phytochemicals/pharmacology ; },
abstract = {Background/Objectives: Mecasin (KCHO-1) is a standardized multi-herb formulation containing diverse bioactive compounds predicted to engage multiple molecular targets. This study applied an integrative network pharmacology approach to explore how Mecasin may interact with Alzheimer's disease (AD)-related molecular networks. Methods: Bioactive constituents from 9 herbs were screened through OASIS and PubChem, and their predicted targets were cross-referenced with 8886 AD-associated genes from GeneCards. Overlapping genes were analyzed using protein-protein interaction mapping, Gene Ontology, and KEGG to identify potential Mecasin-AD core nodes and pathways. Co-expression, co-regulation, and molecular docking analyses were performed to further characterize mechanistic relevance. Results: Network integration identified 6 core genes-AKT1, STAT3, IL6, TNF, EGFR, and IL1B-positioned within signaling pathways related to neuronal survival, inflammatory regulation, and cellular stress responses, including FoxO, JAK-STAT, MAPK, and TNF pathways. Molecular docking suggested that several Mecasin compounds may interact with targets such as AKT1 and TNF. Conclusions: These in silico findings indicate that Mecasin, a multi-component formulation containing numerous phytochemicals that generate broad compound-target associations, may interface with interconnected neuroimmune pathways relevant to AD. While exploratory, the results highlight potential multi-target mechanisms that merit further investigation and provide a systems-level framework to inform future experimental validation.},
}

*Alzheimer Disease/drug therapy/genetics/metabolism
Humans
*Network Pharmacology
Molecular Docking Simulation
Signal Transduction/drug effects
Protein Interaction Maps/drug effects
*Neuroinflammatory Diseases/drug therapy
Proto-Oncogene Proteins c-akt/metabolism
*Plant Extracts/pharmacology
*Phytochemicals/pharmacology

@article {pmid41514478,
year = {2026},
author = {Noman, M and Qadir, H and Ahmed, S and Rehman, NU and Shah, FA and Riaz, M and Ahmad, N and Ul-Haq, Z and Irshad, N},
title = {Santonin Attenuates Alzheimer's-Like Pathology via Multitarget Modulation of the NLRP3 Inflammasome, BDNF Signaling, and Amyloidogenic Pathways: An Integrated Experimental and Computational Study.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00957},
pmid = {41514478},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.},
}

@article {pmid41514416,
year = {2026},
author = {Tian, Q and Liu, M and Zhong, F and Liu, X and Lü, Y},
title = {Lecanemab treatment for mild alzheimer's disease with high risk of cerebral hemorrhage: a case report.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-025-04581-y},
pmid = {41514416},
issn = {1471-2377},
abstract = {BACKGROUND: Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages.

CASE PRESENTATION: A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred.

CONCLUSIONS: This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration.},
}

@article {pmid41514337,
year = {2026},
author = {McGurran, H and Graceffo, E and Kumbol, V and Jendrach, M and Hinkelmann, L and Brehm, M and Ravatt, L and Krüger, C and Wallach, T and Haake, A and Wegmann, S and Heppner, FL and Schülke, M and Lehnardt, S},
title = {MicroRNA-29a-5p contributes to neuroinflammation through TLR7.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03680-4},
pmid = {41514337},
issn = {1742-2094},
abstract = {MicroRNAs (miRNAs) canonically regulate post-transcriptional gene expression, but they can also serve as ligands for Toll-like receptors (TLRs). These receptors and their associated signalling pathways contribute to inflammatory responses involved in various central nervous system (CNS) diseases, including Alzheimer's disease (AD). Here, we investigated the effects of extracellularly delivered miRNA in the context of neuroinflammation. We identified several miRNAs specifically dysregulated in AD and/or neuroinflammatory states, which directly activate the single-stranded RNA sensors mouse TLR7 and human TLR7/8. Among them, extracellular miR-29a-5p induced cytokine and chemokine release from murine primary microglia, altered expression of TLR signalling elements, and enhanced Aβ phagocytosis. Furthermore, this miRNA induced neuronal injury dependent on microglial TLR7 expression, but also in a cell-autonomous fashion, in vitro. Intrathecal injection of miR-29a-5p into mice led to microglial accumulation and neuronal injury in the cerebral cortex through TLR7 after 3 days. Brains of wild-type and APP/PS1 mice, an established AD mouse model, treated with multiple intrathecal miR-29a-5p injections over 120 days exhibited changes in cytokine/chemokine expression and neuronal injury. RNAseq analysis of the cerebral cortex of both miRNA-treated genotypes revealed downregulation of MAPK-associated pathways.Our study establishes AD-associated miRNAs such as miR-29a-5p as TLR7 agonists and signalling molecules for microglia, thereby altering the neuroinflammatory response.},
}

@article {pmid41514172,
year = {2025},
author = {Dewhurst, HE and Natarajan, N and Gogniat, MA and Lopez, OL and Cohen, AD and Snitz, BE},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106047},
doi = {10.1002/alz70856_106047},
pmid = {41514172},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Biomarkers/metabolism ; tau Proteins/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; *Alzheimer Disease/diagnostic imaging ; *Brain/diagnostic imaging/metabolism/pathology ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; *Sex Characteristics ; },
abstract = {BACKGROUND: Recent evidence suggests there are sex differences in verbal memory with most evidence supporting a female advantage in cognitively unimpaired older adults, while findings in females with mild cognitive impairment (MCI) are more inconsistent. Paradoxically, females are disproportionately affected by Alzheimer's disease (AD). Sex differences in amyloid and tau burden and volumetric brain changes that proceed cognitive decline may help explain sex differences in AD risk. Examining sex as a moderating factor of associations between brain biomarkers and verbal memory could give insight into pathways of AD sex differences.

METHOD: In Study 1, we examined differences in baseline verbal memory (CVLT long delayed recall) in a sample of older adults without dementia (N = 342, 51.8% Female), adjusting for age (M=78, SD=9.01), race (83% White) and education (M=15 years, SD=2.7), and stratifying by adjudicated cognitive status (cognitively unimpaired individuals (CU), n = 231 and MCI, n = 111). In Study 2, a sub-sample of participants (n = 172) completed 3T MRI, PiB-PET (amyloid), and AV-1451-PET (tau) imaging at follow-up, quantifying an AD-associated cortical thickness (CT) composite region, global amyloid burden, and tau burden in the medial temporal (MTL) and meta-temporal (MT) regions. Sex stratified regression models examined relationships between biomarkers and concurrent delayed recall scores, followed by moderation models testing for a sex*biomarker interaction on delayed recall.

RESULT: Study 1: In adjusted ANOVA models, delayed recall was higher in females (M=10.3, SD=2.6) than males (M=9.5, SD=2.9) in CU (p = 0.01) but not MCI (females: M=7.1, SD=3.6; males: M=6.1, SD=3.3). Study 2: In sex stratified regression models adjusted for age, education, and race, CT was the only biomarker associated with CVLT DR and only in females (B=6.45, p = 0.01), not males (B=-3.01, p = 0.34), and not in non-stratified models. In moderation models, the CT*sex interaction trended towards significant (p = 0.08). There was no sex*biomarker interaction for global amyloid or tau in MTL and MT regions.

CONCLUSION: Female advantage in verbal memory was found in unimpaired but not older adults with MCI, consistent with female vulnerability to disease progression. Sex differences were not observed in the relationship between AD biomarkers and verbal memory, but results suggest cortical thickness may reflect female vulnerability to neurodegeneration more generally.},
}

Humans
Female
Male
Aged
Biomarkers/metabolism
tau Proteins/metabolism
*Cognitive Dysfunction/diagnostic imaging/metabolism
Positron-Emission Tomography
Magnetic Resonance Imaging
Neuropsychological Tests
*Alzheimer Disease/diagnostic imaging
*Brain/diagnostic imaging/metabolism/pathology
Aged, 80 and over
Amyloid beta-Peptides/metabolism
*Sex Characteristics

@article {pmid41514101,
year = {2026},
author = {Giorelli, M},
title = {Artistic expression in famous painters affected by Alzheimer's disease: Willem de Kooning, William Utermohlen, and Carolus Horn.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {134},
pmid = {41514101},
issn = {1590-3478},
}

@article {pmid41513910,
year = {2026},
author = {Huang, F and Zhu, P and Chen, N and Qiu, A},
title = {A token efficient vision framework using patch residual transformer for Alzheimer's disease diagnosis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33965-w},
pmid = {41513910},
issn = {2045-2322},
support = {No. 2022ZD0209000//the National Research Foundation, China/ ; 15201124//RGC GRF project/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and early diagnosis using structural magnetic resonance imaging (sMRI) is crucial for timely intervention. Recently, the Vision Transformer (ViT) has been applied to sMRI-based AD diagnosis, but it often struggles with information redundancy when handling high-dimensional data, leading to focus loss and missed critical features. To address this, we proposed a Patch Residual Transformer (PRT)-a token-efficient vision framework designed for AD diagnosis and the prediction of mild cognitive impairment (MCI) conversion (i.e., stable MCI vs. progressive MCI). The PRT model partitions sMRI into patches and incorporates a novel Patch Residual Block (PRB), which includes two key components: Top-K patch selection and linear stitch patch token fusion (LSPTF). Top-K component meticulously assesses and ranks patches to identify the most crucial ones for AD diagnosis and MCI conversion prediction. The LSPTF employs retention and linear stitch strategies that enable ViT to concentrate on the most critical regions, thereby avoiding focus loss, achieving patch diversification, optimizing model performance, and accelerating training. We validated our method on two large-scale datasets, Alzheimer's Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies-3 (OASIS-3). Our results demonstrate that PRT outperforms existing slice-, patch-, ROI-, and subject-level approaches in both AD diagnosis and MCI conversion prediction. Additionally, the model demonstrates strong generalization and robust salience map consistency across datasets.},
}

@article {pmid41513739,
year = {2026},
author = {Mlinarič, T and Van Den Kerchove, A and Barinaga, ZI and Van Hulle, MM},
title = {EEG-based classification of alzheimer's disease and frontotemporal dementia using functional connectivity.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-35316-9},
pmid = {41513739},
issn = {2045-2322},
support = {C24/18/098//KU Leuven/ ; GPUDL/20/031//KU Leuven/ ; C24/18/098//KU Leuven/ ; G0A4321N//Fonds Wetenschappelijk Onderzoek/ ; G0A4321N//Fonds Wetenschappelijk Onderzoek/ ; G0A4118N//Fonds Wetenschappelijk Onderzoek/ ; 101118964//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; 857375//Horizon 2020/ ; AKUL 043//Herculesstichting/ ; },
}

@article {pmid41513646,
year = {2026},
author = {Feng, H and Zhao, Q and Guo, F and Yan, J and Zhao, N and Ma, J and Sun, R and Shen, K and Ge, Y and Zhang, X and Zhang, L and Liu, Y},
title = {Amyloid-ID: photocatalytic profiling of amyloid deposits in Alzheimer's disease tissue.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-025-68017-4},
pmid = {41513646},
issn = {2041-1723},
support = {22374148//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Deposition of amyloid proteins and their associated interactome is a hallmark of Alzheimer's disease (AD) and other amyloidosis diseases, with their composition implying disease etiology. However, precise in-situ micro-dissection of amyloid deposits in AD brain tissue remains a challenge. In this work, we first divert the excited state energy of Thioflavin T from singlet fluorescence to triplet photocatalytic amyloid protein labeling through molecular engineering, while maintain its pan-amyloid binding affinity and selectivity. We further demonstrate that the amyloid labeling is catalyzed via type-I radical-based photosensitization with diverse residue modification sites. In female AD mouse brain tissue without homogenization, Amyloid-ID in-situ captures and profiles amyloid deposits, reliably reporting the often-lost tau biomarker. Finally, we provide comparative amyloidomics resources across 3 commonly used AD mouse models, revealing conjunct mitochondrial entangling pattern within amyloid deposits. Overall, we report a photocatalytic proteomics strategy (namely Amyloid-ID) to profile amyloid deposits directly from AD brain tissue.},
}

@article {pmid41513640,
year = {2026},
author = {Abdulkhaliq, AA and Kim, B and Almoghrabi, YM and Khan, J and Ajoolabady, A and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Pratico, D},
title = {Amyloid-β and Tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay.},
journal = {Cell death & disease},
volume = {17},
number = {1},
pages = {21},
pmid = {41513640},
issn = {2041-4889},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal cell death in later stages. In this review, we aimed to critically discuss and highlight recent advances in the pathological footprints of amyloid-β and tau in AD. Specifically, we focused our attention on the interplay and synergistic effects of amyloid-β and tau in the pathogenesis of AD. We hope that our paper will provide new insights and perspectives on these pathological features of AD and spark new ideas and directions in AD research and treatment.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Animals
Brain/metabolism/pathology

@article {pmid41513633,
year = {2026},
author = {He, S and Mittra, N and Bao, H and Bhattacharjee, A and Dodds, SG and Dupree, JL and Han, X},
title = {Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {338},
pmid = {41513633},
issn = {2041-1723},
support = {R01AG061872; RF1AG061729; R01AG085545//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG066546; P30AG013319; P30AG044271; T32AG021890//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; T32AG021890//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Animals ; *Sulfoglycosphingolipids/metabolism ; *Microglia/metabolism/pathology ; *Myelin Sheath/metabolism ; *Gliosis/metabolism/pathology/genetics ; Mice ; *Membrane Glycoproteins/metabolism/genetics ; Mice, Knockout ; Female ; Male ; *Receptors, Immunologic/metabolism/genetics ; Disease Models, Animal ; Astrocytes/metabolism/pathology ; Alzheimer Disease/metabolism/pathology ; Lipid Metabolism ; Mice, Inbred C57BL ; Homeostasis ; Brain/metabolism/pathology ; Neuroinflammatory Diseases/metabolism/pathology ; Cognitive Dysfunction/metabolism ; Lipidomics ; },
abstract = {Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder enlargement, and lipid dyshomeostasis. To better understand the relationship between neuroinflammation and lipid disruption induced by ST deficiency, we established a ST-deficient mouse model with a constitutive Trem2 knockout. Our study demonstrates that TREM2 regulates ST deficiency-induced neuroinflammation and astrocyte activation at the transcriptomic level but does not affect stage 1 disease-associated microglia or astrogliosis at the protein level. Additionally, ST loss-induced lipidome disruption, free water retention, and cognitive impairment persist in the absence of TREM2. Further, these phenotypes are more severe in females compared to males. Collectively, these results emphasize the essential role of TREM2 in mediating lipid loss-associated microglia-mediated neuroinflammation, but not astrogliosis or myelin lipid disruption. Moreover, we demonstrated that attenuating TREM2-mediated neuroinflammation has a limited impact on brain ST loss-induced lipidome alteration or AD-like central and peripheral disorders. Our findings suggest that preserving the lipidome and astrocyte balance may be crucial in decelerating the progression of AD.},
}

Animals
*Sulfoglycosphingolipids/metabolism
*Microglia/metabolism/pathology
*Myelin Sheath/metabolism
*Gliosis/metabolism/pathology/genetics
Mice
*Membrane Glycoproteins/metabolism/genetics
Mice, Knockout
Female
Male
*Receptors, Immunologic/metabolism/genetics
Disease Models, Animal
Astrocytes/metabolism/pathology
Alzheimer Disease/metabolism/pathology
Lipid Metabolism
Mice, Inbred C57BL
Homeostasis
Brain/metabolism/pathology
Neuroinflammatory Diseases/metabolism/pathology
Cognitive Dysfunction/metabolism
Lipidomics

@article {pmid41513599,
year = {2025},
author = {Kumar, R and Rashid, T and Charisis, S and Li, K and Ho, NH and Brandigampala, SR and Toga, AW and Kukull, WW and Risacher, SL and Wang, D and Mojtabai, M and Honnorat, N and Archer, DB and Tosun, D and Wang, DH and Bennett, DAA and Martinez, DM and Jefferson, AL and Resnick, SM and Saykin, AJ and Seshadri, S and Cuccaro, ML and Davatzikos, C and Hohman, TJ and Habes, M and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e105854},
doi = {10.1002/alz70856_105854},
pmid = {41513599},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; *Alzheimer Disease/pathology/diagnostic imaging ; Atrophy/pathology ; *Biomarkers ; *Brain/pathology/diagnostic imaging ; Aged ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: The ability to precisely characterize neurodegenerative diseases at early stages remains a challenge. Understanding the relationship between magnetic resonance Imaging (MRI)-derived brain volumes and neuropathological outcomes is key to advancing early and accurate diagnosis of neurodegenerative diseases. While MRI-based volumetrics are widely used to assess structural changes in vivo, their link to neuropathological findings remains underexplored. This study examines associations between region-specific brain atrophy and neuropathological markers, including Alzheimer's Disease Neuropathologic Change (ADNC), CERAD score, Braak staging, and Thal amyloid phase, leveraging volumetric data across multiple aging cohorts.

METHOD: T1-weighted MRI scans from participants in longitudinal dementia cohorts (ROS, MAP, MARS, and NACC) were pre-processed, and brain volumes of 120 cerebral regions of interest (ROIs) were calculated using Multi-Atlas Segmentation Utilizing Ensembles (MUSE). Associations between ROI volumes and neuropathological metrics were analysed using linear regression, adjusting for age at scan, difference between age at death and age at scan, sex, intracranial volume, and site/scanner. Neuropathological metrics, including ADNC, CERAD scores, Thal phase, Braak staging, and vascular metrics like atherosclerosis were analysed as continuous variables grouped categorically (e.g., Thal phase recoded into three categories: 0, 1, and 2). Statistical significance was determined using Benjamini-Hochberg method (p <0.05).

RESULT: Among 755 participants (mean age at scan: 80.57±10.23 years; mean age at death: 85.49±10.45 years; 44% male), ADNC was associated with atrophy in temporal and parietal regions, notably middle and inferior temporal gyri, angular gyrus, and amygdala. CERAD scores correlated with atrophy in middle temporal, para-hippocampal, and fusiform gyrus, Thal phase with atrophy in middle temporal, angular gyrus, and precuneus and Braak staging showed atrophy in entorhinal cortex, middle temporal gyrus, and para-hippocampal regions. Atherosclerosis was associated with atrophy in prefrontal cortex, and parieto-occipital regions.

CONCLUSION: These findings highlight the potential of MRI-derived volumetrics as non-invasive biomarkers of underlying Alzheimer's pathology. Our findings demonstrate notable atrophy in medial temporal, lateral temporoparietal, and midline parietal regions, supporting recognized AD patterns of neurodegeneration, consistent with pivotal studies by Habes et al.,(2016), Dickerson et al.,(2009). Associations between amyloid, tau burdens and atrophy in temporal, parietal, and limbic regions underscore their diagnostic value in neurodegeneration.},
}

Humans
Male
Female
Magnetic Resonance Imaging
*Alzheimer Disease/pathology/diagnostic imaging
Atrophy/pathology
*Biomarkers
*Brain/pathology/diagnostic imaging
Aged
Longitudinal Studies
Aged, 80 and over

@article {pmid41513598,
year = {2025},
author = {de Jesus Vanni, IJ and Ferrari-Souza, JP and Valer, MAA and Barcellos, LFB and Bieger, A and Leffa, DT and Povala, G and Lussier, FZ and Brum, WS and Aguzzoli, C and Corin, A and De Bastiani, MA and Carello-Collar, G and Borelli, WV and Rahmouni, N and Therriault, J and Trudel, L and Macedo, AC and Souza, DO and Ferreira, PCL and Bellaver, B and Rosa-Neto, P and Pascoal, TA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107522},
doi = {10.1002/alz70856_107522},
pmid = {41513598},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood ; Positron-Emission Tomography ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/diagnostic imaging ; Aged ; Amyloid beta-Peptides/metabolism ; Disease Progression ; Neuropsychological Tests ; *Cognitive Dysfunction/diagnostic imaging ; Plaque, Amyloid/diagnostic imaging ; Aniline Compounds ; Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Phosphorylation ; },
abstract = {BACKGROUND: Recently proposed biomarker-based biological staging schemes may improve risk prediction of cognitive impairment in Alzheimer's disease (AD). Evidence demonstrates that tau positron emission tomography (PET) reliably identifies individuals at high risk for clinical progression. While plasma phosphorylated tau at threonine 217 (p-tau217) has been proposed as a cost-effective biomarker, its added prognostic value to tau PET remains under-explored. Here, we tested the utility of combining plasma p-tau217 and tau PET for predicting risk of clinical progression in cognitively unimpaired (CU) individuals.

METHOD: We evaluated 156 CU individuals from the A4 Study placebo group with positron emission tomography (PET) for amyloid-β (Aβ) plaques ([[18]F]Florbetapir) and tau tangles ([[18]F]Flortaucipir), plasma p-tau217 and longitudinal neuropsychological testing. Aβ-positive (A+) individuals were classified as p-tau217-positive (A+Tp-tau217+), tau PET-positive in the medial temporal lobe (A+TMTL+) and in the neocortex (A+TNEO+). Cutpoints were determined as the mean + 2.0 standard deviations (SD) of the corresponding tau biomarker in Aβ-negative controls from the LEARN substudy. Time-to-event analyses considered clinical progression as a 1 point increase in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) score, and dichotomized A/T biomarkers were used as predictors.

RESULT: Demographics of the study population are reported in Table 1. Cox proportional-hazard models showed a gradual increase in the risk of clinical progression in the A+TMTL+ (HR=2.25, p = 0.0034) and A+TNEO+ (HR=3.14, p < 0.0001) groups versus the A+ (reference) group. In analyses incorporating p-tau217 to the models, we found that the A+Tp-tau217+ group showed a significantly increased risk for clinical progression compared to A+ group when added to the TMTL model but not to the TNEO model. (Figure 1). Model fit indexes indicated that adding p-tau217 to the models improved the predictive performance of the TMTL model, but not of the TNEO model (Table 2).

CONCLUSION: We found that p-tau217 positivity does not lead to a clear added prognostic value to tau PET in assessing risk of clinical progression in individuals with preclinical AD, particularly when measuring neocortical tau PET signal. These findings support imaging biomarkers as the primary prognostic tools for predicting cognitive impairment in early AD stages.},
}

Humans
*tau Proteins/blood
Positron-Emission Tomography
*Biomarkers/blood
Male
Female
*Alzheimer Disease/diagnostic imaging
Aged
Amyloid beta-Peptides/metabolism
Disease Progression
Neuropsychological Tests
*Cognitive Dysfunction/diagnostic imaging
Plaque, Amyloid/diagnostic imaging
Aniline Compounds
Brain/diagnostic imaging/metabolism
Aged, 80 and over
Phosphorylation

@article {pmid41513597,
year = {2025},
author = {van Tol, BGJ and Groot, C and van de Giessen, E and Pijnenburg, YAL and Coomans, EM and Ossenkoppele, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106365},
doi = {10.1002/alz70856_106365},
pmid = {41513597},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism/diagnosis ; *Positron-Emission Tomography ; *tau Proteins/metabolism ; *Biomarkers/metabolism ; Carbolines ; Male ; Aged ; Female ; *Brain/diagnostic imaging/pathology/metabolism ; Predictive Value of Tests ; Sensitivity and Specificity ; Radiopharmaceuticals ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: The tau-PET radiotracer [18F]flortaucipir enables in vivo detection of tau pathology in Alzheimer's Disease (AD) and has recently been FDA- and EMA-approved for clinical use. To support its implementation, we assessed tau-PET's positive predictive value (PPV) and negative predictive value (NPV) for clinico-pathological AD while accounting for age, amyloid-status, and pre-PET diagnostic certainty.

METHOD: We computed the PPV and NPV of tau-PET using a formula that considers two types of false-positivity: clinico-pathological (positive tau-PET, yet tau does not significantly contribute to cognitive decline) and pathological (positive tau-PET, yet no/low tau is found at autopsy; Figure 1C). A systematic review yielded a weighted sensitivity of 93.6% and specificity of 83.9% for [18F]flortaucipir to detect postmortem Braak V/VI tau pathology (N = 349; Figure 1A). PPV and NPV were calculated across age groups using previously derived tau-PET positivity prevalence estimates in cognitively unimpaired individuals and hypothetical clinician-estimated prior probabilities of clinico-pathological AD (Figure 1B), resulting in the probability that cognitive impairment is primarily caused by AD-related tau pathology. We evaluated the PPV and NPV of tau-PET as a standalone biomarker and in combination with amyloid-PET.

RESULT: The PPV of standalone tau-PET was highest in individuals with higher prior AD probabilities and younger ages (Figure 2A). For example, at a prior AD probability of 70%, the PPV for AD was 92% at ages 50-55, declining to 87% at ages 85-90. Tau-PET NPV was consistently high across ages and prior AD probabilities, effectively ruling out AD (Figure 2B). Obtaining tau-PET results after knowing amyloid-status markedly increased PPV for AD compared to both standalone tau-PET or amyloid-PET. The greatest increases in PPV from combining amyloid- and tau-PET, relative to amyloid-PET alone, occurred with lower pre-amyloid AD probabilities and older ages (up to a 37% increase; Figure 3A). Similarly, when tau-PET was obtained after amyloid-PET, strong increases in NPV were observed, particularly when prior AD probability was high (up to a 48% increase, Figure 3D).

CONCLUSION: Tau-PET demonstrates high PPV and NPV for clinico-pathological AD as a standalone marker, with added diagnostic value when amyloid-status is already known. These findings underscore tau-PET's value for optimizing the diagnostic process.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism/diagnosis
*Positron-Emission Tomography
*tau Proteins/metabolism
*Biomarkers/metabolism
Carbolines
Male
Aged
Female
*Brain/diagnostic imaging/pathology/metabolism
Predictive Value of Tests
Sensitivity and Specificity
Radiopharmaceuticals
Aged, 80 and over
Middle Aged

@article {pmid41513592,
year = {2025},
author = {Frisoni, G},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107829},
doi = {10.1002/alz70856_107829},
pmid = {41513592},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Biomarkers ; Amyloid beta-Peptides ; Brain/pathology ; },
abstract = {BACKGROUND: The IWG and AA diagnostic criteria are major references in the Alzheimer's domain. Although they share analogies, some key differences should be recognized.

METHOD: The original IWG 2024 JAMA Neurology and AA 2024 Alzheimers Dement papers will be used as the major data references.

RESULT: I will outline the similarities and differences between the IWG and the AA criteria for Alzheimer's disease from the point of view of the former. I will discuss similarities regarding: Aim of clinical research on AD and other cognitive disorders, Role of co-pathology, Role of brain reserve, Biomarker use, Indication for anti-β-amyloid, Contra-indication for anti-β-amyloid, and Health care delivery model. I will discuss differences regarding: Core question, Scientific discourse, Knowledge source, Definition of AD, Diagnosis of AD, and Interventions for AD.

CONCLUSION: The differences between the two sets of criteria are not "just semantics". A unified definition of AD is essential to advance the field and improve patient care.},
}

Humans
*Alzheimer Disease/diagnosis
*Biomarkers
Amyloid beta-Peptides
Brain/pathology

@article {pmid41513584,
year = {2026},
author = {Ouyang, Z and Jiao, B and Xiao, X and Yang, Q and Zhu, Y and Shen, L and Li, N},
title = {Head injury/traumatic brain injury and the risk of dementia: An observational and Mendelian randomization study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100468},
doi = {10.1016/j.tjpad.2025.100468},
pmid = {41513584},
issn = {2426-0266},
abstract = {BACKGROUND: This study aimed to investigate the link between head injury (HI)/traumatic brain injury (TBI) and dementia risk, as it remains unclear.

METHODS: We examined the associations between HI/TBI-related factors, including the frequency of HIs and the severity of TBI, and the risk of dementia (n = 397,581), as well as neuroimaging outcomes (n = 42,380) using prospective data (50 years at baseline) from the UK Biobank. In the observational analyses, Cox proportional-hazards modeling and logistic regression were used to estimate the associations between factors. Mendelian randomization (MR) was conducted to investigate the underlying causality between TBI (n = 392,423, ncases=19,842) and Alzheimer's disease (AD) (n = 41,944, ncases=21,982).

RESULTS: During the 12.5-year follow-up period, 7524 participants developed dementia. HI and TBI conferred an increased dementia risk (hazard ratio (HR)=1.72, 95 % confidence interval (CI): 1.50-1.97; HR=1.86, 95 % CI: 1.46-2.38, respectively). The risk increased in relation to recurrent HIs (HR=4.05, 95 % CI: 2.24-7.32) or severe TBI (HR=4.50, 95 % CI: 3.18-6.37). Dementia risk was highest during the first 30 months following HI occurrence (HR=2.20, 95 % CI: 1.66-2.92), whereas there was no association after 40 years post-HI. Patients with recurrent HIs also exhibited reduced hippocampal volumes and increased white matter hyperintensity. HI was additionally associated with poorer reasoning ability and longer reaction time. Besides, the MR analysis supported a causal association between TBI and AD (odds ratio (OR)=1.17, 95 % CI: 1.01-1.37).

CONCLUSION: These results imply that HI/TBI is associated with increased dementia risk. Strategies are needed to mitigate the impact of subsequent dementia.},
}

@article {pmid41513583,
year = {2026},
author = {Fandos, N and Pascual-Lucas, M and Sarasa, L and Terencio, J and Sáez, ME and Tartari, JP and Sanabria, Á and Sotolongo-Grau, O and Cano, A and Tárraga, L and Gurruchaga, MJ and Ruíz, A and Montalban, X and Boada, M and Alegret, M and Marquié, M and Allué, JA and , and , },
title = {Plasma Aβ42/Aβ40 determined by mass spectrometry is associated with longitudinal changes in amyloid accumulation, brain atrophy, and conversion to mild cognitive impairment due to Alzheimer's disease in individuals with subjective cognitive decline: 5-year follow-up of the FACEHBI cohort.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100465},
doi = {10.1016/j.tjpad.2025.100465},
pmid = {41513583},
issn = {2426-0266},
abstract = {BACKGROUND: The accurate identification of individuals at risk of Alzheimer's disease (AD) through blood-based biomarkers remains challenging.

OBJECTIVES: To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline.

This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years.

MEASUREMENTS: Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition.

RESULTS: Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177-0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14-7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17-9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559-51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory.

CONCLUSIONS: Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.},
}

@article {pmid41513580,
year = {2025},
author = {Chen, ZX and Wang, FP and Li, YP and Wu, MT and Chen, MY and Huang, FH and Wen, YP and Wang, XH and Yu, L and Wu, JM and Wu, AG and Zhou, XG},
title = {Neuroprotective activity of mung bean (Vigna radiata) coat extract via AMPK-dependent autophagy in Alzheimer's and Parkinson's models.},
journal = {Journal of integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.joim.2025.12.003},
pmid = {41513580},
issn = {2095-4964},
abstract = {OBJECTIVE: Alzheimer's disease (AD) and Parkinson's disease (PD) are major age-related neurodegenerative disorders that currently lack effective disease-modifying therapies. This study investigated the neuroprotective potential and underlying mechanisms of natural products derived from medicine-food homology (MFH) plants, with a focus on autophagy modulation in AD and PD models.

METHODS: Twenty MFH plant extracts were screened using the Caenorhabditis elegans amyloid-β peptide (Aβ) proteotoxicity model CL4176. Mung bean coat extract (MBCE) was identified as a promising candidate and subsequently evaluated in transgenic C. elegans models of AD and PD to assess its effects on pathological protein aggregation, oxidative stress, and behavioral impairments. Autophagy activation was assessed using fluorescence microscopy and lysosomal activity assays. MBCE's effects on protein aggregation and apoptosis were further validated in rat pheochromocytoma (PC-12) cells. Mechanistic insights were obtained through pharmacological inhibition of autophagy and AMP-activated protein kinase (AMPK) signaling, as well as AMPK knockdown. A bioactivity-guided analysis was performed to identify the major active constituents of MBCE.

RESULTS: MBCE significantly alleviated Aβ- and microtubule-associated protein tau (Tau)-induced neurotoxicity in C. elegans by reducing protein aggregation, oxidative stress, and locomotor deficits. It also suppressed α-synuclein accumulation and preserved dopaminergic neuron integrity in PD models. MBCE enhanced stress resistance and activated autophagy, as evidenced by increased autophagosome formation, decreased sequestosome-1 (p62/SQSTM1) levels, and elevated lysosomal activity. RNA interference knockdown assays confirmed that MBCE's neuroprotective effects were dependent on autophagy activation. In PC-12 cells, MBCE similarly induced AMPK-mediated autophagy, reduced the accumulation of disease-related proteins, and mitigated cytotoxicity. Notably, genetic knockdown or pharmacological inhibition of AMPK or autophagy abolished these effects. Vitexin and isovitexin, the main constituents of MBCE, were identified as key contributors to its autophagy-inducing and neuroprotective activities.

CONCLUSION: MBCE mitigates neurodegenerative pathology in AD and PD models by promoting AMPK-dependent autophagy and reducing toxic protein aggregation. These findings support the potential of MBCE as a functional food-based therapeutic strategy for neurodegenerative diseases. Please cite this article as: Chen ZX, Wang FP, Li YP, Wu MT, Chen MY, Huang FH, Wen YP, Wang XH, Yu L, Wu JM, Wu AG, Zhou XG. Neuroprotective activity of mung bean (Vigna radiata) coat extract via AMPK-dependent autophagy in Alzheimer's and Parkinson's models. J Integr Med. 2025; Epub ahead of print.},
}

@article {pmid41513467,
year = {2026},
author = {Jones, AR and Jarrahi, A and Karpowich, K and Brown, LP and Schulz, KM and Prosser, RA and Crouch, AC},
title = {Neck Vascular Biomechanical Dysfunction Precedes Brain Biochemical Alterations in a Murine Model of Alzheimer's Disease.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0293-25.2025},
pmid = {41513467},
issn = {2373-2822},
abstract = {Age-related vascular changes accompany or precede the development of Alzheimer's disease (AD) pathology. The comorbidity of AD and arterial stiffening may suggest that vascular changes have a pathogenic role. Carotid artery mechanics and hemodynamics have been associated with age-related cognitive decline. However, the impact of hemodynamics and vascular mechanics on regional vulnerability within the brain have not been thoroughly explored previously. Compared to the arterial system, the brain venous circulation on cognitive impairment is much less understood despite the venous system's role in transport. To study vasculature impact on biochemistry in AD models, we must first establish the differences in vasculature mechanics and hemodynamics in a common AD model compared to healthy controls. With this baseline data, future studies on manipulating vasculature integrity in mice becomes feasible. Young and aged female 3xTg mice and age-matched controls were imaged using a combination of ultrasound and mass spectrometry. Wall shear stress (WSS) varied across age and AD models (p<0.05). Both mean velocity and pulsatility index (PI) varied across age and AD (p<0.05). Liquid chromatography mass spectrometry (LC-MS) of brain tissue revealed several lipids that were statistically different (p<0.05) between age and AD, and matrix-assisted laser desorption/ionization (MALDI) MS imaging revealed region specific differences between groups. Combining both ultrasound imaging and mass spectrometry, we were able to detect significant changes in the vascular biomechanics of neck vasculature prior to observing significant changes in the brain biochemistry. Our work revealed significant vascular difference in the 3xTg compared to healthy controls and, to our knowledge, is the first to study vascular biomechanics via ultrasound in the 3xTg AD mouse model.Significance Statement While carotid artery mechanics have been linked to cognitive decline, their contribution to region-specific brain vulnerability remains underexplored. This study establishes a crucial foundation by comparing neck vascular biomechanics and brain biochemistry between young and aged AD mice and age-matched controls. Using ultrasound imaging and mass spectrometry, we detected significant differences in wall shear stress, pulsatility index, and mean velocity. Vascular alterations were observed prior to significant biochemical changes in brain tissue, suggesting a mechanistic role of vasculature dysfunction in AD progression. Our findings provide evidence of altered neck vascular biomechanics in the 3xTg mouse model using ultrasound, emphasizing the potential of vascular imaging as an early diagnostic and therapeutic target in Alzheimer's disease.},
}

@article {pmid41513460,
year = {2025},
author = {Sachdev, P and Yin, H and Niu, H and Reyderman, L and Irizarry, MC and Verbel, D},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107031},
doi = {10.1002/alz70856_107031},
pmid = {41513460},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Male ; Female ; Aged ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Middle Aged ; Aged, 80 and over ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Single analyte blood-based biomarkers such as p-tau181 and p-tau217 are promising biomarkers for identifying Alzheimer's disease (AD) pathology. However, multi-analyte blood-based biomarker panels are needed to further improve the detection, differential diagnosis, and screening of AD and to predict disease progression and assess response to therapy. The Alamar NULISASeq CNS Disease Panel ("NULISASeq") simultaneously profiles 120 proteins associated with neurodegeneration, synaptic, and inflammatory pathways to support these goals. Multiplexed panels also maximize the potential of precious clinical trial biospecimens while also providing the sensitivity required to measure low abundant analytes.

METHODS: Plasma samples were collected during screening from a Phase 3 program for elenbecestat (MissionAD) in early AD and analyzed using NULISASeq. Data normalization was performed using the vendor protocol to form NULISA Protein Quantification (NPQ) units, used for statistical analysis. Analysis of Variance (ANOVA) was used to determine statistical significance of the difference in each target protein level between amyloid+ and amyloid- subjects as determined by PET visual read. p-values were adjusted for multiplicity. Cohen's D was calculated to show the effect size of difference in target protein levels. The correlation of overlapping target protein levels between NULISASeq and other assays was evaluated.

RESULTS: A total of 124 subjects were included in the statistical analysis (74 amyloid+ and 50 amyloid-). Statistical significance was observed in 7 plasma proteins (GFAP, MAPT, NEFH, SNAP25, pTau-181, pTau-217, pTau-231) between amyloid+ and amyloid- subjects. pTau-217 showed the largest effect size. In predicting amyloid status, using pTau-217 alone also resulted in the highest AUC (0.87). Combining these proteins did not result in much improvement in prediction. NULISASeq protein levels of common ATN biomarkers showed high correlation with that of other assays in both plasma and CSF.

CONCLUSION: Targeted multiplexed panels such as NULISASeq quantifies multiple analytes in a single run thereby reducing the amount of precious input material and the time required for analysis. This offers advantage over fluid and neuroimaging-based measurements tailored to singular targets. We have demonstrated the utility of a multiplexed panel for reliable detection of amyloid status as well as highlighted the potential of discovering novel biomarkers associated with AD.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Male
Female
Aged
tau Proteins/blood
Amyloid beta-Peptides/blood
Middle Aged
Aged, 80 and over
Positron-Emission Tomography

@article {pmid41513459,
year = {2025},
author = {Ola, AJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107749},
doi = {10.1002/alz70856_107749},
pmid = {41513459},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Biomarkers ; Female ; Male ; *Deep Learning ; *Neuroimaging/methods ; Nigeria ; Aged ; Magnetic Resonance Imaging ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: The application of deep learning in Alzheimer's disease (AD) diagnosis has shown promise, but most studies focus on Western populations, potentially limiting their applicability in African contexts. There is a critical need for validated diagnostic tools that account for population-specific characteristics in neuroimaging analysis.

METHOD: We developed a transfer learning-enhanced DenseNet121 architecture for AD classification. The model was initially pre-trained on the OASIS dataset to learn general AD-related features, followed by fine-tuning on a local dataset from the University College Hospital (UCH), Ibadan, Nigeria. The local dataset comprised 140 subjects (63 dementia, 77 non-dementia cases). Advanced preprocessing techniques, including skull-stripping, spatial normalization, and grey matter segmentation, were applied to optimize image quality and feature extraction.

RESULT: Our model achieved exceptional performance metrics with an accuracy of 97.32% and an AUC score of 0.9916. The sensitivity and specificity were 98.37% and 96.04% respectively, with a precision of 96.80% and an F1 score of 97.58%. This performance significantly surpasses previous studies and demonstrates the effectiveness of our transfer learning approach in capturing population-specific characteristics while maintaining high diagnostic accuracy.

CONCLUSION: The successful development and validation of our population-specific model represents a significant advancement in AD diagnosis for African populations. The high performance metrics validate our transfer learning approach and demonstrate that high-quality AD diagnosis models can be developed for specific populations while leveraging existing datasets for initial feature learning. This work provides a framework for developing locally-validated diagnostic tools in low-resource settings.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
*Biomarkers
Female
Male
*Deep Learning
*Neuroimaging/methods
Nigeria
Aged
Magnetic Resonance Imaging
Sensitivity and Specificity

@article {pmid41513450,
year = {2025},
author = {Norambuena, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e110903},
doi = {10.1002/alz70856_110903},
pmid = {41513450},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; *Biomarkers/metabolism/cerebrospinal fluid ; *Tauopathies/diagnosis/metabolism ; Brain/metabolism/pathology ; },
abstract = {Tau was first described in a 1975 PNAS paper from Marc Kirschner's lab as a brain protein that stimulates the polymerization of tubulin into microtubules (https://doi.org/10.1073/pnas.72.5.1858). Unbeknown at that time was the fact that tau is the building block of neurofibrillary tangles, and a central player in the pathogenesis of Alzheimer's disease (AD) and the numerous non-Alzheimer's tauopathies. Tau's discovery thus serves as a textbook example of how advances in basic science lie at the foundation of clinical medicine. To commemorate the 50th anniversary of the first publication about tau, this Featured Research Session will highlight the work of 6 speakers, spanning basic to clinical scientists, and those who bridge the gap between these opposite, but complementary ends of the AD research community. The talks will cover major advances in tau research and how they have influenced the AD field. They will include a discussion on the complex structural and molecular heterogeneity of tau proteins, mechanisms mediating its toxicity and spread, its clinical utility as both an imaging and fluid biomarker, and innovative therapeutic strategies to mitigate its toxicity. Talks will be delivered by Michel Goedert, Keith Johnson, Bess Frost, Henrik Zetterberg. and the co-organizers, Miranda Orr and George Bloom. Each speaker will have 15 minutes to present new data, provide relevant background information and historical context, and answer questions from the audience.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/diagnosis
*Biomarkers/metabolism/cerebrospinal fluid
*Tauopathies/diagnosis/metabolism
Brain/metabolism/pathology

@article {pmid41513448,
year = {2025},
author = {Seshagiri, CV and Jackson, BL and Hernandez, M and Leach, JM and Kern, R and Boasso, A and Hajos, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107772},
doi = {10.1002/alz70856_107772},
pmid = {41513448},
issn = {1552-5279},
mesh = {Humans ; *Electroencephalography ; *Alzheimer Disease/physiopathology/therapy/diagnosis ; Male ; Female ; Acoustic Stimulation ; Aged ; Biomarkers ; Photic Stimulation ; *Brain/physiopathology ; *Gamma Rhythm/physiology ; },
abstract = {BACKGROUND: The recent Overture (NCT03556280) clinical trial demonstrated reduced decline in cognitive and functional abilities and reduced brain atrophy in participants with mild to moderate Alzheimer's disease (AD) after 6-months of daily, at-home treatment with Cognito Therapeutics' Spectris™ investigational medical device (Hajós et al. 2024). Spectris uses auditory and visual sensory stimulation to evoke gamma-frequency steady-state oscillations. Here, we evaluate the acute EEG response to auditory and visual stimulation separately and compare with combined audiovisual stimulation.

METHOD: All Overture participants underwent a screening EEG that included measurements of response to Spectris auditory, visual and audiovisual stimulation. Volume and brightness levels were matched for all stimulation within a subject. EEG was collected using gel caps (ANT-Neuro, Philadelphia, PA) from 30 channels (10/20). EEG was preprocessed, visually inspected for a continuous 40s segment with minimal artifacts, and the power spectral density (PSD) was computed at each channel for each modality. The gamma response power was calculated as the ratio of the power at the stimulation frequency [40Hz] to the power in the surrounding gamma frequencies [32-48Hz, exclusive of 39-41Hz]. Statistics reported from ANOVA and Tukey's multiple comparisons test. Average global power reported as mean ± S.E.

RESULT: Of 74 participants randomized, 41 participants had sufficient data quality from all 3 stimulation modalities for analysis. Figure 1 shows maps of the spatial distribution of the gamma response per modality. The number of channels with gamma response above a threshold of 6dB was greatest for audiovisual - 24 vs 21 (auditory) or 22 (visual). The average global power across all electrode channels shows a significant effect of stimulation modality (p < 0.001). Audiovisual simulation [10.73 dB ± 0.56] was higher than auditory [7.39 dB ± 0.52, p < 0.001] and visual [10.01 dB ± 0.52, p = 0.49], but the difference was only significant between audiovisual and auditory. Similar results are seen when looking at Frontal or Occipital channels only.

CONCLUSION: Spectris combined audiovisual stimulation produces the greatest spatial extent and the strongest average global gamma response. Further development and optimization of sensory stimulation therapy may maximize evoked brain responses through modality modifications.},
}

Humans
*Electroencephalography
*Alzheimer Disease/physiopathology/therapy/diagnosis
Male
Female
Acoustic Stimulation
Aged
Biomarkers
Photic Stimulation
*Brain/physiopathology
*Gamma Rhythm/physiology

@article {pmid41513446,
year = {2025},
author = {Sperling, RA and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107830},
doi = {10.1002/alz70856_107830},
pmid = {41513446},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/metabolism ; tau Proteins/metabolism ; Cognitive Dysfunction/diagnosis ; Disease Progression ; },
abstract = {BACKGROUND: The major differences between the Alzheimer's Association (AA) and International Working Group (IWG) positions are focused on cognitively unimpaired (CU) individuals with abnormal AD biomarkers. Here we aim to explicate the Alzheimer's Association's (AA) workgroup position on the preclinical stage of Alzheimer's disease (AD).

METHOD: The AA Workgroup defines AD as the pathophysiological process in the brain, which begins with accumulation of amyloid and tau pathology more than a decade prior to clinically evident impairment. We acknowledge that some individuals with abnormal AD biomarkers will not progress to cognitive impairment within their lifetime, and explicitly recommend against testing or disclosing test results to asymptomatic people outside of a research setting at this time. The recognition, however, that AD is a continuum of disease that includes the preclinical phase is essential for developing treatments that may be most efficacious prior to clinical impairment, when there is already substantial neuronal damage.

RESULT: The requirement for clinical symptoms to diagnose AD is inconsistent with the 21st century definitions of almost all other chronic diseases, including cardiovascular disease, cancer, and diabetes. It is very reasonable to discuss "risk" in terms of likelihood of developing impairment over a given time frame - but this is risk of manifesting symptoms related to the underlying disease. A person cannot simultaneously have a disease and be at risk for that disease. If clinical symptoms are required to define disease, it seems inconsistent that the IWG would classify an asymptomatic autosomal dominant carrier as "presymptomatic disease". The level of biomarker abnormality is relevant to the timeframe of progression, as >50% of CU with high amyloid and tau progress to MCI/dementia within 5 years but waiting for biomarker "certainty" of imminent clinical progression to identify "disease" runs the risk of intervening too late.

CONCLUSION: Both IWG and AA groups carefully consider the potential risks of "overdiagnosis" and stigma raised by using the "A" word. Similar to the revolution that occurred in cancer, the AA prioritizes research in early identification of disease and intervention as an important step towards reducing that stigma.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
*Biomarkers/metabolism
tau Proteins/metabolism
Cognitive Dysfunction/diagnosis
Disease Progression

@article {pmid41513436,
year = {2025},
author = {Estanga, A and Elorriaga, IT and Altuna, M and Ecay-Torres, M and Garcia-Sebastian, M and Erramuzpe, A and Martinez-Lage, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e105593},
doi = {10.1002/alz70856_105593},
pmid = {41513436},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Neuropsychological Tests/statistics & numerical data ; Aged ; *Cognitive Dysfunction/psychology/diagnosis/genetics ; *Biomarkers ; *Cognitive Aging/physiology/psychology ; Middle Aged ; Cognitive Reserve ; Life Style ; Apolipoprotein E4/genetics ; *Aging/psychology ; },
abstract = {BACKGROUND: Cognitive aging describes changes in thinking, learning, and memory abilities as people age. While chronological age measures time lived, cognitive age reflects mental function, influenced by health, education, lifestyle, and social factors. The aims of this study were: to estimate individual's cognitive age based on neuropsychological test results; to determine the cognitive age delta (CAD, difference between an individual's predicted and actual chronological age) as a measure of cognitive aging; to examine the association between cognitive aging and lifestyle factors to identify potential contributors to cognitive maintenance with aging.

METHOD: Cross-sectional study. Population-based recruitment from cohort with extensive clinical-biological phenotyping (Gipuzkoa-Alzheimer-Project -PGA-) in the Basque Country. CADs were computed using a Multiple Linear Regression model on neuropsychological test results. Deltas were compared between cognitively unimpaired (CU) and mildly cognitively impaired (MCI) participants using t-tests, and analyzed correlations with factors including APOE4 genotype, bilingualism, years of education, vocabulary WAIS-III as an estimate of intellectual level, cognitive reserve questionnaire (CRQ), and leisure and productive activity participation, perceived stress, and physical activity. Analyses used AgeML, an open-source Python package.

RESULT: Sample of 411 participants: 62 MCI individuals (average age 58±8 years, 52% female) and 349 CU individuals (average age 57±7 years, 56% female; see Table-1 for participant characteristics). MCI subjects showed higher Cognitive Age (mean difference +3.82 years). Correlated factors with aging in CU and MCI participants are in Table-2. In the CU group, CRQ score, vocabulary WAIS-III score participation in leisure and productive activities, years of education and the Hollingshead Social position index were significantly correlated with CAD. In the MCI group, the differences for lifestyle factors were not statistically significant after Bonferroni and FDR correction, though APOE4 carrier status had a detrimental effect in the sample.

CONCLUSION: We found factors of interest related to intellectual and social activities to target in the design of lifestyle interventions to maintain cognitive health and slow cognitive aging, with a particular focus on CU individuals. These findings are consistent with previous studies and reinforce the need to target the identified lifestyle factors.},
}

Humans
Male
Female
Cross-Sectional Studies
Neuropsychological Tests/statistics & numerical data
Aged
*Cognitive Dysfunction/psychology/diagnosis/genetics
*Biomarkers
*Cognitive Aging/physiology/psychology
Middle Aged
Cognitive Reserve
Life Style
Apolipoprotein E4/genetics
*Aging/psychology

@article {pmid41513300,
year = {2026},
author = {Xi, JY and Li, XQ and Hu, W and Bai, JJ and Xiang, YN and Hu, J and Liao, Y and Gu, J and Lin, X and Hao, YT},
title = {Identifying priority diseases and injuries to promote equality as measured by health-adjusted life expectancy: a population-based study.},
journal = {BMJ global health},
volume = {11},
number = {1},
pages = {},
doi = {10.1136/bmjgh-2025-020558},
pmid = {41513300},
issn = {2059-7908},
mesh = {Humans ; *Life Expectancy ; Adult ; Middle Aged ; Adolescent ; Aged ; Male ; Female ; Child, Preschool ; Child ; Young Adult ; Infant ; *Wounds and Injuries/mortality/epidemiology ; Infant, Newborn ; *Quality-Adjusted Life Years ; Aged, 80 and over ; Global Health ; },
abstract = {STUDY OBJECTIVE: Promoting healthy lifespan equity is a pivotal challenge in the global wave of population ageing, aiming to enable the majority of people in today's long-lived societies to reach a similar age in good health. This study aims to develop a systematic analytical framework to identify age-specific priority diseases and injuries for intervention, thereby comprehensively improving healthy lifespan equity measured by health-adjusted life expectancy (HALE, the average number of years a person can expect to live in full health).

METHODS: First, we quantify the contribution of reducing the disease burden at each age to changes in overall HALE and healthy lifespan equity. Then, we decompose these contributions into portions attributable to mortality versus disability, ensuring no residual. Finally, we combine these weights with measures of the stability and relative importance of various causes to produce a list of priority causes for intervention across the entire life course.

RESULTS: Globally, the age-specific leading causes where mortality prevention shall be a priority to achieve healthy lifespan equity are enlisted as follows: neonatal disorders (0 years), malaria (1-4 years), drowning (5-9 years), road injuries (10-24 years), HIV/AIDS (25-44 years) and ischaemic heart disease (45-84 years and over 85 years). The age-specific leading causes of disability in need of prioritisation regarding health lifespan equity are as follows: dietary iron deficiency (0-9 years), headache disorders (10-34 years), low back pain (35-69 years), age-related and other hearing loss (70-84 years) and Alzheimer's disease and other dementias (over 85 years). Notably, the specific ranking and relative importance of these causes varied substantially by region and sex, underscoring the need for context-specific strategies.

DISCUSSION: Our comprehensive framework can inform policy-makers of whether resources need to be reallocated to meet the healthy lifespan equity challenges in an ageing era.},
}

Humans
*Life Expectancy
Adult
Middle Aged
Adolescent
Aged
Male
Female
Child, Preschool
Child
Young Adult
Infant
*Wounds and Injuries/mortality/epidemiology
Infant, Newborn
*Quality-Adjusted Life Years
Aged, 80 and over
Global Health

@article {pmid41513298,
year = {2025},
author = {Liu, L and Hou, J and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107762},
doi = {10.1002/alz70856_107762},
pmid = {41513298},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; Middle Aged ; *Cognitive Dysfunction/diagnosis/genetics ; Apolipoproteins E/genetics ; Cohort Studies ; Machine Learning ; Alzheimer Disease ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cognitive decline is a major public health concern, with growing evidence linking sensory dysfunction, biological age, and APOE genotype to an increased risk of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD-related dementia (AD/ADRD). Advanced machine learning methods, such as Least Absolute Shrinkage and Selection Operator (Lasso) regression and Extreme Gradient Boosting (XGBoost), offer robust predictive capabilities for identifying high-risk individuals. This study leverages data from the Health and Retirement Study (HRS) to develop and validate predictive models integrating these key factors.

METHODS: We analyzed a nationally representative cohort of 13,222 U.S. adults aged ≥50 years from the 2008 HRS dataset. Sensory function was assessed via measures of vision, hearing, and taste impairment. Biological age, a novel index, was derived from clinical biomarkers associated with cardiovascular, kidney, and metabolic (CKM) disorders-including hypertension, systolic blood pressure, serum cystatin C, and hemoglobin A1c-alongside chronological age. Cognitive function was evaluated using a validated 27-point scale, with cognitive decline defined as the lowest quartile (Q1). APOE alleles were genotyped to assess genetic risk. Lasso regression was applied for feature selection, while XGBoost was used to develop high-performance prediction models. Model performance was evaluated using cross-validation and assessed through the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, and specificity metrics.

RESULTS: Among 13,222 participants, 7.6% experienced visual decline, 23.3% had moderate to severe hearing decline, and 4.9% reported loss of appetite. Sensory impairments (vision, hearing, and taste loss) and biological age were significant contributors to cognitive decline risk, with APOE-ε4 carriers exhibiting the highest susceptibility. Lasso regression and XGBoost outperformed traditional logistic regression models in classification accuracy. The inclusion of sensory function measures significantly enhanced predictive performance (AUC-ROC >73%).

CONCLUSION: Our study demonstrates the utility of machine learning-based models in cognitive decline risk assessment, emphasizing the predictive value of sensory dysfunction, biological age, and APOE genotype. These findings underscore the importance of early screening and targeted interventions for at-risk populations. Future research should explore model generalizability across diverse cohorts and incorporate additional biomarkers to enhance precision and clinical applicability.},
}

Humans
Male
Female
*Biomarkers/blood
Aged
Middle Aged
*Cognitive Dysfunction/diagnosis/genetics
Apolipoproteins E/genetics
Cohort Studies
Machine Learning
Alzheimer Disease
Aged, 80 and over

@article {pmid41513293,
year = {2025},
author = {Chan, T and Rahmouni, N and Zheng, Y and Gonçalves, MP and Therriault, J and Macedo, AC and Trudel, L and Socualaya, KMQ and Hosseini, SA and Hall, BJ and Wang, YT and Aumont, E and Arias, JF and Bezgin, G and Servaes, S and Hopewell, R and Hsiao, C and Vitali, P and Pascoal, TA and Zetterberg, H and Benedet, A and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107774},
doi = {10.1002/alz70856_107774},
pmid = {41513293},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood/cerebrospinal fluid ; Male ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/blood/diagnostic imaging ; Aged ; *tau Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Positron-Emission Tomography ; Cohort Studies ; Middle Aged ; Immunoassay ; Quebec ; },
abstract = {BACKGROUND: With the anticipated arrival of disease-modifying treatments for Alzheimer's disease (AD) in Canada, integrating biomarkers into clinical practice is crucial to enhancing diagnostic accuracy and optimizing referrals for treatment. Lumipulse G1200 (Fujirebio) is a fully automated immunoassay instrument that streamlines the analysis of these biomarkers. In this study, we evaluated the diagnostic performance of Lumipulse G1200 plasma and CSF immunoassays in detecting AD pathology within a Quebec population cohort.

METHOD: Plasma and CSF samples of 102 participants from the TRIAD cohort (median age 67 years, 54% female) were analysed. Kruskal-Wallis with post hoc Benjamini-Hochberg false discovery rate (BH) correction compared the levels of biomarkers among the diagnostic groups. Discriminative performance for Aβ ([18]F-NAV4694) and tau ([18]F-MK6240) PET status was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC). Amyloid PET global SUVR > 1.55 and tau PET metaROI SUVR>2.5STD of the young controls determined Aβ and Tau PET positivity, respectively. Spearman's correlation examined the association between plasma p-tau217 and p-tau181 with amyloid and tau PET SUVR.

RESULT: Plasma p-tau181 and p-tau217 were higher in individuals with clinical diagnosis of AD compared to the cognitively unimpaired (CU) or MCI not due to AD (MCI-). Plasma p-tau217 very strongly correlated with both Aβ and tau PET SUVR (ρ=0.805 and 0.797 respectively, p-value<2.2e-16), as compared to plasma p-tau181 (ρ=0.629 and 0.644 respectively, p < 4.097e-10). Both assays identified with comparable high accuracy elevated Aβ pathology (plasma p-tau217, AUC, 0.96, 95% CI: 0.92-1.00; p-tau181, AUC 0.88, CI 0.81- 0.96). However, plasma p-tau217 had higher discriminative performance than p-tau181 for tau PET (p-tau217, AUC 0.99, CI: 0.98-1.00; p-tau181, AUC 0.94, CI 0.89-0.98, DeLong's test p-value<0.01). CSF p-tau181, p-tau181/Aβ42 and Aβ42/40 had excellent discriminative performance for Aβ and tau PET positivity. Moreover, plasma p-tau217 had similar performance as CSF p-tau181 for predicting Aβ and tau PET positivity.

CONCLUSION: Lumipulse G1200 immunoassays showed excellent agreement with amyloid and tau PET. Their ease of use and high diagnostic accuracy make them strong candidates for clinical implementation.},
}

Humans
Female
*Biomarkers/blood/cerebrospinal fluid
Male
*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood/diagnostic imaging
Aged
*tau Proteins/blood/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid/blood
Positron-Emission Tomography
Cohort Studies
Middle Aged
Immunoassay
Quebec

@article {pmid41513292,
year = {2025},
author = {Day, GS and Przybelski, SA and Jain, MK and Lachner, C and Piura, YD and Aduen, P and Schecter, L and Fought, AJ and Diaz-Galvan, P and Lowe, VJ and Schwarz, CG and Boeve, BF and Petersen, R and Kantarci, K and Graff-Radford, NR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106309},
doi = {10.1002/alz70856_106309},
pmid = {41513292},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Positron-Emission Tomography ; Aged ; *tau Proteins/metabolism ; Magnetic Resonance Imaging ; Biomarkers/metabolism ; Hispanic or Latino ; Longitudinal Studies ; *Brain/diagnostic imaging/metabolism ; Black or African American ; Aniline Compounds ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged, 80 and over ; Carbolines ; Middle Aged ; Ethylene Glycols ; White Matter/diagnostic imaging ; White ; },
abstract = {BACKGROUND: Tau-PET neuroimaging is increasingly applied to diagnose and stage, track progression, and assess response to putative disease-modifying treatments in individuals with Alzheimer disease. However, it remains to be seen whether findings established in predominantly non-Hispanic White (nHW) cohorts will generalize to Black and Latino participants who are underrepresented in dementia research.

METHOD: Community-dwelling Black (n = 83) and Latino participants (n = 27) completed MRI (with quantification of white matter hyperintensity volumes), and amyloid- (PiB or florbetapir) and tau- (flortaucipir) PET brain imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Global and regional tau-PET standardized uptake value ratios (normalized to the cerebellar crus) were determined in Black and Latino participants and compared with findings from an independent cohort of nHW participants (n = 110), 1:1-matched for age, sex, education, and global Clinical Dementia Rating®. Conditional logistic modeling compared 47 regions of interest, adjusted for false discovery rate. Relevant associations between flortaucipir retention and clinical outcomes were assessed using Spearman rank correlations.

RESULT: Eighty-three Black (mean 72±10.8-years-old, 63% female, 33% cognitively impaired) and 27 Latino participants (mean 65.8-years-old, 56% female, 11% cognitively impaired) completed neuroimaging. Data were compared with findings in 110 matched nHW individuals. Global tau-PET burden was similar between matched cohorts (Black and nHW participants, mean SUVR: 1.34±0.39 vs 1.36±0.37, p = 0.71; Latino and nHW participants, mean SUVR: 1.17±0.09 vs 1.20±0.11, p = 0.66). Lower flortaucipir uptake was noted in the caudate (p = 0.005) and putamen (p = 0.022) of Black/Latino participants (vs nHW), although differences attenuated following adjustment for white matter hyperintensity volume. Global flortaucipir retention increased with age (Black: Rho=0.31; Latino: Rho=0.46; nHW: Rho=0.27; p <0.05), amyloid Centiloids (Black: Rho=0.65; Latino: Rho=0.41; nHW: Rho=0.58; p <0.05), and cognitive impairment (i.e., Clinical Dementia Rating® Sum-of-Box scores, Black/Latino: Rho=0.31, p = 0.07; nHW: 0.76, p <0.001).

CONCLUSION: Tau-PET patterns were similar across ethnoracial groups after adjusting for white matter hyperintensity volumes-a biomarker of small vessel disease. Flortaucipir retention increased with age, amyloid accumulation, and cognitive impairment across all cohorts. These findings affirm the clinical and research applications of tau PET in diverse cohorts.

ACKNOWLEDGEMENTS: Flortaucipir precursor and technology was supported by Avid Radiopharmaceuticals.},
}

Humans
Female
Male
Positron-Emission Tomography
Aged
*tau Proteins/metabolism
Magnetic Resonance Imaging
Biomarkers/metabolism
Hispanic or Latino
Longitudinal Studies
*Brain/diagnostic imaging/metabolism
Black or African American
Aniline Compounds
*Alzheimer Disease/diagnostic imaging/metabolism
Aged, 80 and over
Carbolines
Middle Aged
Ethylene Glycols
White Matter/diagnostic imaging
White

@article {pmid41495836,
year = {2026},
author = {Perez, GA and Lai, Z and Edwards Iii, GA and Dundee, JM and Leahy, SN and Qi, C and Qi, Y and Park, YJ and Lu, TC and Uddin, MD and Zhao, R and Zheng, H and Li, H and Jankowsky, JL},
title = {Neuronal subtype governs amyloid structure, cellular response, and cognitive outcome in genetically targeted APP mouse models.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {2},
pmid = {41495836},
issn = {1750-1326},
abstract = {UNLABELLED: Pathological heterogeneity is increasingly appreciated in Alzheimer’s disease, yet we do not know how distinct aggregate conformations arise or influence cognitive outcomes. In an amyloid mouse model, we found that different brain regions formed structurally distinct Aβ deposits, prompting us to test whether neuronal subtypes shape aggregate conformation. To address this, we created transgenic mice expressing the same APP construct in either glutamatergic or GABAergic neurons. APP expression in GABAergic neurons resulted in diffuse plaques with high Aβ42/Aβ40 ratios and minimal gliosis, while glutamatergic expression produced neuritic plaques with activated glia. Despite similar Aβ levels, only mice with neuritic plaques exhibited cognitive deficits. These results show that the neuronal source of APP shapes Aβ plaque structure, influencing both cellular response and behavioral outcome. Our findings affirm that amyloid conformation and gliosis—rather than total Aβ load—drive disease progression, and suggest that regional differences in neuronal composition may govern vulnerability.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00919-9.},
}

@article {pmid41513286,
year = {2025},
author = {Qiao, MN and Bhattarai, P and Yilmaz, E and Rookyard, AW and Das, LN and Zerlin-Esteves, M and Reyes-Dumeyer, D and Lee, AJ and Lantigua, RA and Medrano, M and Mejia, DR and Honig, LS and Brown, LM and Kizil, C and Mayeux, R and Vardarajan, BN},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107767},
doi = {10.1002/alz70856_107767},
pmid = {41513286},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Male ; Female ; tau Proteins/cerebrospinal fluid ; Zebrafish ; Amyloid beta-Peptides/cerebrospinal fluid ; Animals ; Aged ; Neurofilament Proteins/cerebrospinal fluid ; New York City ; Dominican Republic ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; Brain/pathology/metabolism ; },
abstract = {BACKGROUND: We investigated the relationship between the cerebrospinal fluid (CSF) proteome in Alzheimer's disease (AD) and the clinical and biomarker-assisted diagnoses, and with CSF biomarker levels of AD.

METHODS: CSF was collected in 500 individuals of non-Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City. CSF biomarkers of AD were measured including p-tau181, Aβ40, Aβ42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co-abundant modules of proteins were tested with the clinical diagnosis of AD, as well as biologically defined AD pathological process based on CSF p-tau181 and other biomarker levels. Results from replicated in 397 participants from the Accelerated Medicine Partnership-Alzheimer's Disease CSF cohort and significantly associated proteins were functionally validated in postmortem human brains and zebrafish models.

RESULTS: CSF levels of 41 proteins were significantly associated with p-tau181 levels after multiple testing correction. Notably phospholipase D3 (PLD3, p = 2.41E-09), APOE (p = 4.25e-08) and osteopontin (OSTP, p = 1.4E-16) were increased and autotaxin (ENPP2, p =  8.39E-09) and ceruloplasmin (CERU, p = 2.72E-07) were decreased among individuals with high p-tau181 levels. These proteins were also associated with CSF Aβ42/Aβ40 ratio and total Tau levels but not with NfL. OSTP was also associated with CSF levels of GFAP (p = 1.32e-05). We did not identify any protein association with clinical AD. Among proteins associated with p-tau181 levels, pathways related to axon development (p = 2.4E-12), axonogenesis (p = 1.45E-11) and regulation of axonogenesis (p = 5.1E-09) were enriched. Immunostaining on postmortem human and zebrafish brains found that ENPP2 expression reduces significantly with AD and amyloidosis, respectively. LPA administration into the zebrafish CSF mitigated Aβ42-induced vascular, neural, and glial changes.

CONCLUSION: Unbiased profiling of circulating CSF proteins identified key proteins associated with β-amyloid and phosphorylated tau pathology. Biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Male
Female
tau Proteins/cerebrospinal fluid
Zebrafish
Amyloid beta-Peptides/cerebrospinal fluid
Animals
Aged
Neurofilament Proteins/cerebrospinal fluid
New York City
Dominican Republic
Glial Fibrillary Acidic Protein/cerebrospinal fluid
Middle Aged
Aged, 80 and over
Brain/pathology/metabolism

@article {pmid41513266,
year = {2025},
author = {Jack, CR and Frisoni, GB},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107828},
doi = {10.1002/alz70856_107828},
pmid = {41513266},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Biomarkers ; Amyloid beta-Peptides ; Brain/pathology ; },
abstract = {BACKGROUND: The IWG and AA diagnostic criteria are major references in the Alzheimer's domain. Although they share analogies, some key differences should be recognized.

METHOD: The original IWG 2024 JAMA Neurology and AA 2024 Alzheimers Dement papers will be used as the major data references.

RESULT: I will outline the similarities and differences between the IWG and the AA criteria for Alzheimer's disease from the point of view of the former. I will discuss similarities regarding: Aim of clinical research on AD and other cognitive disorders, Role of co-pathology, Role of brain reserve, Biomarker use, Indication for anti-β-amyloid, Contra-indication for anti-β-amyloid, and Health care delivery model. I will discuss differences regarding: Core question, Scientific discourse, Knowledge source, Definition of AD, Diagnosis of AD, and Interventions for AD.

CONCLUSION: The differences between the two sets of criteria are not "just semantics". A unified definition of AD is essential to advance the field and improve patient care.},
}

Humans
*Alzheimer Disease/diagnosis
*Biomarkers
Amyloid beta-Peptides
Brain/pathology

@article {pmid41513259,
year = {2026},
author = {Vissel, B},
title = {Anti-amyloid antibodies for Alzheimer's disease are not truly disease modifying.},
journal = {BMJ (Clinical research ed.)},
volume = {392},
number = {},
pages = {s28},
doi = {10.1136/bmj.s28},
pmid = {41513259},
issn = {1756-1833},
}

@article {pmid41513255,
year = {2025},
author = {Rajabli, R and Soltaninejad, M and Collins, DL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107784},
doi = {10.1002/alz70856_107784},
pmid = {41513255},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Magnetic Resonance Imaging ; *Biomarkers ; Male ; Female ; Aged ; *Brain/diagnostic imaging/pathology ; Neuroimaging/methods ; Deep Learning ; },
abstract = {BACKGROUND: Developing diagnostic and prognostic tools for Alzheimer's disease is challenging due to clinical variability across stages. While many studies have focused on case-control classification and conversion prediction, fewer have explored MRI-based prediction of clinical assessment scores, such as the Alzheimer's Disease Assessment Scale (ADAS), despite its potential for measuring disease severity and aiding prognosis. Deep learning could enhance these predictions, but limited labeled data in Alzheimer's disease research constrains model training. To address this, we investigated whether a pretrained, robust brain age prediction model could be fine-tuned to predict clinical scores more effectively.

METHOD: We built an ensemble (n = 5) model to predict brain age from 3D brain MRI. To ensure generalizability, we applied robust preprocessing methods, extensive data augmentation, and regularization techniques, achieving a Mean Absolute Error (MAE) of 3.17 years on average on multiple unseen external test datasets (Rajabli, 2024). We split 11,041 MRIs from the Alzheimer's Disease Neuroimaging Initiative (ADNI1, ADNI2, and ADNI-Go) dataset into a training set (n = 5,536), validation set (n = 2,815), and test set (n = 2,690), ensuring that no subject appeared in more than one set (ADNI is a longitudinal cohort). We then fine-tuned our model to predict ADAS13 on the training set and evaluated it on the validation and test sets.

RESULT: In ADNI, the mean ADAS13 score is 17.92 with a standard deviation of 11.42. We achieved a Mean Absolute Error (MAE) of 5.66, 6.46 and 5.90 on the training, validation and test sets, respectively, for predicting ADAS13. The R[2] score on the test set is 0.58 (r = 0.76, p << 0.01). Figure 1 displays the scatter plot of predicted ADAS13 versus true ADAS13 values for the test set.

CONCLUSION: Using only 50% of the available data for training, we introduced a prediction model which generalized well to the test set, demonstrating the robustness of our model. Our approach required less data while achieving superior results compared to previous methods (such as Bhagwat 2019), paving the way for training more generalizable networks with limited data-a crucial factor for medical imaging datasets.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
*Magnetic Resonance Imaging
*Biomarkers
Male
Female
Aged
*Brain/diagnostic imaging/pathology
Neuroimaging/methods
Deep Learning

@article {pmid41513254,
year = {2025},
author = {Windon, CC and Gatsonis, C and Romanoff, J and Hanna, L and Dilworth-Anderson, P and Carrillo, MC and Gareen, IF and Glavin, E and Hillner, BE and March, A and Rissman, RA and Siegel, BA and Smith, K and Whitmer, RA and Weber, CJ and Wilkins, CH and Rabinovici, GD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107734},
doi = {10.1002/alz70856_107734},
pmid = {41513254},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Positron-Emission Tomography ; Biomarkers/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Aged, 80 and over ; Longitudinal Studies ; Middle Aged ; *Alzheimer Disease/diagnostic imaging ; Prospective Studies ; United States ; Adult ; Medicare ; },
abstract = {BACKGROUND: Amyloid PET use has been associated with change in clinical management among cognitively impaired older adults but various ethnoracial groups were underrepresented in prior studies. New IDEAS examined whether this association exists among cognitively impaired ethnoracially diverse Medicare beneficiaries and beneficiaries presenting with clinically "atypical" (non-memory predominant) presentations of Alzheimer's disease (AD).

METHODS: New IDEAS was a national, multi-site, prospective, longitudinal study that enrolled Medicare beneficiaries with mild cognitive impairment (MCI) or dementia who underwent amyloid PET scan as recommended by their treating dementia specialists at "real-world" clinics. The study examined association between amyloid PET and subsequent change in clinical management within 90 days of PET. Primary endpoint was change in management between pre- and post-PET visits defined as a composite inclusive of change in AD and non-AD drugs and change in counseling about safety and future planning. Proportions of change in management between pre- and post-PET visit by group are reported as well as logistic regression examining association between composite change in management and multiple factors.

RESULTS: Median age of 4363 participants is 75 (range 35-98) years and 55.4% are female, 63.8% having MCI and 65.4% (95% CI 64.0, 66.8) amyloid PET positive. The sample includes 938 (21.5%) Black/African American, 707 (16.2%) Hispanic/Latino, and 2718 (62.3%) other individuals with 1330 (30.5%) participants with atypical presentations of AD (Table 1). Overall change in management occurred in 54.7% (95% CI 51.5, 57.9) of Black/African American, 53.7% (50.1, 57.4) of Hispanic/Latino, and 60.2% (58.3, 62.0) of other individuals. By clinical presentation, 44.1% (40.7, 47.6) of atypical clinical MCI, 52.6% (48.4, 56.7) of atypical dementia, 63.9% (61.8, 66.0) of typical MCI, and 59.9% (56.8, 62.8) of typical dementia participants had an overall change in management (Table 2). Logistic regression demonstrated significant interactions between Black/African American identity and positive amyloid PET scan (OR 1.64, 95% CI 1.14, 2.36; p 0.008) (Table 3).

CONCLUSIONS: New IDEAS demonstrated that amyloid PET use among ethnoracially diverse Medicare beneficiaries and those with atypical and typical clinical presentations of AD leads to changes in clinical management, highlighting the value of this biomarker in a real-world clinical care setting.},
}

Humans
Female
Male
Aged
Positron-Emission Tomography
Biomarkers/metabolism
*Cognitive Dysfunction/diagnostic imaging/metabolism
Aged, 80 and over
Longitudinal Studies
Middle Aged
*Alzheimer Disease/diagnostic imaging
Prospective Studies
United States
Adult
Medicare

@article {pmid41513251,
year = {2025},
author = {Bolton, CJ and Zhang, P and Peterson, AJ and Liu, D and Hohman, TJ and Blennow, K and Zetterberg, H and Jefferson, AL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106533},
doi = {10.1002/alz70856_106533},
pmid = {41513251},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/cerebrospinal fluid ; Aged ; tau Proteins/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Neuropsychological Tests ; *GAP-43 Protein/cerebrospinal fluid ; Cross-Sectional Studies ; Longitudinal Studies ; *Cognitive Dysfunction/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {BACKGROUND: Women are at an increased risk of dementia due to Alzheimer's disease (AD) compared to men, a difference due in part to the role of female sex hormones. Estrogen, in particular, plays a key role in neuroplasticity. However, as women age and estrogen levels decline, high levels of neuroplasticity may be unsustainable. This study investigates the interaction of sex with a marker of neuroplasticity, growth-associated protein-43 (GAP-43), on AD biomarkers and cognitive decline.

METHOD: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 161, 72±6 years, 31% female) underwent fasting lumbar puncture and comprehensive neuropsychological assessment at study entry and serially over a mean 6.4-year follow-up period. Cerebrospinal fluid (CSF) levels of GAP-43, b-amyloid1-42 (Ab1-42), tau, and phosphorylated-tau (p-tau) were analyzed in batch. Linear regression models related baseline CSF GAP-43 cross-sectionally and longitudinally to CSF biomarkers and cognition adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)-e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow-up models assessed GAP-43 x sex interactions on AD biomarkers and cognitive outcomes.

RESULT: In cross-sectional analyses, higher GAP-43 was associated with higher levels of all CSF AD biomarkers (p-values<0.0001), worse language performance (b=-0.0005, p = 0.04) and worse visuospatial performance (b=-0.0004, p = 0.005). GAP-43 interacted with sex on CSF tau and p-tau levels (p-values<0.0001) such that associations were stronger in females compared to males. In longitudinal analyses, higher baseline GAP-43 was associated with declining Ab42 levels (b=-0.01, p <0.0001) and declining performance in tasks of language, executive function, and visuospatial abilities (p-values<0.02), indicating greater AD pathology and declining cognition. GAP-43 interacted with sex on longitudinal language, processing speed, executive functioning, and visuospatial performance trajectories (p-values<0.05), such that significant associations were found in women (p-values<0.02) but not men (p-values>0.26).

CONCLUSION: In this cohort of community-dwelling older adults, we found higher baseline levels of GAP-43, indicating increased neuroplasticity, are related to cross-sectional increases in tau pathology, especially in women, and longitudinal decline in cognition, exclusively in women. Findings suggest that differential responses to neuroplasticity in aging could help explain long-recognized sex differences in tau pathology and cognitive decline.},
}

Humans
Female
Male
*Biomarkers/cerebrospinal fluid
Aged
tau Proteins/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Neuropsychological Tests
*GAP-43 Protein/cerebrospinal fluid
Cross-Sectional Studies
Longitudinal Studies
*Cognitive Dysfunction/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid
Aged, 80 and over

@article {pmid41513247,
year = {2025},
author = {Edwards, NC and Lao, PJ and Alshikho, MJ and Hahm, J and Rizvi, BM and Flores-Aguilar, L and Petersen, M and O'Bryant, SE and Handen, BL and Gutierrez, J and Wilcock, DM and Head, E and Brickman, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105529},
doi = {10.1002/alz70856_105529},
pmid = {41513247},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/blood ; Middle Aged ; Magnetic Resonance Imaging ; *tau Proteins/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/pathology ; *Down Syndrome/diagnostic imaging/complications ; Adult ; Brain/diagnostic imaging/pathology ; *Cerebrovascular Disorders/diagnostic imaging ; Longitudinal Studies ; White Matter/diagnostic imaging/pathology ; },
abstract = {BACKGROUND: Adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology by age 40, despite few vascular risk factors. MRI shows cerebrovascular disease (CVD) that precedes or begins contemporaneously with markers of AD pathology. We have found that vascular lesions observed on MRI interact with a marker of astrocytosis to promote tau pathology and neurodegeneration. However, it's unclear how CVD and astrocytosis interact with elevated Aβ to influence AD progression. We investigated whether markers of CVD and astrocytosis are linked to longitudinal changes in tau biomarkers and their interaction with Aβ levels.

METHOD: We included 114 participants (mean age[SD]=45.1[6]) from the Alzheimer's Biomarkers Consortium-Down Syndrome with baseline Aβ PET imaging ([11C]PiB or [18F]florbetapir) and three follow-up visits with MRI and plasma biomarker data. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI, and plasma biomarkers (GFAP, p-tau181) were measured at baseline and follow-ups. Centiloid values were derived from Aβ standard uptake value ratio values and standardized across a scale from 0 to 100. Linear mixed effects models first estimated whether baseline WMH volume was associated change in GFAP concentration and whether baseline GFAP was associated with change in p-tau181 concentration. Separate models then tested if each baseline measure interacted with amyloid centiloid values. Models included site, age, sex/gender, and years from baseline as fixed effects and a random effect for participant intercept.

RESULT: Baseline WMH volume predicted an increase in GFAP over time (β=0.22[0.12, 0.31], AIC=-102.84), and baseline GFAP predicted an increase in p-tau181 (β=0.36[0.24, 0.4], AIC=-122.66). However, baseline GFAP did not predict WMH change (β=0.07[-0.1, 0.14], AIC = -25.7) nor did p-tau181 predict GFAP change (β=0.009[-0.18, 0.09], AIC=-33.41). Higher WMH volume predicted increased GFAP, especially in those with higher amyloid levels (β=0.38[0.26, 0.45], AIC=-146.3), and higher GFAP predicted increased p-tau181, particularly in those with higher amyloid levels (β=0.49[0.32, 0.55], AIC=-154.86).

CONCLUSION: Cerebrovascular lesions promote astrocyte-related inflammation, particularly in the context of elevated amyloid pathology, which has a downstream effect on tau pathophysiology in adults with DS. The results support the hypothesis that the interface between CVD and astrocytosis is critical in AD progression in people with DS.},
}

Humans
Male
Female
Biomarkers/blood
Middle Aged
Magnetic Resonance Imaging
*tau Proteins/blood
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/pathology
*Down Syndrome/diagnostic imaging/complications
Adult
Brain/diagnostic imaging/pathology
*Cerebrovascular Disorders/diagnostic imaging
Longitudinal Studies
White Matter/diagnostic imaging/pathology

@article {pmid41513243,
year = {2025},
author = {Li, J and Gan, L and Bezgin, G and Chan, T and Hall, BJ and Rahmouni, N and Wang, YT and Aumont, E and Hosseini, SA and Socualaya, KMQ and Trudel, L and Therriault, J and Macedo, AC and Arias, JF and Zheng, Y and Olivia-Lopez, D and Montembeault, M and Li, R and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105624},
doi = {10.1002/alz70856_105624},
pmid = {41513243},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Biomarkers/metabolism ; Positron-Emission Tomography ; Aged ; Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Growing evidence indicates that the coexistence of visual and auditory impairments increases the risk of developing Alzheimer's disease (AD). However, the mechanisms through which these sensory deficits influence the progression of AD, particularly their impact on amyloid and tau pathology, remain unclear. We hypothesize that alterations in the audio-visual dynamic network play a critical role in mediating the spread of amyloid-related tau pathology during the early stages of AD.

METHOD: This study included multimodal imaging data, including functional MRI, [[18]F]NAV4694 amyloid-PET, and [[18]F]NAV4694 tau-PET, from the TRIAD cohort (n = 216, Table 1). Participants were classified as amyloid-beta (Aβ) positive (A+) or negative (A-) based on established global uptake values of [[18]F]NAV4694 (global standardized uptake value ratio [SUVR] > 1.55). Tau positivity (T+) or negativity (T-) was determined using [[18]F]MK6240, with a temporal meta-ROI SUVR threshold > 1.30. Tau staging was based upon Braak stage classification. Brain dynamics in resting-state fMRI data were analyzed with a multilayer modularity algorithm in MATLAB, focusing on primary sensory and higher-order networks.

RESULT: Module allegiance within the auditory network (AN) and visual networks (VN) was lower in the A+T+ group compared to the A-T- group. Additionally, flexibility within the frontoparietal network (FPN) was increased, while recruitment within the FPN and integration between AN and VN were reduced in the A+T+ group compared to A-T- group (Figure 1). Integration between AN and VN negatively correlated with [[18]F]MK6240 SUVR in Braak stage 1 through 5 and the temporal meta-ROI, as well as with neocortical [[18]F]NAV4694 SUVR. Furthermore, AN-VN integration mediated the relationship between neocortical [[18]F]NAV4694 SUVR and [[18]F]MK6240 SUVR in Braak stage 1 and 2 (Figure 2).

CONCLUSION: Our study suggests that audio-visual network integration during the early stages of tau pathology mediates amyloid-related tau accumulation. This supports a framework in which decline brain network integration may facilitates the early spread of amyloid-driven tau pathology across interconnected brain regions.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/metabolism
Magnetic Resonance Imaging
tau Proteins/metabolism
Biomarkers/metabolism
Positron-Emission Tomography
Aged
Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/metabolism
Middle Aged
Cohort Studies

@article {pmid41513241,
year = {2025},
author = {Bieger, A and Borelli, WV and Ferrari-Souza, JP and Brum, WS and Schlickmann, TH and Arnold, D and Pascoal, TA and Souza, DO and Aguzzoli, C and Rosa-Neto, P and Schilling, LP and Zimmer, ER and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107740},
doi = {10.1002/alz70856_107740},
pmid = {41513241},
issn = {1552-5279},
mesh = {Humans ; Male ; *Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging ; Female ; Biomarkers/cerebrospinal fluid ; Aged ; tau Proteins/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Hippocampus/pathology/diagnostic imaging ; Atrophy/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/pathology ; Disease Progression ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Hippocampal atrophy is a well-established hallmark of Alzheimer's disease (AD), closely associated with cognitive decline and disease progression, even in the earliest symptomatic stages. Despite growing evidence that subfield-specific atrophy patterns could serve as sensitive biomarkers for early diagnosis and tracking disease progression, there remains a significant gap in understanding how these subfields are differentially impacted across different stages of AD. In this study, we explore longitudinal rates of atrophy in hippocampal subfields in individuals with amnestic mild cognitive impairment (MCI).

METHOD: Hippocampal subfields volumes were extracted from volumetric, T1-weighted MRI images from the Alzheimer's Disease Neuroimaging Initiative using Freesurfer (v 7.4.1). We included individuals with MCI who underwent cerebrospinal fluid (CSF) collection and MRI studies at baseline and after 1 year. Participants were categorized according to baseline CSF levels of amyloid and phosphorylated-tau proteins as: A-T-, A+T-, A-T+, and A+T+. Using generalized linear models, we evaluated the effect of biomarker subgroups on hippocampal subfield atrophy rates, controlling for age, sex, and whole hippocampal volume.

RESULT: Table 1 summarizes demographic data for each biomarker group. Using the A-T- group as reference, higher rates of atrophy were observed in the A-T+ group in the subiculum, bilaterally. The A+T- group showed differences in the left presubiculum and in the subiculum, bilaterally. In the A+T+ group, faster atrophy was observed in the bilateral parasubiculum, bilateral subiculum, bilateral presubiculum, bilateral CA1, right CA4, and right dentate gyrus (granule cell and molecular layers) - Figure 1.

CONCLUSION: This study reveals distinct patterns of hippocampal subfield atrophy in amnestic MCI, according to amyloid-beta (A) and phosphorylated tau (T) biomarker profiles. The A-T+ group exhibited a unique pattern of subfield vulnerability, primarily affecting the subiculum, suggesting that tau pathology alone may target specific regions of the hippocampus. In contrast, the A+T+ group showed widespread atrophy across multiple subfields, indicating that combined amyloid and tau pathology leads to more extensive hippocampal degeneration. These findings highlight the potential of subfield-specific atrophy patterns as sensitive biomarkers for differentiating early AD stages and tracking disease progression. Future studies should investigate how these patterns correlate with cognitive decline and their predictive value for dementia conversion.},
}

Humans
Male
*Cognitive Dysfunction/cerebrospinal fluid/pathology/diagnostic imaging
Female
Biomarkers/cerebrospinal fluid
Aged
tau Proteins/cerebrospinal fluid
Magnetic Resonance Imaging
*Hippocampus/pathology/diagnostic imaging
Atrophy/pathology
Amyloid beta-Peptides/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/pathology
Disease Progression
Longitudinal Studies
Aged, 80 and over
Middle Aged

@article {pmid41513238,
year = {2025},
author = {Burns, AP and Fortel, I and Zhan, L and Lazarov, O and Mackin, SR and Demos, AP and Bendlin, BB and Leow, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107724},
doi = {10.1002/alz70856_107724},
pmid = {41513238},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Biomarkers ; *Alzheimer Disease/genetics/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology ; *Brain/diagnostic imaging/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Diffusion Magnetic Resonance Imaging ; Disease Progression ; },
abstract = {BACKGROUND: Excessive neural hyperexcitation has been implicated in early cognitive decline and progression to Alzheimer's disease (AD). Restoring the balance between excitation and inhibition (E/I) with interventions like levetiracetam may offer clinical benefits, particularly for those at heightened risk. Recent cross-sectional studies suggest that female APOE-ε4 carriers may be especially vulnerable to hyperexcitation, but longitudinal evidence remains limited. We therefore investigated whether E/I dysregulation over time differs by sex and APOE-ε4 status in older adults who were cognitively unimpaired at baseline. Figure 1 illustrates the concept of early hyperexcitation preceding AD symptoms.

METHOD: We analyzed multimodal MRI data (resting-state functional MRI and diffusion-weighted imaging) from 106 older adults with at least one cognitively unimpaired scan and three or more longitudinal sessions. Most sessions were rated as clinically unimpaired (CDR = 0), though a subset transitioned to early mild cognitive impairment (CDR = 0.5 or 1). We applied an inverse Ising model regularized by empirical structural connectivity (Figure 2) to derive a whole-brain excitation-inhibition ratio (EIR). Linear mixed modeling tested whether EIR trajectory varied by sex, binary APOE-ε4 status, age at first scan, and time since first scan.

RESULT: A significant three-way interaction (Figure 3) indicated that female APOE-ε4 carriers demonstrate an elevated hyperexcitable EIR trajectory (p = 0.018). Pairwise comparisons further showed higher EIR slopes for female ε4 carriers compared to female non-carriers (p = 0.042). This effect remained significant after adjusting for age, time, and amyloid status, though it was somewhat diminished in participants with fewer longitudinal observations. Regional analyses focusing on default mode and limbic networks found higher baseline excitatory tone in females (p = 0.02), aligning with the global results.

CONCLUSION: These findings provide longitudinal support for a heightened susceptibility to hyperexcitation in female APOE-ε4 carriers, underscoring the importance of sex and genetic risk in preventive and therapeutic strategies for AD. Our multimodal approach integrating structural and functional network data highlights E/I balance as a promising biomarker and treatment target, with levetiracetam representing one potential intervention. Larger studies are needed to confirm how sex- and genotype-specific E/I dysregulation influences dementia risk and therapeutic efficacy.},
}

Humans
Female
Male
Aged
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Biomarkers
*Alzheimer Disease/genetics/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging/genetics/physiopathology
*Brain/diagnostic imaging/physiopathology
Longitudinal Studies
Aged, 80 and over
Diffusion Magnetic Resonance Imaging
Disease Progression

@article {pmid41513237,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Higgins, C and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107699},
doi = {10.1002/alz70856_107699},
pmid = {41513237},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; Aged ; *Alzheimer Disease/diagnosis/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; *Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism ; *Brain/metabolism/diagnostic imaging ; Neuropsychological Tests ; tau Proteins ; Aged, 80 and over ; },
abstract = {BACKGROUND: Early identification of patients who are likely to have abnormal brain amyloid-beta (Aβ) levels is crucial for identifying patients with Alzheimer's disease (AD) and prioritizing suitable candidates for disease-modifying treatments (DMTs). Therefore, there is an urgent need to develop an efficient, cost-effective, and scalable method for early identification of brain Aβ+ status. This study evaluated the performance of ML-enabled models combining the Digital Clock and Recall (DCR), digital Trail-Making Test-Part B (dTMT-B), and various blood-based biomarkers (BBMs) in predicting brain Aβ-PET status.

METHOD: 930 participants (mean age 72.0±6.7; 56.8% female; 23% minorities) in the Bio-Hermes-001 study were classified as cognitively unimpaired, mild cognitive impairment, or probable Alzheimer's dementia, and 35.1% were Aβ+ on 18F-florbetapir PET scan. Three-class, cross-validated ensemble models combined multimodal process-based features of DCR and dTMT-B performance including drawing metrics, temporal-spatial features of stylus manipulation, speech and acoustic features, APOE status, and BBMs p-tau217, Aβ42/40, p-tau181. All models had <22% indeterminate cases.

RESULT: For predicting Aβ-PET status, the DCR+dTMT-B+P-tau217 model had an AUC=0.943 (NPV=0.946; PPV=0.871), and with APOE added, it achieved AUC=0.954 (NPV=0.963; PPV=0.907). The DCR+dTMT-B+Aβ42/40 model had an AUC=0.929 (NPV=0.936; PPV=0.820), and with APOE added, it achieved AUC=0.948 (NPV=0.952; PPV=0.892). The DCR+dTMT-B+P-tau181 model had an AUC=0.911 (NPV=0.915; PPV=0.774), and with APOE added, it achieved AUC=0.941 (NPV=0.939; PPV=0.831). Addition of Aβ42/40 to the DCR+dTMT-B+P-tau181+APOE model resulted in an AUC=0.949 (NPV=0.960; PPV=0.883).

CONCLUSION: A multimodal model based on DCR, dTMT-B, ±APOE, and various BBMs had excellent performance in predicting Aβ-PET status, at levels comparable to CSF biomarkers of AD. ML-enabled digital cognitive assessments that leverage process-based metrics, such as the DCR and dTMT-B, enable cost-effective integration into clinical workflows to identify patients who are most likely to have Aβ+ PET status, allowing for prioritizing the most suitable candidates for DMTs.},
}

Humans
Female
Male
*Biomarkers/blood
Aged
*Alzheimer Disease/diagnosis/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
*Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism
*Brain/metabolism/diagnostic imaging
Neuropsychological Tests
tau Proteins
Aged, 80 and over

@article {pmid41513218,
year = {2025},
author = {Gaona-Partida, PR and Magana-Ramirez, CM and Grill, JD and Gillen, DL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107729},
doi = {10.1002/alz70856_107729},
pmid = {41513218},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; *Biomarkers/metabolism ; *Alzheimer Disease/diagnostic imaging/ethnology/metabolism ; Male ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; Aged, 80 and over ; Neuroimaging ; Ethnicity ; White People ; },
abstract = {BACKGROUND: In early and preclinical Alzheimer's disease AD clinical trials, amyloid biomarker criteria have resulted in differential ineligibility among racial and ethnic groups. We sought to quantify differences in PET-derived amyloid levels across racial and ethnic groups of similar clinical diagnosis and presumed disease etiology.

METHOD: We utilized data from the Standardized Centralized Alzheimer's and Related Dementias Neuroimaging (SCAN), a newly implemented initiative funded by the National Institute on Aging in conjunction with the National Alzheimer's Coordinating Center (NACC). Our primary outcome was PET-derived amyloid burden using standardized uptake value ratios (SUVRs) shared through the SCAN initiative. Racial and ethnic status were categorized as Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and the remaining participants collated into together (Other), using data obtained from NACC's Uniform Data Set (UDS). We used ordinary least-squares regression to model differences in mean amyloid levels across racial and ethnic groups, with stratification by clinical diagnosis and presumed disease etiology while adjusting for potential confounding factors.

RESULT: We analyzed data on N = 661 NACC participants that had corresponding amyloid PET data available. Table 1 provides basic demographics of the study sample. Figure 1 depicts the distribution of amyloid levels by racial and ethnic group, clinical diagnosis, and presumptive etiology. Table 2 yields the estimated mean differences in SUVR levels by racial and ethnic group stratified by clinical diagnosis and presumptive etiology. After adjustment for potential confounding factors we estimated that NHB participants with cognitive impairment (impaired not MCI or MCI) and probable AD had mean SUVR -0.503 lower than comparable NHW participants (95% CI: (-0.737, -0.270); p-value: <0.001). Among participants with a dementia diagnosis and probable AD the estimated mean difference was -0.242 (95% CI (-0.529,0.045); p-value: 0.099) comparing NHB to NHW.

CONCLUSION: These results add to a growing literature examining amyloid biomarkers across racial and ethnic groups. A limitation of this study is the small sample sizes in several of the groups analyzed. Further research is needed to assess these observed potential differences and the implications to AD trial eligibility and treatment.},
}

Humans
Positron-Emission Tomography
*Biomarkers/metabolism
*Alzheimer Disease/diagnostic imaging/ethnology/metabolism
Male
Female
Aged
*Brain/diagnostic imaging/metabolism
Aged, 80 and over
Neuroimaging
Ethnicity
White People

@article {pmid41513217,
year = {2025},
author = {Zajicek, K and Lapins, A and Mather, MA and Gefen, T and Castellani, RJ and Weintraub, S and Vassar, RJ and Mesulam, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107697},
doi = {10.1002/alz70856_107697},
pmid = {41513217},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology ; Female ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; Diagnosis, Differential ; },
abstract = {BACKGROUND: Most patients clinically diagnosed with dementia due to Alzheimer's disease (AD) are over the age of 65 and exhibit a slowly progressive amnestic clinical syndrome. In contrast, those diagnosed clinically with Frontotemporal Dementia (FTD) tend to have younger age of onset and clinical presentations with behavioral and/or language decline. With the advent of cerebrospinal fluid (CSF) AD biomarkers with high sensitivity and specificity, differentiation between dementia due to AD vs FTD can be made with significantly more confidence during life. Though CSF biomarker testing for AD has excellent diagnostic accuracy for straightforwardly positive or negative results, guidance for interpretation of "borderline" or "indeterminate" results, which is common in clinical practice, is limited.

METHOD: We summarize available clinical, biomarker, and autopsy data for a 56-year-old woman enrolled into the Northwestern University Alzheimer's Disease Research Center with a 3-year history of rapidly progressive decline in language and behavior, borderline cerebrospinal fluid (CSF) biomarkers for AD, but was found to have high level Alzheimer's Disease Neuropathic Change (ADNC) at autopsy.

RESULTS: CSF testing for AD occurred when the patient was in a severe stage of dementia, 1.5 years into the disease process and 15 months before death. Whereas the Aβ42/total tau index (ATI) value fell within the AD range, phosphorylated tau (p-tau) was only borderline elevated (Ab42 = 380 pg/mL, total tau = 414 pg/mL, ATI = 0.62, p-tau = 58.8 pg/mL). Genetic testing was negative for known mutations that cause FTD. The neuropathological findings at autopsy indicated high ADNC. There were incidental Lewy bodies in the brainstem, but no significant FTLD-tau or TDP-43 neuropathologic changes.

CONCLUSION: This case illustrates an atypical, rapidly progressive clinical presentation of autopsy-confirmed AD with CSF biomarkers for AD in the "borderline" range relatively close to death. In clinical practice, cases where biomarkers are "borderline" are not uncommon and pose challenges to differentiating between dementias due to different underlying neurodegenerative diseases. Learning from atypical presentations such as this one may augment diagnostic accuracy and clinical disease management. Further research is needed to establish correspondence of "borderline" or "indeterminate" CSF biomarkers to neuropathological findings seen at autopsy.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis/pathology
Female
Middle Aged
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Frontotemporal Dementia/cerebrospinal fluid/diagnosis
Diagnosis, Differential

@article {pmid41513181,
year = {2026},
author = {Vyas, J and Jamenis, AS and Kaku, K and Shah, Y and Miner, KM and Bhatia, TN and Kim, RE and Bai, R and Hamel, E and Leak, RK and Gangjee, A},
title = {Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {133},
number = {},
pages = {130536},
doi = {10.1016/j.bmcl.2026.130536},
pmid = {41513181},
issn = {1464-3405},
abstract = {There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.},
}

@article {pmid41512968,
year = {2026},
author = {Plubell, DL and Remes, PM and Wu, CC and Jacob, CC and Merrihew, GE and Hsu, C and Shulman, N and MacLean, BX and Heil, L and Poston, KL and Montine, T and MacCoss, MJ},
title = {Development of highly multiplex targeted proteomics assays in biofluids using a nominal mass ion trap mass spectrometer.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101506},
doi = {10.1016/j.mcpro.2026.101506},
pmid = {41512968},
issn = {1535-9484},
abstract = {The development of targeted assays that monitor biomedically relevant proteins is an important step in bridging discovery experiments to large scale clinical studies. Targeted assays are currently unable to scale to hundreds or thousands of targets. We demonstrate the generation of large-scale assays using a novel hybrid nominal mass instrument. The scale of these assays is achievable with the Stellar[TM] mass spectrometer through the accommodation of shifting retention times by real-time alignment, while being sensitive and fast enough to handle many concurrent targets. Assays were constructed using precursor information from gas-phase fractionated (GPF) data-independent acquisition (DIA). We demonstrate the ability to schedule methods from orbitrap and linear ion trap acquired GPF DIA library, and compare the quantification of a matrix-matched calibration curve from orbitrap DIA and linear ion trap parallel reaction monitoring (PRM). Two applications of these proposed workflows are shown with a cerebrospinal fluid (CSF) neurodegenerative disease protein PRM assay and with a Mag-Net enriched plasma extracellular vesicle (EV) protein survey PRM assay. In CSF, our assay targets proteins discovered previously to be associated with Alzheimer's disease in a small independent sample set. For the Mag-Net enriched plasma survey assay, we observe that proteins selected based on their measurement robustness are still able to capture differences in abundance across disease groups in a small sample set. These highlight the application of highly multiplex, targeted protein assays in clinical research.},
}

@article {pmid41512910,
year = {2025},
author = {Takieldeen, Y and Yang, HC and Shahid, SS and Ebrahimi, T and Al-Ali, K and Riley, K and Graner, B and Wilcock, DM and Saykin, AJ and Wu, YC and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107738},
doi = {10.1002/alz70856_107738},
pmid = {41512910},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Aged ; *White Matter/diagnostic imaging/pathology ; Biomarkers/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Pilot Projects ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/pathology ; Neuroimaging ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: White matter hyperintensities (WMHs) in Alzheimer's disease (AD) are often linked to microvascular disease, but emerging evidence suggests AD-specific pathologies also play a role. This pilot study leverages multimodal imaging to examine WMH volume, microstructure, and perfusion, uncovering distinct vascular and AD-related contributions through their associations with amyloid and tau.

METHOD: Thirty cognitively normal (CN), 30 mild cognitive impairment (MCI), and 10 AD participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI3) underwent T1-weighted, fluid-attenuated inversion recovery (FLAIR), T2*-weighted, multi-shell diffusion MRI, arterial spin labeling (ASL) perfusion, amyloid positron emission tomography (PET), tau PET, and vascular risk assessment. WMH volume was extracted using HyperMapp3r algorithm and Lesion Segmentation Tool (LST), and associated with amyloid and tau burden. To address WMH spatial heterogeneity, imaging metrics were assessed across WMHs, perilesional regions, and adjacent normal appearing white matter (NAWM). Adjacent NAWM was chosen over whole-brain NAWM to ensure regional comparability within the same white matter tract and reduce intra-subject variability.

RESULT: WMH volume was higher in AD compared to MCI and CN (Figure 1A), independent of age, sex, and intracranial volume (F(5, 60)=11.28, p <0.001). Amyloid burden (β=0.045, p <0.001) was a predictor of WMH volume, independent of vascular risk, while tau was not. When stratifying by amyloid beta status and vascular risk, WMH burden followed a trend where it was highest in amyloid-positive individuals with high vascular risk (A+V+), followed by amyloid-positive with low vascular risk (A+V-), then amyloid-negative with high vascular risk (A-V+), and lowest in amyloid-negative with low vascular risk (A-V-) (Figure 1B). Across all groups, WMHs showed the most microstructural damage versus perilesion and NAWM, with a consistent trend across metrics. However, the differences were significant for intracellular volume fraction, axial, radial, and mean diffusivity (Figure 2). Significant between-group differences were found in orientation dispersion, mean, and axial diffusivity within WMHs (Figure 3).

CONCLUSION: This study highlights the interplay of vascular and neurodegenerative pathologies in WMH development in AD, with amyloid burden independently contributing to WMH volume and vascular risk amplifying its effects. Future work will examine spatial WMH distribution across amyloid and vascular risk cohorts to clarify their contributions to WMH development and progression.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*Cognitive Dysfunction/diagnostic imaging/pathology
Aged
*White Matter/diagnostic imaging/pathology
Biomarkers/metabolism
tau Proteins/metabolism
Positron-Emission Tomography
Pilot Projects
Magnetic Resonance Imaging
*Brain/diagnostic imaging/pathology
Neuroimaging
Aged, 80 and over
Amyloid beta-Peptides/metabolism

@article {pmid41512908,
year = {2025},
author = {Valencia, SM and Sanchez, JP and Niño, DFA and Baena, AY and Londono, N and Ramirez, S and Trujillo, SP and Gomez, D and Díaz, DC and Possin, KL and Orrego, NT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105619},
doi = {10.1002/alz70856_105619},
pmid = {41512908},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Adult ; Cross-Sectional Studies ; *Neuropsychological Tests ; Biomarkers ; *Alzheimer Disease/genetics/diagnosis ; Presenilin-1/genetics ; Colombia ; Middle Aged ; *Cognitive Dysfunction/diagnosis/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias are rising at an alarming rate (>300%), leading to human and economic losses, particularly in resource-limited low- and middle-income countries. This exacerbates health disparities and underscores the urgent need for scalable early detection tools to support preventive intervention strategies. Emerging digital cognitive assessment tools, such as TabCAT-BHA, a 15-minute tablet-based battery, offer a practical alternative for identifying early cognitive markers. Colombia's autosomal dominant PSEN1-E280A genetic variant cohort, causative of early-onset familial AD, provides a unique opportunity to examine preclinical cognitive changes associated with the disease. As the need for innovative cognitive markers rises, evidence on their validity is essential for determining their clinical utility. The objective is to evaluate the validity of TabCAT-BHA for detecting cognitive differences between asymptomatic PSEN1-E280A carriers and non-carriers and correlating with established, traditional cognitive tests of the same domains.

METHOD: This cross-sectional study included 135 asymptomatic participants: 79 PSEN1-E280A carriers and 56 non-carriers, mean age: 32.5 years. TabCAT-BHA encompasses memory, executive function, processing speed, visuospatial ability, and language cognitive measures. Neuropsychological paper-pencil assessment was carried out for similar domains through a 25-minute evaluation using widely used tests. Descriptive statistics summarized demographic and cognitive performance. Independent sample t-tests were used to assess cognitive performance differences between groups. Correlation coefficients evaluated concurrent validity between TabCAT-BHA and traditional paper-pencil neuropsychological tests.

RESULTS: Both groups were comparable in terms of sex, age, and educational level. Non-carriers demonstrated a trend toward better performance across all cognitive domains. Statistically significant differences were observed in TabCAT-BHA's memory, visuospatial ability, and language metrics between groups, while traditional evaluations identified differences only in memory tests. Correlation analyses revealed moderate relationships between TabCAT-BHA and traditional tests across same domains, with lower correlations with different domains.

CONCLUSION: TabCAT-BHA detected broader cognitive differences across multiple domains between PSEN1-E280A mutation carriers and non-carriers, underscoring its utility in identifying early cognitive changes during the preclinical stage of AD. Its demonstrated concurrent validity with traditional evaluations further highlights its potential as a scalable, efficient tool for preclinical AD detection, particularly in low- and middle-income countries where resource constraints limit access to traditional diagnostic approaches.},
}

Humans
Male
Female
Adult
Cross-Sectional Studies
*Neuropsychological Tests
Biomarkers
*Alzheimer Disease/genetics/diagnosis
Presenilin-1/genetics
Colombia
Middle Aged
*Cognitive Dysfunction/diagnosis/genetics

@article {pmid41512881,
year = {2025},
author = {Lee, SY and Emanuel, OM and Matusz, EF and Wang, WE and Arias, F and Levy, SA and Velez-Uribe, I and Barker, WW and Rosselli, M and Vaillancourt, DE and Armstrong, MJ and Cid, REC and Loewenstein, DA and Duara, R and Smith, GE and Asken, BM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107710},
doi = {10.1002/alz70856_107710},
pmid = {41512881},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Positron-Emission Tomography ; Biomarkers/blood ; *tau Proteins/blood ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/blood ; *Sleep Apnea Syndromes/diagnostic imaging/complications/blood ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Middle Aged ; Brain/diagnostic imaging/metabolism ; Aniline Compounds ; Carbolines ; },
abstract = {BACKGROUND: Sleep apnea is a potential risk factor for Alzheimer's Disease (AD). Associations between sleep apnea and elevated AD biomarkers like amyloid beta (Aβ) and p-tau have been reported, but it is unclear if or how sleep apnea influences the connection between the two. The link between sleep apnea and AD also has not been extensively studied in the context of relevant demographic, sociocultural, and common genetic factors. Therefore, we assessed the moderating effects of sleep apnea on the association between Aβ-PET and plasma p-tau217 and whether this moderation differed based on sex, ethnicity, or APOE e4 carrier status.

METHOD: We studied 1Florida ADRC participants (N = 288) with normal cognition, mild cognitive impairment, or dementia (Table 1). Presence or absence of sleep apnea was determined from the National Alzheimer's Coordinating Center Health History. All participants had plasma samples analyzed for p-tau217 (ALZPath) and completed Aβ-PET with [18F] florbetaben or florbetapir. Global standardized uptake value ratio (SUVR; whole cerebellum reference) was calculated and converted to the Centiloid (CL) scale. We used multiple linear regression to assess the interaction of Aβ-PET and sleep apnea status on plasma p-tau217, controlling for age, sex, and CDR sum of boxes. To determine whether sleep apnea moderator effects differed by APOE e4 carrier status, sex, or ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), we employed three-way interactions.

RESULT: Sleep apnea moderated Aβ-PET associations with p-tau217 (β = 0.26, p = .022; Figure 1), such that greater amyloid burden related more strongly to higher plasma p-tau217 in those with sleep apnea versus without. A significant three-way interaction of Aβ-PET x sleep apnea x ethnicity on plasma p-tau217 (β = -0.52, p = .024; Figure 2) revealed that sleep apnea only moderated this association in non-Hispanic/Latino participants. Sleep apnea moderation was not dependent on sex or APOE e4 carrier status.

CONCLUSION: Addressing sleep apnea as a modifiable risk factor may promote slowing or resistance to AD. Larger and longitudinal studies are needed to comprehensively examine sleep apnea in older adults. Exploring sleep apnea effects in more representative samples with consideration of social and structural determinants of brain health will help clarify the role of sleep on AD onset and progression.},
}

Humans
Male
Female
Aged
Positron-Emission Tomography
Biomarkers/blood
*tau Proteins/blood
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging/blood
*Sleep Apnea Syndromes/diagnostic imaging/complications/blood
Aged, 80 and over
Apolipoprotein E4/genetics
Middle Aged
Brain/diagnostic imaging/metabolism
Aniline Compounds
Carbolines

@article {pmid41512880,
year = {2025},
author = {Agrawal, D and Malo, PK and Krishnamurti, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107723},
doi = {10.1002/alz70856_107723},
pmid = {41512880},
issn = {1552-5279},
mesh = {Humans ; Aged ; Aged, 80 and over ; Female ; Male ; *Speech Perception/physiology ; *Alzheimer Disease/complications ; Biomarkers ; *Hearing Loss/complications ; *Cognitive Dysfunction ; },
abstract = {BACKGROUND: Age related hearing loss (HL) is highly prevalent in older adults and is frequently exacerbated by cognitive decline, such as Alzheimer's disease (AD). While speech communication primarily focusses on segmental content, the prosody- i.e suprasegmental aspects encompassing rhythm, stress and intonation play a critical role in conveying meaning, emotion and syntactic structure. As prosody relies on both auditory and cognitive mechanisms, both of which most of the time are significantly impaired in AD. This study investigates how cognitive impairment affects prosody perception in older adults with HL_AD compared to individuals with HL but no AD.

METHOD: Participants were grouped into two: 1) six older adults (65-85 years) with HL-AD, and 2) six older adults with HL but no AD. The Vocalic Sensitivity Test (VST), which measures prosodic elements such as word stress, grammatical function, emotional prosody, and intonation, was used. The VST involved listening to time-compressed speech and identifying prosodic features. Stimuli were delivered through TDH-39 earphones, and responses were recorded on a laptop with dual raters to ensure reliability. The Mann-Whitney U-test was used to check for the differences in VST scores between the study groups. Median and interquartile range (IQR) are reported, and the statistical significance was based on 10000 samples using the Monte Carlo method at 5% level of significance.

RESULT: Monte Carlo simulated significance levels showed a significant difference between the groups for intonation (control: median (IQR) 8.00 (4.75); HL-AD: 3.50 (2.50); p =  0.032), word stress (control: 8.00 (5.75); HL-AD: 3.50 (2.00); p =  0.044), grammatical function (control: 6.50 (3.50); HL-AD: 3.00 (2.75); p =  0.025) and total VST score (control: 27.00 (12.25); HL-AD: 14.50 (3.75); p =  0.033). However, there was no significant difference for emotional prosody (control: 4.50 (2.75); HL-AD: 3.50 (1.25); p =  0.276).

CONCLUSION: This study reveals that older adults with AD_HL experience considerable difficulty distinguishing prosodic aspects of speech, particularly in word stress, grammatical function, and intonation. Thus improving prosodic perception along with auditory and cognitive abilities is crucial for better communication outcomes, social interaction, and speech comprehension, all of which would improve the quality of life.},
}

Humans
Aged
Aged, 80 and over
Female
Male
*Speech Perception/physiology
*Alzheimer Disease/complications
Biomarkers
*Hearing Loss/complications
*Cognitive Dysfunction

@article {pmid41512865,
year = {2026},
author = {Toda Robert, A and McQuade, A and Koppes-den Hertog, SJ and Erlebach, L and Kronenberg-Versteeg, D and Kampmann, M and Giera, M and van der Kant, R},
title = {Comparative lipidomics of iPSC-derived microglia protocols reveal lipid droplet and immune differences mediated by media composition.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102779},
doi = {10.1016/j.stemcr.2025.102779},
pmid = {41512865},
issn = {2213-6711},
abstract = {Altered microglial lipid metabolism is heavily implicated in Alzheimer's disease (AD) and aging. Recently, protocols were developed to generate human induced pluripotent stem cell-derived microglia-like cells (iMGL) to study microglial function in vitro, including embryoid body-based methods and induced transcription factor (iTF)-dependent approaches. Here, we performed comparative lipidomics on iMGL from these methods and report major differences in multiple lipid classes, including triglycerides (TGs), a storage form of fatty acids implicated in microglial reactivity. TGs are strongly increased in iTF microglia due to the absence of a media supplement (B-27). Supplementing iTF microglia with B-27, or its component L-carnitine, reduces TGs and promotes a homeostatic state. B-27 also renders iTF microglia metabolically responsive to immune stimuli. Overall, our data show that iMGL differentiation methods have a major impact on microglial lipidomes and warrant attention when studying AD and neuroinflammatory processes involving lipids.},
}

@article {pmid41512849,
year = {2025},
author = {King-Robson, J and Soreq, E and Cartlidge, MRE and Harrison, M and Murray-Smith, H and Aimola, L and Poole, M and Ardle, RM and Keshavan, A and Cash, DM and Coath, W and Robinson, L and Sharp, DJ and Schott, JM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105509},
doi = {10.1002/alz70856_105509},
pmid = {41512849},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; tau Proteins/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Aged ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Sleep/physiology ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: Sleep and circadian disruption are associated with increased dementia risk. Digital sleep biomarkers may provide an ecologically valid and low-burden means of remote population-level screening for incipient dementia. We explored the feasibility and predictive value of a digital sleep biomarker, developed from data collected using the Withings Sleep Analyzer (WSA), a ballistocardiographic under-mattress pressure sensor which collects sleep and physiological data unobtrusively, to detect Alzheimer-related biomarkers in a presymptomatic cohort.

METHOD: Participants from the Insight 46 study (all born in March 1946) underwent serial assessment, including plasma phosphorylated tau (pTau)217 ALZpath and 18F-Florbetapir β-amyloid PET at age ∼73 and 18F-MK-6240 Tau PET at age ∼77. Amyloid status (-/+) and Tau Braak staging (-/Braak1+/Braak3+) were derived using automated pipelines. The WSA was deployed at age ∼78, installed under participants' mattresses by the study participant/family. Continuous sleep, circadian, and physiological parameters were collected. A leave-one-out cross validation approach was employed to develop models predicting PET status after feature selection (Figure 1). Results were compared to plasma pTau217.

RESULT: n = 161 had both WSA and Tau PET data (12.4% Braak1+, 6.2% Braak3+); n = 153 participants also had β-amyloid PET (25% β-amyloid+ at Centiloid>=12). In total we collected 63,720 nights (174 years) of sleep data, corresponding to a mean±SD of 239.8±108.7 nights/participant (age at collection 78.3±0.2 yrs; 49% female). n = 404 had plasma pTau217. A final trained model identified asymptomatic individuals with Braak3+ tau pathology with area under the receiver operating characteristic curve (AUROC)=0.75; comparable to plasma pTau217 (Figure 2) after iterative feature selection (Figure 3). Trained models were less effective at identifying earlier pathological stages (Tau Braak1+, β-amyloid+).

CONCLUSION: Deploying a remote sleep and circadian monitoring device in a countrywide population-based cohort in their late 70s is feasible. A model based on iterative feature selection was able to identify individuals with significant Tau (Braak3+) pathology with AUROC similar to plasma pTau217. This provides proof-of-concept that digital sleep biomarkers may be useful in identifying individuals at high risk of developing clinical AD. Work is underway to refine the model further, replicate these results in other cohorts, and identify the shortest duration of recording required for robust prediction.},
}

Humans
*Biomarkers/blood
Male
Female
tau Proteins/blood
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Aged
*Alzheimer Disease/diagnosis/diagnostic imaging
*Sleep/physiology
Aged, 80 and over
Cohort Studies

@article {pmid41512848,
year = {2025},
author = {Singh, S and Rudolph, MD and Bateman, TR and Hughes, TM and Sai, KKS and Craft, S and Gurcan, MN and Popuri, K and Beg, MF and Zhang, L and Ma, D},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107676},
doi = {10.1002/alz70856_107676},
pmid = {41512848},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; *Biomarkers ; Positron-Emission Tomography ; Male ; Disease Progression ; Female ; *Neuroimaging/methods ; *Brain/diagnostic imaging/pathology ; Aged ; Cognitive Dysfunction/diagnostic imaging/pathology ; Deep Learning ; Machine Learning ; Atrophy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is defined by multi-domain biomarkers according to the revised classification framework. Machine learning models may benefit from an effective combination of multiple modalities. This study aims to incorporate multi-modal neuroimaging data (T1-MRI and amyloid-PET) to improve the predictive power of deep learning models, capturing both the amyloid (A) and atrophy (N) patterns in the brain to derive dementia risk score (DRS) and prediction risk of future progression of dementia at the early stage of the AD.

METHOD: We used the multi-modal neuroimaging data from the ADNI 1,2 and GO datasets (Table 1). The CN and AD subjects were used to train a classification model through 5-fold cross-validation to learn AD-related neuroimaging features and derive the dementia risk scores. The derived models were then applied to subjects who were diagnosed as MCI at their baseline measurements to predict the future risk of progression to dementia. Both T1-MRI and Amyloid-PET data were rigid-registered to the MNI space and skull-stripped. ResNet50 models with initial model weights pre-trained from MedicalNet were fine-tuned to train classification tasks for MRI and PET independently. The resulting single-modal DRS was then averaged to achieve a fused multi-modal DR. The multi-modal DRS was then used to infer the final prediction for future dementia onset. Predictive performance was evaluated via balanced accuracy and AUC.

RESULT: When classifying AD/CN, the balanced accuracy is 94.53% for the MRI-only model, 86.53% for the PET-only model; and 97.29% for the fused model. For predicting future MCI progression, the balance accuracy was 71.17% for MRI-only model, 71.79% for the PET-only model, and 74.59% for the fused model (Table 2, Figure 1).

CONCLUSION: This study underscores the potential of leveraging multi-modal deep learning models toward improving accuracy in AD prediction and tracking progression. Results demonstrated complementary strengths of MRI and PET. The reduced performance on pMCI prediction indicates room for improvement with further fine-tuning process, more advanced multi-modal fusion strategy, as well as the best modality (e.g. FDG-PET and tau-PET). Future plans involve multi-modal fusion at an early stage of the model and further evaluate model generalizability using independent datasets such as NACC data.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
Magnetic Resonance Imaging
*Biomarkers
Positron-Emission Tomography
Male
Disease Progression
Female
*Neuroimaging/methods
*Brain/diagnostic imaging/pathology
Aged
Cognitive Dysfunction/diagnostic imaging/pathology
Deep Learning
Machine Learning
Atrophy

@article {pmid41512820,
year = {2025},
author = {Abdelmoity, O and Wisch, JK and Handen, BL and Christian, BT and Mapstone, M and Rosas, HD and Lai, F and Lee, JH and Krinsky-McHale, SJ and Schmitt, FA and Harp, JP and Hom, CL and Lott, IT and Hartley, SL and Zaman, S and Ptomey, L and Burns, JM and Ibanez, L and Rafii, MS and Head, E and Ances, B},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107707},
doi = {10.1002/alz70856_107707},
pmid = {41512820},
issn = {1552-5279},
mesh = {Humans ; *Down Syndrome/genetics/diagnostic imaging ; *tau Proteins/blood ; Male ; Female ; Biomarkers/blood ; Positron-Emission Tomography ; *Apolipoprotein E4/genetics ; *Alzheimer Disease/genetics/diagnostic imaging ; Middle Aged ; Aged ; Brain/diagnostic imaging/metabolism ; Longitudinal Studies ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Down syndrome (DS) represents a genetic form of Alzheimer's disease (AD) with an earlier expected symptom onset compared to late onset AD (LOAD). It is thought that the extra copy of the Amyloid Precursor Protein (APP) gene, located on chromosome 21 contributes to the earlier onset due to increased amyloid deposition in the brain. Hyperphosphorylation of tau protein is also thought to be elevated in the beginning stages of AD pathology within DS. Although APOEε4 has been associated with greater AD risk in LOAD, prior cross-sectional investigations into the effects of APOEε4 in DS have suggested that there is no additional impact of APOEε4 on the accumulation of amyloid. We aimed to extend this work by examining the associations between longitudinal plasma pTau217 and amyloid PET as a function of APOEε4 status.

METHOD: Participants with DS were recruited from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. Both p-tau217 (N = 564 results from 223 individuals including 122 that had 3 results each, Lilly MSD) and Amyloid PET ([11C]-PiB or [18F]-AV45) (N = 366 scans with 253 unique participants including 113 that had 2 scans each) were acquired. We analyzed the influence ɛ4 allele carrier status had on changes in pTau217 and amyloid across age using linear mixed-effects modeling, including the age, APOEε4 carrier status and their interaction as covariates. Age was also included as a covariate.

RESULT: Individuals that are carriers of the APOEε4 allele present with similar baseline amyloid and pTau217 values (p = .591 & p = .455 respectively). The rate of amyloid and pTau217 accumulation increased across age similarly for both groups (p = .772 & p = .657 respectively). Although not statistically significant, visual inspection suggests that, with a larger number of participants, individuals between the ages of 45 and 50 who are ɛ4 allele carriers may exhibit elevated pTau217 levels compared to non-carriers.

CONCLUSION: We did not observe increased amyloidosis or tau phosphorylation in APOEε4 carriers with DS. Future studies targeting individuals aged 45-50 are suggested to investigate the potential APOEε4 effect on tau phosphorylation observed in this narrow chronological window, which is close to the average expected age of symptom onset of 52.5 years for DS.},
}

Humans
*Down Syndrome/genetics/diagnostic imaging
*tau Proteins/blood
Male
Female
Biomarkers/blood
Positron-Emission Tomography
*Apolipoprotein E4/genetics
*Alzheimer Disease/genetics/diagnostic imaging
Middle Aged
Aged
Brain/diagnostic imaging/metabolism
Longitudinal Studies
Amyloid beta-Peptides/metabolism

@article {pmid41512538,
year = {2026},
author = {Yao, D and Zhang, N and Yao, Q and Xie, Y and Tian, R and Wu, X and Kuang, W},
title = {Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations.},
journal = {European journal of medicinal chemistry},
volume = {305},
number = {},
pages = {118542},
doi = {10.1016/j.ejmech.2025.118542},
pmid = {41512538},
issn = {1768-3254},
abstract = {Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (Ki = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct SNAr radiofluorination, [18]F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D7.4 measurement indicated [18]F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with [18]F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. [18]F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of [18]F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.},
}

@article {pmid41512495,
year = {2026},
author = {Liu, Y and Yao, L and Liu, J and Li, H and Zeng, Y and Xu, Y},
title = {Leveraging hemispheric asymmetry in structural MRI with an attention-guided 3D CNN for early prediction of Alzheimer's conversion.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {197},
number = {},
pages = {108534},
doi = {10.1016/j.neunet.2025.108534},
pmid = {41512495},
issn = {1879-2782},
abstract = {Early identification of mild cognitive impairment (MCI) progressing to Alzheimer's disease (AD) is of paramount importance. Despite the notable advances in deep learning in this domain, current approaches are largely based on global brain analysis and often overlook the hemispheric asymmetry, which is a critical biomarker for AD progression. Although longitudinal studies can capture temporal dynamics, their clinical feasibility is constrained by the need for multiple follow-up visits. To address this issue, we propose HemiNet, a lightweight 3D convolutional neural network based on hemispheric difference analysis, enabling accurate prediction of MCI progression from structural MRI at a single time point. HemiNet is designed with three key modules. First, the asymmetry discrepancy mining strategy is employed to quantify interhemispheric structural differences, derive disease-specific biomarkers, and effectively capture multi-level asymmetry features. Second, the contralateral hemispheric fusion mechanism is designed to adaptively unify bilateral features through discrepancy-aware gating combined with depthwise separable convolution, thus strengthening asymmetry patterns indicative of AD. Finally, the pathology focal attention mechanism is applied with sequential channel-spatial attention to highlight pivotal pathological regions, such as the hippocampus and temporal lobe, thereby enhancing the discriminative capacity of the learned features. Extensive experiments and cross-validation on the ADNI dataset demonstrate that HemiNet achieves an AUC of 84.01% and an accuracy of 78.19% for MCI prediction. This study validates the value of hemispheric asymmetry analysis for early AD detection and presents an efficient, lightweight, and interpretable method for MCI progression prediction from a single scan.},
}

@article {pmid41512461,
year = {2025},
author = {Rodrigues, GB and Ribeiro, IC and da SIlva, MCR and Rizzi, L and Gonçalves, BC and Aventurato, ÍK and Silva, A and Pinheiro, TL and Santos, LE and Felice, FG and Cendes, F and Balthazar, MLF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107675},
doi = {10.1002/alz70856_107675},
pmid = {41512461},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Aged ; Female ; *Cognitive Dysfunction/blood/diagnostic imaging/physiopathology ; *Amyloid beta-Peptides/blood ; Magnetic Resonance Imaging ; tau Proteins/blood ; *Alzheimer Disease/blood ; *Brain/diagnostic imaging/physiopathology ; Middle Aged ; Neuropsychological Tests ; Peptide Fragments/blood ; *Default Mode Network/physiopathology/diagnostic imaging ; },
abstract = {BACKGROUND: Disruptions in brain network connectivity are strongly associated with the progression of cognitive decline in the Alzheimer's disease (AD) continuum, including mild cognitive impairment (MCI). This study aimed to investigate the relationship between alterations in functional brain connectivity within the default mode network (DMN) in patients with MCI and plasma biomarker levels typically altered in AD (Aβ40, Aβ42, Tau, pTau-181, Aβ42/Aβ40, Aβ42/pTau, Aβ42/tTau, pTau/tTau).

METHODS: Eighteen patients (mean age = 65 years) diagnosed with MCI according to the 2018 NIA-AA and Alzheimer's Association criteria, based on medical and neuropsychological evaluation at the Hospital das Clínicas, University of Campinas (HC-UNICAMP), Brazil, were selected for blood collection and subsequent functional magnetic resonance imaging (fMRI) scans. Plasma samples were stored and analyzed using the automated SIMOA HD-X immunoassay system (Quanterix, Billerica, MA). Resting-state fMRI (RS-fMRI) data were acquired using a 3T Achieva-Intera PHILIPS® scanner. Both imaging data and correlation analyses were processed using the UF2C toolbox within MATLAB and SPM12, with results corrected for false discovery rate (FDR).

RESULTS: Two notable negative correlations were found between the right hippocampus and right precuneus and the Aβ42/Aβ40 ratio (Spearman's correlation: r = -0.76, p =  0.033). No significant correlations were observed for other plasma biomarkers after FDR correction.

CONCLUSION: Since network reorganization is a characteristic feature of MCI and AD, with regions exhibiting increased or decreased activity, the observed inverse relationship between Aβ42/Aβ40 and functional connectivity between the right hippocampus and right precuneus (indicating that an increase in Aβ42/Aβ40 is associated with decreased functional connectivity, and vice versa) supports the disease's underlying pathophysiology. This finding provides a potential avenue for research and diagnostic monitoring. Further studies are needed to explore the functional impact of these alterations and their relevance to disease progression.},
}

Humans
*Biomarkers/blood
Male
Aged
Female
*Cognitive Dysfunction/blood/diagnostic imaging/physiopathology
*Amyloid beta-Peptides/blood
Magnetic Resonance Imaging
tau Proteins/blood
*Alzheimer Disease/blood
*Brain/diagnostic imaging/physiopathology
Middle Aged
Neuropsychological Tests
Peptide Fragments/blood
*Default Mode Network/physiopathology/diagnostic imaging

@article {pmid41512459,
year = {2025},
author = {Lahna, D and Schwartz, D and Roese, NE and Hurworth, J and Woltjer, RL and Mattek, N and Kaye, JA and Silbert, LC},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107686},
doi = {10.1002/alz70856_107686},
pmid = {41512459},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/pathology/diagnostic imaging ; Neuropsychological Tests ; *White Matter/pathology/diagnostic imaging ; Biomarkers ; *Cognitive Dysfunction/pathology ; Aged, 80 and over ; *Brain/pathology ; *Dementia, Vascular/pathology ; },
abstract = {BACKGROUND: MRI-visible white matter (WM) perivascular space (PVS) burden is associated with aging as well as with various disease states, including Alzheimer's Disease (AD) and vascular cognitive impairment (VCI). The objective of this study was to examine relationships between PVS in subcortical WM with tissue pathologies associated with AD and VCI and premortem neuropsychological test performance.

METHOD: 172 subjects received a 1.5T MRI including coronal SPGR and spin echo PD/T2 as part of research at the Oregon Alzheimer's Disease Research Center (OADRC). All participants underwent neuropsychological testing, and a subset (n = 76) had NACC pathology data available (Table 1). MRI volumes were resampled to 1mm isotropic resolution. The T1 was skull stripped, denoised, and registered to a synthetic FLAIR volume generated by taking the product of the PD and T2. Tissue types were segmented (Freesurfer 7.1.1) from the skull stripped and denoised T1 volume. PVS segmentation was accomplished using a local heterogeneity approach on NAWM (non-synFLAIR hyperintense) voxels in T1-weighted volumes with object-level morphology constraints used to identify likely MRI-visible PVS. Multiple linear regressions were performed using PVS burden metrics as independent variables with cognitive tests as dependent variables while controlling for age, sex and brain volume (for PVS predictors) and the time interval between in vivo MRI and death (for pathology predictors) RESULT: Mean age at MRI and death were 86.6 and 96.0 years, respectively. Greater WM PVS burden (count and volume) was related to poorer performance on tests of frontal executive function (Trails B, Category Fluency, digit symbol) and increased pathological markers of both large and small vessel cerebrovascular disease (Table 2). Total PVS was not related to memory (delayed recall), global cognition (MMSE) or AD pathology.

CONCLUSION: In vivo MRI-visible PVS burden within the subcortical WM is associated with a cognitive profile and neuropathologic findings consistent with cerebrovascular disease, supporting its use as a vascular marker in aging studies. Future work should consider longitudinal analysis to confirm the temporal order of increases in MR-visible PVS burden and cognitive decline.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
*Alzheimer Disease/pathology/diagnostic imaging
Neuropsychological Tests
*White Matter/pathology/diagnostic imaging
Biomarkers
*Cognitive Dysfunction/pathology
Aged, 80 and over
*Brain/pathology
*Dementia, Vascular/pathology

@article {pmid41512332,
year = {2025},
author = {Mitchell, SW and Chan, T and Trudel, L and Hosseini, SA and Macedo, AC and Gonçalves, MP and Rahmouni, N and Hall, BJ and Socualaya, KMQ and Therriault, J and Servaes, S and Bezgin, G and Zheng, Y and Aumont, E and Wang, YT and Arias, JF and Real, APB and Jia, WL and Hopewell, R and Hsiao, C and Soucy, JP and Vitali, P and Pascoal, TA and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107705},
doi = {10.1002/alz70856_107705},
pmid = {41512332},
issn = {1552-5279},
mesh = {Humans ; Male ; Biomarkers/metabolism ; Female ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; tau Proteins/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cross-Sectional Studies ; *Tauopathies/diagnostic imaging/metabolism ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Brain and cognitive resilience (BR, CR) reflect the capacity to maintain structural integrity and cognitive function despite pathological tau deposition in Alzheimer's disease (AD). Tau pathology can be characterized in terms of spatial extent of tauopathy (SEOT) or load using standardized uptake value ratio (SUVR). The aim was to compare SEOT and SUVR in their association with BR and CR. To replicate findings from Ossenkoppele et al. (2020) using MK-6240 PET imaging and evaluate demographic, genetic, and imaging factors associated with BR and CR. The objective of this study is to assess the value of SEOT metrics in resilience models and compare their predictive power to standardized uptake value ratio (SUVR) and to evaluate cross sectional interactions between tau pathology, cognitive resilience, and cognitive decline.

METHOD: We assessed 126 amyloid-β-positive participants TRIAD cohort with tau-PET using [[18]F]MK6240 and cognitive assessments (MMSE). SEOT was quantified as the proportion of voxels considered as abnormal relative to young controls. We used Participants recruited from TRIAD cohort, including individuals with mild cognitive impairment (MCI) or AD, positive amyloid-β biomarkers, MK-6240 PET imaging data.

RESULT: Higher Whole Cortex MK SUVR is associated with lower MMSE scores, showing increased tau pathology correlates with cognitive decline. MCI patients maintain higher MMSE scores despite some tau accumulation, while AD patients show greater variability and decline. The negative trend suggests tau deposition contributes to cognitive impairment, but other factors may also play a role. 2. Whole Cortex MK SUVR vs. MMSE the negative correlation between Whole Cortex SEOT and MMSE appears stronger, with a more pronounced decline in cognitive function (MMSE scores) as SEOT increases, suggesting SEOT may be a more sensitive marker of disease progression in AD patients.

CONCLUSION: Whole Cortex SEOT exhibits a stronger negative correlation with MMSE compared to Whole Cortex MK-6240 SUVR, indicating that SEOT may serve as a more sensitive marker of cognitive decline in Alzheimer's disease and mild cognitive impairment. Further research is needed to validate SEOT's potential as a diagnostic or prognostic biomarker in neurodegenerative conditions.},
}

Humans
Male
Biomarkers/metabolism
Female
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
*Cognitive Dysfunction/diagnostic imaging/metabolism
tau Proteins/metabolism
*Brain/diagnostic imaging/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cross-Sectional Studies
*Tauopathies/diagnostic imaging/metabolism
Neuropsychological Tests

@article {pmid41512324,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Higgins, C and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107677},
doi = {10.1002/alz70856_107677},
pmid = {41512324},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnosis/diagnostic imaging/metabolism ; *Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism ; Positron-Emission Tomography ; *Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Neuropsychological Tests ; *Brain/diagnostic imaging/metabolism ; Aniline Compounds ; Aged, 80 and over ; },
abstract = {BACKGROUND: The efficacy of disease-modifying treatments (DMTs) for Alzheimer's disease (AD) hinges on early detection of cognitive impairment and abnormal brain amyloid-beta (Aβ) levels. Moreover, AD clinical trials face significant barriers of high screening failure rates and expensive prescreening. Therefore, there is an urgent need to address these challenges by developing a more efficient and cost-effective method for early AD identification and differentiation from other etiologies. This study evaluated the performance of a combination of Linus Health Digital Clock and Recall (DCR), a 3-minute digital cognitive assessment, and digital Trail-Making Test-Part B (dTMT-B) in detecting cognitive impairment and predicting brain Aβ-PET status.

METHOD: 930 participants (mean age 72.0±6.7; 56.8% female; 23% minorities) in the Bio-Hermes-001 study were classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or probable Alzheimer's dementia (pAD), and 35.1% were Aβ+ on 18F-florbetapir PET scan. A 3-class, cross-validated machine-learning ensemble model combined multimodal process-based features of DCR and dTMT-B including drawing metrics, temporal-spatial features of stylus manipulation, speech and acoustic features, demographics, and APOE status. All models had <22% indeterminate (Ind.) cases.

RESULT: The DCR+dTMT-B model had AUC=0.906 (NPV=0.816; PPV=0.900) for differentiating HC vs. MCI/pAD vs. Ind., AUC=0.891 (NPV=0.872; PPV=0.808) for differentiating HC vs. MCI vs. Ind., AUC=0.950 (NPV=0.941; PPV=0.870) for differentiating HC vs. pAD vs. Ind., and AUC=0.920 for differentiating MCI vs. pAD vs. Ind. (NPV=0.886; PPV=0.840). For predicting Aβ-PET status, the DCR+dTMT-B model had AUC=0.890 (NPV=0.914; PPV=0.754), whereas the DCR+dTMT-B+APOE model achieved AUC=0.933 (NPV=0.933; PPV=0.815).

CONCLUSION: A multimodal model combining process-based features of DCR and dTMT-B had very good to excellent performance in cognitive-impairment detection and excellent performance in Aβ-PET status prediction, with the DCR+dTMT-B+APOE model performing comparably to CSF biomarkers of AD. This model enables prioritizing the most suitable patients for BBM testing and DMTs, and substantially increases the efficiency of recruitment for AD clinical trials.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/diagnosis/diagnostic imaging/metabolism
*Cognitive Dysfunction/diagnosis/diagnostic imaging/metabolism
Positron-Emission Tomography
*Biomarkers/metabolism
Amyloid beta-Peptides/metabolism
Neuropsychological Tests
*Brain/diagnostic imaging/metabolism
Aniline Compounds
Aged, 80 and over

@article {pmid41512323,
year = {2025},
author = {Trammell, AR and Wingo, AP and Parker, MW and Goldstein, FC and Lah, JJ and Rodriguez, AD and McIntosh, R and Wingo, TS},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107687},
doi = {10.1002/alz70856_107687},
pmid = {41512323},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Female ; Male ; Aged ; Carotid Intima-Media Thickness ; *Alzheimer Disease/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Mounting evidence shows relationships between the cerebrovasculature, cognitive decline, neurodegeneration, and amyloid accumulation that underscores the contribution of cerebrovascular atherosclerotic disease (CA) to the pathogenesis of Alzheimer's disease and related dementias (AD/ADRD). Previously, we identified 114 brain proteins associated with CA as measured by carotid artery intimal media thickness (IMT). That finding suggests that surrogate brain biomarkers of CA may hold promise as sensitive markers for early ADRD detection. Compared to brain tissue, cerebrospinal fluid (CSF) is more accessible and can be collected from living persons. Thus, among the brain proteins profiled, we also profiled 6 (CBR1|P16152, ENDOD1|O94919, MOG|Q16653. PCSK1|P29120, PLP1|P60201, and QDPR|P09417) in CSF. In this follow-up study, we explored the CSF proteome for associations between profiled proteins and CA as measured by carotid artery IMT. Hence, this study aims to explore potential biomarkers of CA and ADRD risk by examining associations between CSF proteins and IMT.

METHOD: All CSF samples and vascular measurements were collected from Emory Goizueta Alzheimer's Disease Research Center research participants. We described the CSF collection steps and multiplex proteomic steps previously.[7] We performed proteomic analysis on 86 CSF samples, followed by linear regression adjusted for age, sex, and cognitive diagnosis (control vs. impaired) to test associations with CA. We applied BoxCox transformation to IMT measures to improve normality and we excluded participants with AD.

RESULT: Data for 83 people were analyzed. The sample's mean age was 65.8 (8.02); 60% were female, 70% were white adults, and 69% were controls. Among white participants, QDPR|P09417 (neurotransmitter production) was associated with higher IMT. For AA participants, PLP1|P60201 (myelin sheath) was associated with higher IMT. In meta-analysis (both groups), QDPR|P09417 and MOG|Q16653 (myelin sheath) were associated with higher mean carotid IMT.

CONCLUSION: Vascular disease can co-occur with AD. Our results show associations between CSF proteins involved in structural integrity and chemical signaling and CA in a sample with impaired and normal cognition. Further, we detected racial differences in these associations. Given these findings among cognitively normal and impaired people, these proteins may have promise as early disease indicators. More extensive study with a larger sample is needed.},
}

Humans
*Biomarkers/cerebrospinal fluid
Female
Male
Aged
Carotid Intima-Media Thickness
*Alzheimer Disease/cerebrospinal fluid
Middle Aged
Aged, 80 and over

@article {pmid41512318,
year = {2025},
author = {Chan, T and Hosseini, SA and Macedo, AC and Trudel, L and Gonçalves, MP and Rahmouni, N and Hall, BJ and Therriault, J and Socualaya, KMQ and Servaes, S and Bezgin, G and Zheng, Y and Wang, YT and Aumont, E and Arias, JF and Real, APB and Jia, WL and Hopewell, R and Hsiao, C and Vitali, P and Pascoal, TA and Rosa-Neto, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107658},
doi = {10.1002/alz70856_107658},
pmid = {41512318},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; Aged ; *Alzheimer Disease/cerebrospinal fluid/blood ; *tau Proteins/cerebrospinal fluid/blood ; *Blood-Brain Barrier/metabolism ; *Neurofilament Proteins/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Ratio between plasma and cerebrospinal fluid (CSF) biomarkers might inform about the peptide clearance from the central nervous system (CNS) to the peripheral body compartments. However, whether this clearance is linked to blood-brain barrier (BBB) alterations in Alzheimer's disease (AD) remains unclear. In this study, we examined the ratio between plasma and CSF neurofilament light chain (NfL) and p-tau181 and its relationship with BBB permeability in individuals across the AD spectrum.

METHOD: We analyzed data of 102 participants (median age 66 years, 54% female) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Plasma and CSF levels of NfL and p-tau181 were measured using Lumipulse G1200 (Fujirebio). The CSF/serum albumin quotient, a marker of BBB integrity, was calculated, where higher values indicate increased permeability. Mann-Whitney U test compared the biomarker ratios among ATN groups. Spearman's correlation examined the association between the plasma/CSF biomarker ratios and amyloid PET ([18]F-NAV4694) global standardized uptake value ratio (SUVR), and between plasma/CSF biomarker ratios and the albumin quotient.

RESULT: Plasma p-tau181/CSF p-tau181 ratio and plasma NfL/CSF NfL ratio were decreased in A+T+ individuals (Figure 1), suggesting impaired CSF clearance in AD. No significant differences in albumin quotient values were observed among ATN groups. Moreoever, increased amyloid burden on PET correlated with reduced plasma/CSF p-tau181 and NfL ratios (Figure 2), further supporting a link between amyloid pathology and impaired clearance mechanisms. Finally, no significant correlation was found between plasma/CSF p-tau181 and NfL ratios and albumin quotient (Figure 3), suggesting that CSF clearance deficit is independent of BBB integrity.

CONCLUSION: Our results support the concept that impaired CSF clearance contributes to the accumulation of AD biomarkers in the CNS. Moreover, the impaired CSF clearance does not seem to be associated with BBB dysfunction. These results highlight CSF clearance as a potential therapeutic target for AD, emphasizing the need to explore mechanisms that enhance peptide drainage from the CNS.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Female
Male
Aged
*Alzheimer Disease/cerebrospinal fluid/blood
*tau Proteins/cerebrospinal fluid/blood
*Blood-Brain Barrier/metabolism
*Neurofilament Proteins/cerebrospinal fluid/blood
Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
Middle Aged
Cohort Studies

@article {pmid41512317,
year = {2025},
author = {Barcellos, LFB and Ferrari-Souza, JP and de Jesus Vanni, IJ and Valer, MAA and Bieger, A and Leffa, DT and Lussier, FZ and Brum, WS and Aguzzoli, C and Corin, A and Bastiani, MA and Carello-Collar, G and Borelli, WV and Rahmouni, N and Therriault, J and Trudel, L and Macedo, AC and Ferreira, PCL and Povala, G and Bellaver, B and Souza, DO and Rosa-Neto, P and Pascoal, TA and Zimmer, ER},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107663},
doi = {10.1002/alz70856_107663},
pmid = {41512317},
issn = {1552-5279},
mesh = {Humans ; Male ; Positron-Emission Tomography ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Aged ; Atrophy/pathology ; *Brain/pathology/diagnostic imaging ; Disease Progression ; Plaque, Amyloid/diagnostic imaging/pathology ; Middle Aged ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) diagnostic and staging criteria rely on imaging biomarkers as robust tools for in vivo disease assessment. Among these, cortical brain atrophy is recognized as a key hallmark of disease progression. However, rates of cortical atrophy in preclinical stages remain insufficiently explored within current staging frameworks. In a group of amyloid β-positive (Aβ+) asymptomatic individuals, we investigated the association of the imaging-based biological AD staging framework with longitudinal brain atrophy patterns.

METHODS: We included 162 Aβ+ participants from the A4 Study placebo group with available magnetic resonance imaging (MRI) and positron emission tomography (PET) for amyloid-β (Aβ) plaques ([[18]F]Florbetapir) and tau ([[18]F]Flortaucipir) at baseline, along with a follow-up MRI at least 2 years after baseline. Tau positivity in the medial temporal lobe (TMTL+) and in the neocortex (TNEO+) were determined as tau PET standardized uptake value ratio (SUVR) of 2.5 standard deviations above the mean derived from a separate population (LEARN substudy) of 55 Aβ-negative individuals. Groups were compared using analysis of covariance (ANCOVA) with Tukey's multiple comparison test, adjusting for relevant covariates.

RESULTS: Demographic characteristics of the population are displayed in Table 1. In cross-sectional analysis, we observed that baseline cortical gray matter volumes differed significantly only between A+TNEO+ and A+T- groups (p = 0.042), with no significant differences between other groups (p >0.05 for both; Figure 1a). Longitudinally, A+TNEO+ individuals exhibited greater rates of cortical atrophy compared to A+T- (p <0.001) and A+TMTL+ (p = 0.007), along with A+TMTL+ individuals showing higher rates of cortical atrophy compared to the A+T- group (p = 0.042; Figure 1b). Subsequent regional analyses revealed that the A+TNEO+ individuals showed higher atrophy compared to both A+T- and A+TMTL+ in temporal and parietal regions (Figure 2).

CONCLUSIONS: Our findings reveal that the imaging-based biological AD staging is closely associated with cortical brain atrophy, showing a gradual acceleration in rates of cortical atrophy across stages. Additionally, our results suggest that serial volumetric measurements of temporoparietal brain regions may be sensitive biomarkers of early disease progression. Taken together, our findings provide valuable insights for applying the imaging-based biological AD staging in preclinical AD.},
}

Humans
Male
Positron-Emission Tomography
Female
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Biomarkers/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Aged
Atrophy/pathology
*Brain/pathology/diagnostic imaging
Disease Progression
Plaque, Amyloid/diagnostic imaging/pathology
Middle Aged

@article {pmid41512316,
year = {2025},
author = {Guo, G and Sathu, H and Rudolph, MD and Bateman, TR and Hughes, TM and Craft, S and Gurcan, MN and Luo, S and Ma, D},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107666},
doi = {10.1002/alz70856_107666},
pmid = {41512316},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/diagnosis ; Male ; Female ; *Biomarkers ; Magnetic Resonance Imaging ; Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; *Neuroimaging/methods ; Atrophy/pathology ; *Cerebral Cortex/diagnostic imaging/pathology ; Neural Networks, Computer ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is the leading cause of dementia. Cortical atrophy patterns derived from T1 MRI are sensitive neuroimaging biomarkers to detect early signs of AD-related neurodegeneration. However, early diagnosis at the prodromal stage is challenging due to the subtle and heterogeneous neuropathological and neurodegeneration patterns over the cortical surface, which cannot be captured by conventional deep learning methods natively. In this study, we developed an explainable cortical graph convolutional network (GCN) that captures the early signs of atrophy patterns in the cortical surface as graph-based features to identify subjects with elevated AD risk.

METHOD: T1 MRI data from the baseline visit of Alzheimer's Disease Neuroimaging Initiative (ADNI; 1645 subjects, 902 Male, 743 Female; stable NC [sNC]: 523, stable [AD]: 339, MCI: 783) dataset was processed through FreeSurfer (v7.4). Five-fold cross-validated models were built using 90% of the CN+AD data as training (stratified by gender and clinical diagnosis), with 10% reserved for independent testing. The dementia risk models were then applied to predict stable mild cognitive impaired (sMCI) vs. progressive MCI (pMCI) to evaluate their performance to predict future risk of dementia onset. A cortical GCN model handles the cortical surface mesh as graphic-based input, where cortical morphological data (thickness and curvature) are defined on each vertex (graph node) and used as predictive features. During training, batch normalization and dropout were applied to each graph convolutional layer to mitigate overfitting and enhance training stability.

RESULT: The cortical GCN classification model achieved a balanced accuracy of 0.736 in differentiating dementia (AD) and cognitively normal (CN) subjects and an average mean balanced accuracy of 0.644 for predicting sMCI from pMCI.

CONCLUSION: This project demonstrated the effectiveness of using cortical GCN to achieve early prediction for future dementia onset for subjects with risk of AD. Future work will focus on independent validation of NACC/ADRC data to evaluate the model's generalizability, as well as enhance the model's explainability through techniques such as Grad-CAM and integrated gradient. These efforts will provide deeper insights into AD's neuroanatomical aspects and contribute to developing more accurate, transparent, and effective diagnostic tools.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/diagnosis
Male
Female
*Biomarkers
Magnetic Resonance Imaging
Aged
*Cognitive Dysfunction/diagnostic imaging/pathology
*Neuroimaging/methods
Atrophy/pathology
*Cerebral Cortex/diagnostic imaging/pathology
Neural Networks, Computer

@article {pmid41512283,
year = {2025},
author = {Morcillo-Nieto, AO and Aranha, MR and Arriola-Infante, JE and Franquesa-Mullerat, M and Zsadanyi, SE and Vaqué-Alcázar, L and Parra, JA and Zhao, Z and Arranz, J and Rodríguez-Baz, Í and Maure-Blesa, L and Videla, L and Barroeta, I and Hoyo, LD and Benejam, B and Fernandez, S and Hernandez, AS and Giménez, S and Alcolea, D and Belbin, O and Lleó, A and Carmona-Iragui, M and Fortea, J and Bejanin, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106414},
doi = {10.1002/alz70856_106414},
pmid = {41512283},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; Magnetic Resonance Imaging ; Longitudinal Studies ; *White Matter/pathology/diagnostic imaging ; Middle Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Down Syndrome/pathology/diagnostic imaging ; tau Proteins/cerebrospinal fluid ; Aged ; Brain/pathology/diagnostic imaging ; Adult ; Cohort Studies ; },
abstract = {BACKGROUND: Down syndrome (DS) is a genetically determined form of Alzheimer's disease (AD) characterized by a low prevalence of traditional age-related vascular risk factors. Emerging evidence indicates that white matter hyperintensities (WMH) are frequent in DS and linked to small vessel disease and neurodegeneration. However, the temporal dynamics of WMH and their relationship with AD pathology remain unexplored in DS. Using an optimal longitudinal preprocessing pipeline, we aimed to determine the evolution of WMH across the AD continuum in DS and define their associations with baseline clinical and pathological characteristics.

METHOD: Longitudinal study including 47 euploid healthy controls (HC) from the SPIN cohort, and 86 individuals with DS from the DABNI cohort, who underwent 2 to 4 3T-MRI visits (Table 1). The DS cohort included individuals with asymptomatic (aDS, n = 66) and symptomatic AD (sDS; n = 18). WMH were segmented on high-resolution FLAIR images using the longitudinal pipeline from the Lesion Segmentation Toolbox in SPM12. Individuals were classified as WMH Regressor, Stable, and Progressor using a previously proposed threshold (±75 mm[3]/year, Al-Janabi et al., 2019). Non-parametric tests assessed the effect of sociodemographic and genetic factors, AD clinical stage, cerebrospinal fluid (CSF) AD biomarkers (Aβ42/Aβ40 ratio, pTau181, and NfL), WMH volume, and microbleed status on annual WMH volume changes.

RESULT: WMH volume significantly decreased with age in DS (rho=-0.37, p <0.001; Figure 1A-B) but not in HC (p = 0.1). This decrease was more pronounced in sDS than aDS (Figure 1C). Regressor individuals were significantly more frequent in sDS (66.67%) than aDS (13.64%) or HC (12.77%). Sex, APOEε4 status, intellectual disability, and microbleed status did not influence WMH changes (Figure 1D-E-F). CSF-pTau181 and NfL, but not Aβ42/Aβ40 ratio, related to annual WMH changes (Figure 2A-B-C). Additionaly, higher baseline WMH volume correlated with decreasing WMH changes (rho=-0.33, p <0.002, Figure 2E). Sensitivity analyses considering white matter atrophy confirmed the robustness of our findings.

CONCLUSION: WMH decreased more frequently over time in DS compared to the general population, particularly in individuals with symptomatic AD and high baseline WMH volume. This unexpected finding, which cannot be attributed to atrophy, offers novel insights into WMH aetiology in DS and has significant implications for targeted interventions using WMH as an outcome.},
}

Humans
Male
Female
Biomarkers/cerebrospinal fluid
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
Magnetic Resonance Imaging
Longitudinal Studies
*White Matter/pathology/diagnostic imaging
Middle Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Down Syndrome/pathology/diagnostic imaging
tau Proteins/cerebrospinal fluid
Aged
Brain/pathology/diagnostic imaging
Adult
Cohort Studies

@article {pmid41512280,
year = {2025},
author = {Smith, R and Alkhodair, Y and Yadegari, M and DeMarco, ML},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107634},
doi = {10.1002/alz70856_107634},
pmid = {41512280},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Apolipoprotein E4/blood/genetics ; Male ; Female ; *Alzheimer Disease/genetics/blood/diagnosis ; Aged ; Genotype ; Apolipoproteins E/genetics/blood ; },
abstract = {BACKGROUND: Anti-amyloid therapies (AAT) for Alzheimer's disease are associated with the risk of amyloid-related imaging abnormalities (ARIA). APOE4 homozygotes (E4/E4) have the highest risk, followed by APOE4 carriers (E4), making APOE genotyping essential for risk assessment. While APOE4 allelic status is routinely determined via DNA (e.g., by RT-PCR), recently developed automated immunoassays offer an alternative approach by measuring the apolipoprotein E4 (apoE4) concentration in plasma (i.e., proteotyping). In this study, we evaluated the diagnostic accuracy of an apoE4 proteotyping assay (Fujirebio Lumipulse) and its suitability for ARIA risk assessment.

METHOD: This diagnostic accuracy study included 104 plasma samples from unique individuals with known APOE genotypes determined by RT-PCR: E2/E3 = 8, E3/E3 = 45, E2/E4 = 1, E3/E4 = 44, and E4/E4 = 6. Plasma samples were analyzed using Fujirebio's Lumipulse G1200 system with the Lumipulse G ApoE4 and Pan-ApoE assays. These assays measure apoE4 and total apoE protein concentrations, respectively, and their ratio is used to infer E4 allelic status (non-E4, E4, or E4/E4). The assays were further evaluated for precision, potential interferences, and sample stability across freeze/thaw cycles.

RESULT: The plasma proteotyping assay demonstrated 100% accuracy in distinguishing the presence or absence of an E4 allele compared to RT-PCR. It correctly classified all non-E4 individuals (n = 53), all E4/E4 (n = 6), and 41 of 45 E4 heterozygotes (4 heterozygotes were misclassified as E4/E4). The ApoE4 and Pan-ApoE assays had total coefficients of variation of 8.5% and 4.0%, respectively. No significant interference was observed for hemolysate up to ∼5.25 g/L of hemoglobin or for lipemia up to ∼500 mg/dL of intralipid. Additionally, freeze-thaw testing showed no significant impact on assay performance for up to 4 freeze/thaw cycles.

CONCLUSION: The evaluated plasma apoE4 phenotyping assay demonstrated perfect accuracy in detecting the presence or absence of an E4 allele. However, it did not reliably distinguish E4 heterozygotes from homozygotes, with several heterozygotes misclassified as E4/E4. In the context of AAT treatment eligibility and ARIA risk assessment, proteotyping is an accurate method for both ruling in and out the presence of an E4 allele but E4/E4 results specifically should be confirmed via genotyping.},
}

Humans
*Biomarkers/blood
*Apolipoprotein E4/blood/genetics
Male
Female
*Alzheimer Disease/genetics/blood/diagnosis
Aged
Genotype
Apolipoproteins E/genetics/blood

@article {pmid41512277,
year = {2025},
author = {Paez, A and Piñol-Ripoll, G and Dogaheh, SB and Gillman, SO and Dakterzada, F and Carnes, A and Barbe, F and Dang-Vu, TT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107602},
doi = {10.1002/alz70856_107602},
pmid = {41512277},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/cerebrospinal fluid ; Aged ; *Alzheimer Disease/cerebrospinal fluid ; *Orexins/cerebrospinal fluid ; Polysomnography ; Prospective Studies ; Neuropsychological Tests ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid ; Sleep/physiology ; Peptide Fragments/cerebrospinal fluid ; },
abstract = {BACKGROUND: Cerebrospinal fluid (CSF) orexin levels are higher in MCI and AD and associated with sleep deterioration, increasing risk of cognitive decline and Alzheimer's disease (AD) progression. Orexin-A is a key sleep-wake cycle regulator. Dual orexin receptor antagonists improve sleep in AD and insomnia and may reduce tau and Aβ deposition in older adults. However, little research has investigated associations between sleep microarchitecture, orexin, neurodegeneration biomarkers, cognitive decline, or mental health in AD.

METHODS: Using data from a prospective cohort study of mild-to-moderate AD (n = 60, 30-female, mean age-74.7), we analysed non-REM sleep spindles, slow oscillations (SO), and their associations with CSF orexin, AD biomarkers, cognition, and mental health over three years. Participants underwent polysomnography (PSG) and CSF draws at baseline, neuropsychological assessment with the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Neuropsychiatric Inventory (NPI) at baseline and 12 months, and Mini-Mental Status Examination (MMSE) at baseline, 12, 24, and 36 months. PSG was scored along American Academy of Sleep Medicine guidelines. Spindle and SO detection were performed using in-house, open-source software packages developed at Concordia University, following Moelle (2011) recommendations for spindles and Staresina's (2015) recommendations for SO. Associations between SO and spindle characteristics (duration, density, power, amplitude) and orexin, Aβ42 and tau at baseline, and baseline orexin and cognition from baseline to 36 months were investigated with false discovery rate-adjusted generalised linear models, controlling for age, sex, apnea-hypopnea index.

RESULTS: We found previously unreported, predictive associations between SO, duration, density, amplitude, and CSF orexin. Orexin also predicted increased ptau181, total-tau, ptau/Aβ42, total-tau/Aβ42. Increased orexin predicted worse cognitive performance (higher ADAS-cog, lower MMSE) from baseline to 36-months and increased neuropsychiatric symptom severity (NPI) from baseline to 12 months. Orexin also moderates relationships between spindles, SO, cognition, and mental health.

CONCLUSIONS: Orexin levels are associated with neurodegeneration biomarkers and cognitive deterioration in AD and moderate relationships between sleep microarchitecture and cognitive changes over time. Orexin may thus constitute a potential target for sleep-related interventions for cognition in neurodegenerative disorders.},
}

Humans
Female
Male
*Biomarkers/cerebrospinal fluid
Aged
*Alzheimer Disease/cerebrospinal fluid
*Orexins/cerebrospinal fluid
Polysomnography
Prospective Studies
Neuropsychological Tests
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Cognitive Dysfunction/cerebrospinal fluid
Sleep/physiology
Peptide Fragments/cerebrospinal fluid

@article {pmid41512276,
year = {2025},
author = {Russ, KA and Lane, KA and Gao, S and Unverzagt, FW and Hendrie, HC and Foroud, TM and Dage, JL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107656},
doi = {10.1002/alz70856_107656},
pmid = {41512276},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; Nigeria/epidemiology ; *tau Proteins/blood ; Longitudinal Studies ; Aged, 80 and over ; *Alzheimer Disease/blood/epidemiology/genetics ; Indiana/epidemiology ; Middle Aged ; *Cognitive Dysfunction/blood/epidemiology ; Black or African American ; White ; },
abstract = {BACKGROUND: The Indianapolis-Ibadan Dementia Project (IIDP) is a longitudinal epidemiological study that evaluated subjects in Indianapolis, Indiana and Ibadan, Nigeria for prevalence and incidence of cognitive decline and dementia between 1991-2012. Plasma collected from the 2001 wave is currently stored at the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD). We analyzed the IIDP plasma to assess whether the ability of p-Tau181 to predict disease differed between subjects in these two geographically, culturally, genetically, and environmentally disparate sites.

METHOD: Plasma collected from study participants was analyzed for Alzheimer's disease biomarkers using the Quanterix Simoa HD-X pTau181 v2 Advantage kits. The mean and standard deviation of the log transformed biomarker data using all subjects with normal cognition from 2001 were used to standardize the biomarker prior to statistical analysis. For this analysis, participants with normal cognition during the 2001 wave and at least one follow-up evaluation were included (N = 755 African Americans; N = 864 Nigerians). Incident cognitive impairment status was determined using the last wave the subject was assessed.

RESULT: Using logistic regression models, p-Tau181 was shown to predict incident cognitive impairment in the African American population (Odds Ratio (OR)=1.52, p < 0.0001) but not in the Ibadan population (OR=1.09, p = 0.42) adjusting for age, sex, education, APOE4 genotype and history of stroke. The results from the logistic regression model for incident cognitive impairment/dementia can be seen in Table 1. Mixed effects models assessing cognitive scores showed significant interactions between time and p-Tau181, indicating that higher p-Tau181 is associated with greater decline for total cognitive score (p = 0.0109) and memory cognitive subscale (p = 0.0031) only in the Indianapolis African American population (Table 2).

CONCLUSION: While geographic location has been seen to influence APOE genotype risk, similar investigations of AD biomarkers has been limited. Our data suggest there are differences in etiology that drives cognitive impairment between the African Americans in Indianapolis and the Africans in Ibadan. Additional analyses must be done to determine what drives these differences and the most effective biomarkers or biomarker combinations for differing populations.},
}

Humans
Male
Female
*Biomarkers/blood
Aged
Nigeria/epidemiology
*tau Proteins/blood
Longitudinal Studies
Aged, 80 and over
*Alzheimer Disease/blood/epidemiology/genetics
Indiana/epidemiology
Middle Aged
*Cognitive Dysfunction/blood/epidemiology
Black or African American
White

@article {pmid41512275,
year = {2025},
author = {Aresta, S and Nemni, R and Zanardo, M and Sirabian, G and Capelli, D and Alì, M and Vitali, P and Bertoldo, EG and Fiolo, V and Bonanno, L and Maresca, G and Battista, P and Sardanelli, F and Pizzini, FB and Castiglioni, I and Salvatore, C and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105530},
doi = {10.1002/alz70856_105530},
pmid = {41512275},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Male ; Female ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Aged ; Neuropsychological Tests ; Magnetic Resonance Imaging ; Disease Progression ; *Artificial Intelligence ; Neuroimaging ; },
abstract = {BACKGROUND: In 2024, eleven European scientific societies/organizations and one patient advocacy association have defined a patient-centered biomarker-based diagnostic workflow for memory clinics evaluating neurocognitive disorders. This study aimed to evaluate the clinical performance of an Artificial Intelligence (AI)-tool applied to neuropsychological assessment and MRI for supporting the staging, clinical profiling, diagnosis, causal hypothesis, and progression of subjects at risk of Alzheimer's disease (AD) following the above-mentioned intersocietal recommendations.

METHOD: This observational, multicentric study enrolled 796 subjects: 705 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, 35 from Centro Diagnostico Italiano (Italy), 26 from IRCCS Policlinico San Donato (Italy), and 30 from IRCCS Bonino Pulejo (Italy). Participants were clinically staged as healthy subjects (HS), subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD-dementia at baseline and 24-month follow-up. Patients were clinically profiled into AD clinical syndromes based on cognitive characteristics and structural neuroimaging findings. First-line biomarkers were also measured. The AI-based software TRACE4AD™ automatically processed neuroimaging and neuropsychological test data to extract cognitive and structural findings. The tool staged subjects as HS/SCI, MCI, or moderate-to-severe-dementia (MSD), profiled the causal hypothesis, and predicted conversion risk to AD-dementia. Agreement between AI and human staging was assessed using Cohen's kappa. AI-performance was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under curve (AUC), and accuracy.

RESULT: For the staging classification the inter-rater AI-humans agreement was substantial for both HS/SCI vs. rest (Cohen's κ = 0.81) and MCI (κ = 0.70) classification, almost perfect for MSD vs. rest (κ = 0.90) classification. For the causal hypothesis classification, the AI performance vs. biomarker-based diagnosis was: PPV 91%, NPV 100%, and accuracy 91%. For the binary classification of progression to AD-dementia at 24-month, the AI performance was: sensitivity 89%, specificity 82%, accuracy 85%, and AUC 83%.

CONCLUSION: The AI-tool demonstrated its usefulness in supporting the clinical treatment of AD patients by assisting with staging, clinical profiling, diagnosis, hypothesis generation for underlying causes, and predicting the risk of progression to AD-related dementia within 24 months.},
}

Humans
*Biomarkers
*Alzheimer Disease/diagnosis/diagnostic imaging
Male
Female
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Aged
Neuropsychological Tests
Magnetic Resonance Imaging
Disease Progression
*Artificial Intelligence
Neuroimaging

@article {pmid41512267,
year = {2025},
author = {Roberts, PS and Li, CY and Ouellette, DS and Qureshi, N and Spivack, E and Nasmyth, M and Sicotte, NL and Tan, ZS},
title = {Linking data to determine risk for 30-day readmissions in dementia.},
journal = {The American journal of managed care},
volume = {31},
number = {12},
pages = {e371-e377},
doi = {10.37765/ajmc.2025.89842},
pmid = {41512267},
issn = {1936-2692},
mesh = {Humans ; *Patient Readmission/statistics & numerical data ; Male ; Female ; Aged ; Retrospective Studies ; Cross-Sectional Studies ; *Electronic Health Records/statistics & numerical data ; *Dementia/therapy/epidemiology ; Risk Factors ; Aged, 80 and over ; },
abstract = {OBJECTIVE: The demand and the landscape of options for dementia care are growing. Standardization of care for persons with Alzheimer disease and related dementias (ADRD) lacks infrastructure across episodes of care. Use of electronic health records (EHRs) in practice settings yields valuable information that can enhance continuity of patient care. The objective of this study was to use EHR-derived variables to identify risk factors for 30-day readmissions in the ADRD population across episodes of care.

STUDY DESIGN: Cross-sectional, retrospective study of older adults (aged ≥ 65 years) with ADRD discharged from a large urban academic medical center between October 1, 2018, and March 31, 2022.

METHODS: Data extracted across episodes of care from the EHR included demographic characteristics, medical variables, and encounter variables.

RESULTS: A total of 14,101 patients diagnosed with ADRD were included in the study. Factors associated with patients being more likely to experience 30-day hospital readmissions included advanced age, male sex, being a non-English speaker, having more severe comorbidities, staying in the hospital for more than 5 days, having had more than 1 surgical procedure in the prior 6 months, having had 3 or more inpatient admissions in the 6 months prior to index admission, having had more than 3 physician consultations in the prior 6 months, and having been discharged to settings other than home (all P < .05).

CONCLUSIONS: By utilizing the EHR to connect medical and encounter data across episodes of care, health care providers and administrators can gain valuable insight into identifying factors contributing to readmissions, which could be used to improve continuity of care for patients and caregivers, ultimately leading to better outcomes and reduced health care costs.},
}

Humans
*Patient Readmission/statistics & numerical data
Male
Female
Aged
Retrospective Studies
Cross-Sectional Studies
*Electronic Health Records/statistics & numerical data
*Dementia/therapy/epidemiology
Risk Factors
Aged, 80 and over

@article {pmid41512235,
year = {2025},
author = {Singh, A and Denkinger, MN and Dieckhoff, K and Liu, J and Serrano, GE and Beach, TG and Leuzy, A and Atri, A and Reiman, EM and Ashton, NJ},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105227},
doi = {10.1002/alz70856_105227},
pmid = {41512235},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Cerebral Amyloid Angiopathy/blood/diagnosis ; Aged ; *Alzheimer Disease/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels leading to increased risk of microbleeds, intracerebral hemorrhages, and progressive cognitive decline. It is estimated that up to 90% of individuals with Alzheimer's disease (AD) exhibit some degree of CAA. Notably, CAA has been identified as a major contributor to the risk of Amyloid-Related Imaging Abnormalities (ARIA), particularly in patients undergoing treatment with anti-amyloid therapies. The use of blood-based biomarkers to accurately detect and assess the severity of CAA is crucial for tailoring treatment plans while reducing the risk of adverse effects.

METHOD: We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for an exploratory biomarker quantification in plasma of patients with CAA or no-CAA (presence of cerebral amyloidotic blood vessels) utilizing samples from the Banner Health Brain and Body Donation Program (BBDP) We evaluated the differential protein expression between groups using a linear model. This model was adjusted for age, sex, APOE e4 carrier status and the presence of Alzheimer's amyloid plaque load (AD-status).

RESULT: We selected 251 participants (age: 85±8.2) from the BBDP cohort with a plasma sample taken < 5 years (1.45±1.26) prior to death. At post-mortem each case was classified as CAA+ (n = 140) or CAA- (n = 111). NULISA™ identified several novel proteomic biomarkers which were up-regulated (CRP, IL4, SAA1), and down-regulated (CCL11, PDLIM5, NPY and GDNF) in CAA pathology carriers (Figure 1). We further performed receiver operating characteristic (ROC) curve analysis comparing models and found that a model including age, sex, AD-status, APOE e4 status, CRP and CCL11 had an area under the curve (AUC) of 0.87 (95%CI, 0.83-0.92) to identify the presence of CAA at post-mortem (Figure 2).

CONCLUSION: Blood-based biomarkers capable of identifying CAA could play an important role in improving treatment outcomes by highlighting ARIA risk prior to treatment initiation. We found that plasma proteins related to inflammation, blood brain barrier dysfunction and cytoskeletal stability were significantly changed in participants with confirmed CAA. Further work will be required to replicate these findings in an independent dataset.},
}

Humans
*Biomarkers/blood
Male
Female
*Cerebral Amyloid Angiopathy/blood/diagnosis
Aged
*Alzheimer Disease/blood
Aged, 80 and over

@article {pmid41512232,
year = {2025},
author = {Kang, JW and Vemuganti, V and Jonaitis, EM and Johnson, SC and Asthana, S and Carlsson, CM and Chin, NA and Engelman, CD and Ulland, TK and Rey, FE and Bendlin, BB},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105650},
doi = {10.1002/alz70856_105650},
pmid = {41512232},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; *Alzheimer Disease/diagnosis ; Neuropsychological Tests ; *Imidazoles/blood ; Executive Function/physiology ; Middle Aged ; Aged, 80 and over ; Gastrointestinal Microbiome/physiology ; },
abstract = {BACKGROUND: Among the various modifiable risk factors for AD development, the gut microbiome stands out as a potential therapeutic target, offering opportunities for intervention in the very early stages to potentially prevent disease onset. Notably, specific gut microbial metabolites may critically modulate metabolic and neuroimmune mechanisms shared with type 2 diabetes (T2D) and atherosclerosis-conditions that increase the risk of neurovascular and neurodegenerative disorders. Among these metabolites, imidazole propionate (ImP), a gut bacteria-derived metabolite of histidine, has garnered attention for its potential to cross the blood-brain barrier and exacerbate neurodegenerative processes.

METHOD: Participants included in the analysis were from Wisconsin ADRC and Wisconsin Registry for Alzheimer's Prevention (WRAP) studies. ImP was determined using the Metabolon platform. Three composite tests for measuring executive functions, along with assessments of two other cognitive domains-immediate learning and delayed recall-were used to compute the global composite scores for the three-test version of the Preclinical Alzheimer's Cognitive Composite (PACC3). The PACC3 scores were derived using three distinct measures of executive functions-Animal Naming Test (PACC3-AN, n = 859), Category Fluency Test (PACC3-CFL, n = 1118), and Trail-Making Test B (PACC3-TRLB, n = 1116)-and subsequently transformed into z-scores. Ordinary Least Squares (OLS) multiple linear regression approach was used to evaluate the relationship between levels of ImP and cognitive scores while accounting for covariates such as age and sex in the analysis.

RESULT: Lower cognitive performance was associated with higher levels of plasma ImP while controlling for age and sex, even in cognitively normal individuals before the onset of detectable cognitive symptoms.

CONCLUSION: Despite the modest associations, the significance of predictors suggests these factors warrant further exploration in understanding their combined contribution to ImP levels and broader neurodegenerative mechanisms.},
}

Humans
Male
Female
*Biomarkers/blood
Aged
*Alzheimer Disease/diagnosis
Neuropsychological Tests
*Imidazoles/blood
Executive Function/physiology
Middle Aged
Aged, 80 and over
Gastrointestinal Microbiome/physiology

@article {pmid41512231,
year = {2025},
author = {Dunne, RA and Taghavi, HM and DiGiacomo, P and Maclaren, J and Bell, M and Carlson, ML and Mormino, EC and Henderson, VW and Spincemaille, P and Zhuang, H and Wang, Y and Rutt, BS and Georgiadis, M and Zeineh, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106116},
doi = {10.1002/alz70856_106116},
pmid = {41512231},
issn = {1552-5279},
mesh = {Humans ; Magnetic Resonance Imaging/methods ; Male ; *Cognitive Dysfunction/diagnostic imaging/metabolism/pathology ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Female ; Biomarkers/metabolism ; *Hippocampus/diagnostic imaging/metabolism/pathology ; Aged ; *Iron/metabolism ; Middle Aged ; Disease Progression ; },
abstract = {BACKGROUND: Hippocampal iron, as measured with imaging, biofluids, and histology, has been associated with Alzheimer's disease (AD), its progression, and potentially neuroinflammatory disease mechanisms. With its high sensitivity to tissue magnetic susceptibility, 7T MRI offers the potential to detect abnormal iron deposition within the hippocampus of AD and mild cognitive impairment (MCI) brains in vivo, especially when combined with dedicated methods such as quantitative susceptibility mapping (QSM). We aim to utilize ultra-high resolution 7T MRI and explore conventional and novel source-separated QSM to quantify hippocampal iron deposition in AD, providing insights into the involvement of brain iron in disease progression.

METHOD: We conducted 7T MRI on 19 ADRC human volunteers, including 8 healthy controls (HC), 6 individuals with MCI, and 5 with AD. MR images were acquired using a GE MR950 scanner utilizing optical prospective motion correction. Automatic Segmentation of Hippocampal Subfields generated segmentations of the subiculum and CA1 (Figure 1), which were manually edited in a diagnosis-blind manner, followed by one-pixel erosion. R2* and source-separated QSM (positive susceptibility sources QSM-χ[+], negative QSM-χ[-]) were computed using MEDI and averaged within the subiculum and CA1. Blinded image quality assessments were conducted. Memory composite scores were correlated with iron measurements available in 18 participants. Nonparametric tests quantified hyperintensity gradation in hippocampal QSM/R2* images and assessed the relationship between memory scores and QSM/R2*.

RESULT: We found a significant ordinal increase of R2* according to participant diagnoses (AD>MCI>HC) in the subiculum (p = 0.0445) and combined subiculum-CA1 (p = 0.0232) subfields (examples of negative and positive findings in Figure 2, boxplots in Figure 3-top), suggestive of increased iron. No significant differences were seen in QSM without source separation, QSM-χ[+], or QSM-χ[-]. However, a significant negative association between memory scores and QSM-χ[+] was observed in CA1 (p = 0.0351, Figure 3-bottom).

CONCLUSION: We found elevated iron in the subiculum-CA1 hippocampal subregions in vivo in MCI and AD using 7T MRI, correlating with degraded memory performance. Our noninvasive visualization of microscopic hippocampal iron deposition utilizing ultra-high resolution 7T MRI in vivo corroborates post-mortem data. This translational finding could serve as a novel neuroimaging biomarker for iron-based AD pathology and inflammation.},
}

Humans
Magnetic Resonance Imaging/methods
Male
*Cognitive Dysfunction/diagnostic imaging/metabolism/pathology
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Female
Biomarkers/metabolism
*Hippocampus/diagnostic imaging/metabolism/pathology
Aged
*Iron/metabolism
Middle Aged
Disease Progression

@article {pmid41512227,
year = {2025},
author = {Ersoezlue, E and Hellmann-Regen, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105585},
doi = {10.1002/alz70856_105585},
pmid = {41512227},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/blood/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; *Cerebral Amyloid Angiopathy/blood/pathology/diagnostic imaging ; Aged, 80 and over ; Cohort Studies ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent causes of dementia, while concomitant diseases such as cerebral amyloid angiopathy (CAA) has a substantial impact on clinical trajectories and therapy, i.e. risk factor for imaging abnormalities under anti-amyloid antibodies. As there are no established biomarkers to identify individual with CAA, we aim to explore potential plasma biomarkers for mechanisms related to CAA in participants in continuum of AD.

METHOD: We included a total of 47 participants from the AD Neuroimaging Initiative study with available plasma biomarkers from a multiplex immunoassay panel (n = 145 analytes from "Biomarkers Consortium MRM data", consisting of proteins related to cancer, cardiovascular disease, metabolic disorders, inflammation, and AD). We stratified the cohort into participants with either T2*-GRE magnetic resonance images (MRI) (n = 21) at baseline or postmortem neuropathological assessment (n = 26). The numbers of definite lobar microbleeds were obtained from central visual readings (Mayo Clinic, Jack Lab), while central neuropathological severity scales for AD (AD neuropathologic change) and CAA (overall neocortical amyloid angiopathy) were included. We defined CAA status as at least two lobar microbleeds in orientation to the Boston criteria and at least moderate density in neuropathology. Plasma analytes were measured twice with a one-year time difference with a maximum of 6.6 years prior to either first MRI or time of death. Non-parametric receiver operating characteristic curves and area under the curve (AUC) values of analytes in differentiation of CAA status.

RESULT: In both cohorts with imaging and NP data, most of the participants exhibited cognitive symptoms and revealed in vivo or neuropathological changes regarding AD (Table-1). Using the imaging, various markers related to inflammation, lipid metabolism, cell adhesion, and sex steroids are found to show a constant increase in CAA (Table-2, Figure 1). Moreover, we identified increases in Clusterin and Complement Factor H levels as well as reduced Alpha-Fetoprotein, characterizing the neuropathological definition of CAA (Table-2, Figure 1).

CONCLUSION: Using both ante-mortem and post-mortem indicators of CAA, several candidate plasma biomarkers of CAA have been found, whereas replications in bigger samples with multiple measurements are crucial to address confounder factors and temporal relationships.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/blood/pathology/diagnostic imaging
Aged
Magnetic Resonance Imaging
*Cerebral Amyloid Angiopathy/blood/pathology/diagnostic imaging
Aged, 80 and over
Cohort Studies
Brain/pathology/diagnostic imaging

@article {pmid41512221,
year = {2025},
author = {Charles, A and Gallardo, MJJ and Suarez, AC and Sugg, E and Li, P and Hu, K and Gao, L},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107638},
doi = {10.1002/alz70856_107638},
pmid = {41512221},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis ; Biomarkers ; Mental Status and Dementia Tests/statistics & numerical data ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {BACKGROUND: Approximately one-third of adults over the age of 65 undergoing surgery experience severe cognitive impairments, including acute confusion, attention deficits, and global cognitive dysfunction. Older adults with greater cognitive impairments are at increased risk for prolonged hospitalization, higher rates of readmission, institutionalization, and long-term cognitive decline, including dementia and Alzheimer's disease. However, the trajectory of postoperative cognitive changes in older adults remains poorly understood. Cognitive assessments such as the Montreal Cognitive Assessment (MOCA) are commonly used in clinical settings but are often interpreted as a single total score, overlooking domain-specific cognitive changes. To address this research gap, this study examines domain-specific cognitive changes in older surgical patients before and after surgery.

METHOD: Seventeen older surgical patients (≥70 years old) undergoing knee, hip, or spine surgery were recruited. Cognitive function was assessed pre- and post-surgery using the Montreal Cognitive Assessment (MOCA). Assessments were captured 1-week before surgery and 1-day post-surgery. A linear mixed-effects model was used to evaluate cognitive function pre- and post-surgery across the following cognitive domains, abstraction, attention, language, orientation, and recall.

RESULT: The analysis revealed an interaction effect between event group (pre- vs. post-surgery) and the MOCA cognitive domains (F(4,126) = 6.97, p < 0.01), indicating that post-operative cognitive functions possibly decline at different rates across cognitive domains. Attention, orientation, and recall demonstrated the strongest effects, where the recall domain showed significant decline following surgery compared to baseline (β = -0.87 (standardized), SE = 0.156, p < 0.01), suggesting a domain-specific vulnerability in memory function.

CONCLUSION: Our findings indicate that postoperative cognitive decline is domain-specific, with memory function exhibiting the greatest vulnerability and possibly a slower recovery trajectory. These results suggest that assessing cognitive domains individually, rather than relying solely on total MOCA scores, may advance early detection of patients at risk for prolonged cognitive impairment. Follow-up studies are warranted to determine whether domain-specific cognitive assessments can serve as predictors of long-term cognitive decline, including postoperative delirium and dementia, ultimately guiding early interventions to improve patient outcomes. This research was supported by AACSF-23-1148490.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/diagnosis
Biomarkers
Mental Status and Dementia Tests/statistics & numerical data
Neuropsychological Tests
Aged, 80 and over

@article {pmid41512220,
year = {2026},
author = {Che, Y and Yu, Z and Ji, S and Yang, D},
title = {Decoding TREM2 Signaling Pathways: Linking Macrophage Glycolysis to Inflammatory Diseases in the CNS.},
journal = {Neurology(R) neuroimmunology & neuroinflammation},
volume = {13},
number = {2},
pages = {e200527},
doi = {10.1212/NXI.0000000000200527},
pmid = {41512220},
issn = {2332-7812},
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction/physiology ; *Macrophages/metabolism ; *Neuroinflammatory Diseases/metabolism/immunology ; *Glycolysis/physiology ; Animals ; Neurodegenerative Diseases/metabolism ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a key immunomodulatory receptor broadly expressed on myeloid cells such as macrophages and microglia. It plays versatile roles in neurodegenerative diseases, tissue repair, and tumor immunity by orchestrating glucose metabolism and inflammatory responses. This review systematically summarizes the structural characteristics of TREM2, its ligand-binding mechanisms, and downstream signaling pathways-including the phosphoinositide 3-kinase/protein kinase B(PI3K/Akt), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription 3 (STAT3) cascades-with a particular focus on its central role in macrophage metabolic reprogramming.In neurodegenerative diseases such as Alzheimer disease, TREM2 contributes to the attenuation of neuroinflammation and slows disease progression by promoting β-amyloid (Aβ) clearance, inhibiting tau hyperphosphorylation, and modulating microglial polarization. Loss-of-function sequence variants, such as R47H, disrupt lipid metabolism, impair phagocytic activity, and destabilize immune homeostasis, thereby significantly increasing disease susceptibility. Furthermore, by enhancing glycolysis and suppressing fatty acid oxidation, TREM2 facilitates macrophage polarization toward a reparative M2 phenotype, promoting neuroregeneration and remyelination in conditions such as spinal cord injury and multiple sclerosis.Within the tumor microenvironment, TREM2 influences tumor progression and therapeutic resistance by modulating the metabolic reprogramming of tumor-associated macrophages (TAMs)-notably through activation of pyruvate kinase muscle isozyme M2 (PKM2)-dependent glycolysis-and promoting an immunosuppressive phenotype. In metabolic disorders such as diabetes and obesity, TREM2 exerts protective effects by inhibiting NLRP3 inflammasome activation and maintaining lipid homeostasis, highlighting its therapeutic potential.This review also outlines the translational prospects of TREM2 as a therapeutic target, including the development of agonists, gene regulatory strategies, and its potential use as a biomarker. Future studies should aim to elucidate the ligand-specific biased signaling and dynamic regulatory networks of TREM2 within tissue microenvironments to advance precision interventions in neuroimmunometabolic diseases.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction/physiology
*Macrophages/metabolism
*Neuroinflammatory Diseases/metabolism/immunology
*Glycolysis/physiology
Animals
Neurodegenerative Diseases/metabolism

@article {pmid41512209,
year = {2026},
author = {Kek-Laflamme, A and Schaper, FLWVJ and Whittingstall, K and Pennell, PB and Young, GS and Marshall, GA and Larivière, S and Sarkis, RA},
title = {Brain Structural Changes and Cognitive-Clinical Profiles in Late-Onset Unexplained Epilepsy.},
journal = {Neurology},
volume = {106},
number = {3},
pages = {e214575},
doi = {10.1212/WNL.0000000000214575},
pmid = {41512209},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; *Epilepsy/diagnostic imaging/psychology/pathology/complications ; *Brain/pathology/diagnostic imaging ; Middle Aged ; *Gray Matter/diagnostic imaging/pathology ; Age of Onset ; Neuropsychological Tests ; Prospective Studies ; *Cognition/physiology ; Atrophy ; },
abstract = {BACKGROUND AND OBJECTIVES: Epilepsy incidence peaks in childhood and again after age 55. Up to half of individuals with late-onset epilepsy lack an identifiable cause, but previous imaging studies suggest subtle mesiotemporal atrophy. In this study, we aimed to quantify whole-brain cortical and deep gray matter alterations in late-onset unexplained epilepsy (LOUE) and to examine their associations with cognitive and clinical measures.

METHODS: We prospectively recruited patients with LOUE through Brigham and Women's Hospital and its affiliated sites and compared them with sociodemographically matched healthy older adults from the Harvard Aging Brain Study. Inclusion criteria for LOUE were at least 1 unexplained seizure after age 55, onset within the past 5 years, and no identifiable cortical lesion on MRI. All participants underwent 3T structural MRI and neuropsychological testing. Cortical thickness and deep gray matter volumes were extracted, and linear models were used to compare patients with LOUE and controls. Correlations were computed between structural alterations and demographic, cognitive, and clinical measures.

RESULTS: We included 59 patients with LOUE (mean age 71.2 ± 7.0 years, 49% female) and 53 controls (mean age 70.7 ± 5.2 years, 53% female). Patients with LOUE showed reduced cortical thickness in sensory and mesiotemporal cortices (d = -0.75, 95% CI [-1.14 to -0.37], FDR-corrected p values [pFDR] < 0.05) and reduced deep gray matter volumes in the pallidum and putamen (d = -0.55, 95% CI [-0.93 to -0.17], pFDR < 0.05). These structural reductions correlated with lower performance on a category fluency task (r = 0.31, pFDR = 0.016) and the extended Preclinical Alzheimer's Cognitive Composite (r = 0.37, pFDR = 0.0041). Conversely, patients showed increased thickness in the left inferior frontal gyrus (d = 0.82, 95% CI [0.43-1.20], pFDR < 0.05) and increased thalamic volume (d = 1.13, 95% CI [0.73-1.53], pFDR < 0.05), which were more pronounced in those with focal seizures sparing consciousness (d = -0.62, puncorr = 0.021).

DISCUSSION: Structural brain changes in LOUE are more extensive than previously recognized and are associated with cognitive vulnerability. Although the cross-sectional design and use of independent cohorts limit conclusions about disease progression, the findings suggest that LOUE may fall along a continuum between epilepsy and neurodegenerative disease.},
}

Humans
Female
Male
Aged
Magnetic Resonance Imaging
*Epilepsy/diagnostic imaging/psychology/pathology/complications
*Brain/pathology/diagnostic imaging
Middle Aged
*Gray Matter/diagnostic imaging/pathology
Age of Onset
Neuropsychological Tests
Prospective Studies
*Cognition/physiology
Atrophy

@article {pmid41512186,
year = {2025},
author = {Barragan, EV and Heuer, HW and Nosheny, RL and Camacho, MR and Navarra, K and Aisen, PS and Rahman-Filipiak, A and Roberts, JS and Ajayi, A and Ayo, O and Cho, SJ and Culhane, JE and Germano, KK and Guzman, VA and Higuera, M and Sotelo, M and Byrd, D and Mindt, MGR and Rabinovici, GD and Boxer, AL},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107586},
doi = {10.1002/alz70856_107586},
pmid = {41512186},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; Middle Aged ; Adult ; *Alzheimer Disease/blood/diagnosis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; United States ; Community-Based Participatory Research ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: Early onset dementia (EOD) affects people at the peak of personal and professional responsibilities and economic productivity. Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) are the most common EOD etiologies, but have not been studied in a sample representative of the general US population. Multiple barriers impede research participation for many groups, but community-engaged research (CER) strategies to enhance recruitment may make research participation more accessible and convenient for all.

METHOD: BEYONDD is an NIH-funded, community-based study focused on understanding the etiology of EOD, uses CER strategies such as remote assessments and return of research results as tools for enhancing sample representativeness. Participants are recruited using social media and local in-person CER strategies and screened via an online platform for eligibility (age 40-64, with concerns about cognitive or behavioral function). Remote completion of online questionnaires, cognitive testing, and an in-home blood draw for standard labs, Aβ42/40 and p-tau217 ratios, and plasma NfL comprise the initial visit. Participants are invited for more comprehensive onsite evaluation at one of 7 BEYOND in-clinic sites, followed by tailored referral to other NIH-funded research programs. Participants can learn their results remotely or in person.

RESULT: Using a novel, CER-based approach for social media ad deployment, BEYONDD has recruited over 1700 potential participants across the US and Puerto Rico; over half (n = 881) completed the online screening survey. Of the 206 participants enrolled in the online procedures, 80% (n = 165) were women and most were Latino (n = 83; 40%) or Black (n = 68; 33%) and over a quarter (n = 74; 36%) reported less than 16 years of education. We have completed over 95 blood draws across 17 states and invited participants for onsite visits. Results have been shared with 22 participants (10 on-site, 12 remotely). Preliminary analyses reveal a high Aβ42/40 positivity rate (∼30%) and the most prevalent routine lab abnormalities include: LDL-Cholesterol (63%), homocysteine (36%), hs-CRP (35%) and HgbA1C (33%). Abnormal p-tau217 ratios (n = 4; 5%) and APS2 scores (n = 3; 4%) have also been identified in this community-based sample.

CONCLUSION: Preliminary results suggest feasibility and acceptability of this innovative CER approach in a more representative sample of the US population.},
}

Humans
Female
Male
*Biomarkers/blood
Middle Aged
Adult
*Alzheimer Disease/blood/diagnosis
tau Proteins/blood
Amyloid beta-Peptides/blood
United States
Community-Based Participatory Research
Surveys and Questionnaires

@article {pmid41512156,
year = {2025},
author = {Geraci, J and Searls, E and Qorri, B and Ho, K and Burk, A and Tsay, M and Cumbaa, C and Pani, L and Alphs, L and Alosco, ML and Mez, J and Au, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107581},
doi = {10.1002/alz70856_107581},
pmid = {41512156},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/physiopathology ; *Alzheimer Disease/diagnosis ; Aged ; *Biomarkers ; Neuropsychological Tests ; Sleep/physiology ; Machine Learning ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) precision medicine will advance through the application of two key technological advances: 1) digital technologies that can more deeply characterize clinically relevant symptoms and 2) machine learning (ML) approaches the can classify subgroups with shared characteristics that could align with specific treatment plants. This study leverages a digital data collection platform for enhanced characterization and NetraAI, an artificial intelligence (AI) platform to analyze multimodal data to differentiate causal and non-causal subpopulations within a cohort and integrates a "No Call" system to exclude ambiguous data points.

METHOD: We analyzed data from 98 Boston University Alzheimer's Disease Research Center participants and 453 variables derived from digital tasks administered over two months. Eight participants were clinically diagnosed as mild cognitive impairment. Digital measures included sleep metrics (57 measures), clinical scales (324 measures), and cognitive performance assessments (72 GoNoGo and Code Substitution measures). Of the 98 subjects, 81 were cognitively unimpaired and 17 transitioned to MCI during the course of study enrollment.

RESULT: Sleep-derived metrics, including 3% and 4% desaturation thresholds (p = 4×10[-5], p = 7×10[-5]), and periodicity (eLFCnb) (p = 0.008) characterized one population of 8 participants, 7 of whom had been diagnosed with MCI. Incorporating maximum heart rate, another sleep metric, distinguished another subpopulation of 8 subjects (6/8 were diagnosed MCI) with elevated heart rate (p = 10[-10]). We examined 81 cognitively intact (e.g., non-transitioners; Class 0) and 17 MCI transitioners (Class 1) related to Go/No-Go and Code Substitution tasks. Go/No-Go Inter-Trial Intervals (ITI), REM sleep percentage, and maximum apnea duration were key predictors. Shorter, more stable ITI times (inter-trial intervals between tasks), higher REM sleep percentage, and shorter apnea durations were strongly correlated with non-transitioners. A 10-fold cross-validation yielded an average accuracy of 80.89%.

CONCLUSION: Our findings present an ongoing effort on the potential of explainable AI to validate digital measures to identify those with MCI. While the current model effectively identifies prevalent non-transitioners, it remains limited in identifying prevalent transitioners. Future research will focus on refining model sensitivity and balancing classification performance.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/physiopathology
*Alzheimer Disease/diagnosis
Aged
*Biomarkers
Neuropsychological Tests
Sleep/physiology
Machine Learning
Aged, 80 and over

@article {pmid41512154,
year = {2025},
author = {Nudelman, KN and Russ, KA and Edler, MC and Faber, KM and Dage, JL and Meyer, JS and Oblak, AL and Foroud, TM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107593},
doi = {10.1002/alz70856_107593},
pmid = {41512154},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/genetics/diagnosis ; *Biological Specimen Banks ; *Dementia/genetics ; },
abstract = {BACKGROUND: The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) supports the etiology, early detection, and therapeutic development for Alzheimer's disease and related dementias (ADRD). One of the goals of NCRAD is to continue to offer high-quality biobanking, biospecimens, standardized ADRD biomarkers, and support for investigators utilizing cutting-edge methods and assays to advance ADRD research.

METHOD: NCRAD currently funds sample processing and banking for ADRD studies, and for AD Research Centers (ADRCs), supports generation of APOE genotype, plasma-based ADRD biomarkers, and supplemental GWAS data. Rigorous quality control ensures the highest quality biospecimens are processed, banked, and distributed, including: sample tracking; DNA and RNA quality measurements; hemoglobin contamination assessment; DNA fingerprinting to assess sample quality and identity; and whole genome sequencing (WGS) data generated for all banked induced pluripotent stem cell (iPSC) lines. Genetic and biomarker data is shared with data repositories including the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and the National Alzheimer's Coordinating Center (NACC).

RESULTS: NCRAD currently banks samples for more than 80 studies, including samples from >130,000 participants with sample types including DNA, RNA, whole blood, plasma, serum, CSF, brain tissue, stool, peripheral blood mononuclear cells (PBMCs), lymphoblast cell lines, fibroblasts, and iPSCs. More than 15,000 samples are from paired visits with more than one sample type available, and many studies bank samples from longitudinal participant visits. The repository distributed 20,000 uniform sample collection kits and received, processed, and stored more than 200,000 new aliquots in 2024. Approximately 440,000 sample aliquots have been distributed to nearly 300 researchers thus far. To date, over 1,000 publications have been generated using NCRAD samples and data.

CONCLUSION: NCRAD has played a key role in development of best practices, protocol development, and uniform sample collection for ADRD studies. NCRAD continues to support cutting-edge research in genetics, genomics, and biomarker research and, more recently, implementation of the Alzheimer's Association Revised Criteria for diagnosing AD by making plasma biomarker data broadly available for ADRC participants. As such, NCRAD has and continues to play a vital part in the advancement of translational ADRD research.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/genetics/diagnosis
*Biological Specimen Banks
*Dementia/genetics

@article {pmid41512146,
year = {2025},
author = {Okamura, N and Ishiki, A and Hiraoka, K and Kobayashi, R and Tomita, N and Mesfin, B and Wu, Y and Harada, R and Kikuchi, A and Takeda, K and Kikuchi, A and Furukawa, K and Watabe, H and Mugikura, S and Kawakatsu, S and Ishii, K and Nihashi, T and Kato, T and Furumoto, S and Tashiro, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e107619},
doi = {10.1002/alz70856_107619},
pmid = {41512146},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Positron-Emission Tomography ; Aged ; *Alzheimer Disease/diagnostic imaging/metabolism/blood ; Biomarkers/blood ; *Cognitive Dysfunction/diagnostic imaging/metabolism/blood ; *Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Radiopharmaceuticals ; Middle Aged ; Glial Fibrillary Acidic Protein/blood ; tau Proteins/blood ; Thiazoles ; Aged, 80 and over ; Aniline Compounds ; },
abstract = {BACKGROUND: [[18]F]SMBT-1, a PET tracer targeting monoamine oxidase B (MAO-B), was developed to visualize reactive astrogliosis in the brain. This study investigated [[18]F]SMBT-1 binding in the brains of patients with Alzheimer's disease (AD) and its association with plasma biomarkers.

METHOD: We performed [[18]F]SMBT-1 scans in 35 healthy elderly controls (HCs), 44 patients with mild cognitive impairment (MCI), and 13 patients with Alzheimer's disease (AD). To compare the regional standardized uptake value ratio (SUVR) between the disease groups, 30-minute dynamic scans were conducted 60 min after administration of [[18]F]SMBT-1. PiB PET or flutemetamol PET was performed to confirm the presence of amyloid-β (Aβ) pathology in the brain. Plasma biomarkers (GFAP, pTau-217, NfL) were measured in 38 subjects who underwent SMBT-1 PET.

RESULT: Compared to the amyloid-negative HC and MCI groups, [[18]F]SMBT-1 accumulation was significantly increased in many brain regions, including the temporal, parietal, occipital, cingulate, and parahippocampal gyri, in amyloid-positive MCI and AD patients. These brain regions coincided with regions considered to be frequent sites of reactive astrogliosis in the AD continuum and overlapped with Aβ accumulation. Plasma GFAP was elevated in MCI and AD patients who showed the elevation of [[18]F]SMBT-1 binding in the neocortex.

CONCLUSION: [[18]F]SMBT-1 binding in the neocortex was elevated in patients with MCI and AD in association with Aβ accumulation, which is consistent with the results of plasma GFAP measurements. These findings suggest that [[18]F]SMBT-1 PET is a useful biomarker of reactive astrogliosis in the brain.},
}