@article {pmid41449469,
year = {2025},
author = {Lopes van den Broek, S and Eriksson, J and Yang, Q and Bucher, NM and Schlein, E and Balestri, LJI and Odell, LR and Sehlin, D and Syvänen, S},
title = {Pretargeted brain PET imaging reveals amyloid-β pathology using a TCO-modified antibody and a fluorine-18-labeled tetrazine.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {72},
pmid = {41449469},
issn = {2047-9158},
support = {2021-01083//Vetenskapsrådet/ ; 2021-03524//Vetenskapsrådet/ ; },
mesh = {Animals ; *Positron-Emission Tomography/methods ; *Amyloid beta-Peptides/metabolism ; Mice ; *Brain/diagnostic imaging/metabolism/pathology ; *Fluorine Radioisotopes ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Blood-Brain Barrier/metabolism ; Cyclooctanes ; Receptors, Transferrin/metabolism ; *Antibodies, Bispecific ; Radiopharmaceuticals ; Mice, Transgenic ; },
abstract = {BACKGROUND: Antibody-based positron emission tomography (PET) imaging holds great promise for visualizing disease-related proteins in the brain. However, its clinical utility is limited by poor antibody penetration across the blood-brain barrier (BBB) and the requirement for long-lived radionuclides due to slow antibody pharmacokinetics. Pretargeted imaging strategies, in which antibody administration and radioligand injection are separated in time, enable the use of short-lived, high-resolution PET-compatible radionuclides such as fluorine-18.

METHODS: A bispecific antibody, Bapi-Fab8D3, which targets both amyloid beta (Aβ) and the transferrin receptor (TfR) for TfR-mediated transport across the BBB, was conjugated with trans-cyclooctene (TCO) to enable in vivo click chemistry. Following antibody administration to Alzheimer's disease (AD) model mice and sufficient time for accumulation at intrabrain Aβ deposits, a fluorine-18-labeled tetrazine was injected to react in vivo with the TCO handles on the antibody. PET imaging, autoradiography, ex vivo quantification, and histological analyses were performed to evaluate the specificity and distribution of the imaging signal.

RESULTS: Bapi-Fab8D3 retained its binding affinity for both Aβ and TfR after TCO-conjugation. In brain sections, reactive TCOs were detected up to three days after antibody injection, indicating successful transcytosis across the BBB and stable target engagement. Pretargeted PET imaging after fluorine-18-labeled tetrazine injection revealed significantly higher signals in AD mice that received TCO-Bapi-Fab8D3 compared to wild-type controls or AD mice that received the unmodified antibody. The uptake pattern corresponded to Aβ plaque distribution, and quantitative analysis showed increased signal in AD-relevant brain regions including the hippocampus and thalamus.

CONCLUSIONS: This study demonstrates successful pretargeted PET imaging of brain Aβ pathology using a systemically administered bispecific antibody capable of BBB penetration and a fluorine-18-labeled tetrazine. These findings establish a generalizable strategy for high-contrast in vivo imaging of brain protein targets using pretargeted PET, with the potential to expand molecular imaging to protein targets in the brain that are currently inaccessible.},
}

Animals
*Positron-Emission Tomography/methods
*Amyloid beta-Peptides/metabolism
Mice
*Brain/diagnostic imaging/metabolism/pathology
*Fluorine Radioisotopes
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Blood-Brain Barrier/metabolism
Cyclooctanes
Receptors, Transferrin/metabolism
*Antibodies, Bispecific
Radiopharmaceuticals
Mice, Transgenic

@article {pmid41449466,
year = {2025},
author = {Malta, SM and Bernardes, LMM and Silva, MH and Santos, ACC and Batista, LL and Rodrigues, TS and do Prado Mascarenhas, FA and Zanon, RG and Espindola, FS and Mendes-Silva, AP and Ueira-Vieira, C},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103543},
doi = {10.1002/alz70859_103543},
pmid = {41449466},
issn = {1552-5279},
mesh = {*Amyloid beta-Peptides/metabolism ; *Peptide Fragments/metabolism ; *Kefir ; *Drug Development ; Animals ; *Neuroprotective Agents/pharmacology ; Peptides/pharmacology ; Humans ; Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Kefir is a probiotic-rich fermented milk beverage composed of a symbiotic consortium of bacteria and yeasts. Emerging evidence has shown its neuroprotective potential, including that of its derived metabolites and fractions, in mitigating β-amyloid (Aβ42)-induced neurotoxicity in cultured neuronal cells and neurodegeneration in Drosophila melanogaster models for Alzheimer's disease (AD). Building on these findings, we explored the in vitro effects of kefir-derived fractions and synthetic peptides on Aβ42 aggregation and disaggregation.

METHOD: Two kefir fractions, Ethyl Acetate (EtOAc) and <10kDa, and two kefir-derived peptides (KDPs) identified in our prior research were tested. For the preventive assay, Aβ42 (10 µM) was co-incubated with kefir fractions (0.25 mg/mL) or KDPs (1, 10 and 100 µM) for 24 hours, with fluorescence readings (Thioflavin T) taken hourly. For the treatment assay, Aβ42 was incubated alone for 48 hours to induce aggregation, followed by treatment with fractions or KDPs, with fluorescence readings taken after an additional 48-hour incubation. All experiments were performed in 96-well plates, with samples in quintuplicate. Statistical analysis was conducted using one-way ANOVA.

RESULT: Fluorescence intensity measurements revealed that, in the preventive assay, all treatments significantly reduced Aβ42 aggregation compared to the untreated control (p<0.0001). In the treatment assay, significant disruption of Aβ42 aggregation was observed with KDP-1 (p=0.0055) and KDP-2 (p<0.0001).

CONCLUSION: This study highlights the potential ability of kefir fractions and synthetic peptides to prevent and disrupt Aβ42 aggregation in vitro, supporting their therapeutic promise in neurodegenerative disorders. Further studies should explore their mechanisms of action and efficacy in vivo.},
}

*Amyloid beta-Peptides/metabolism
*Peptide Fragments/metabolism
*Kefir
*Drug Development
Animals
*Neuroprotective Agents/pharmacology
Peptides/pharmacology
Humans
Alzheimer Disease/drug therapy

@article {pmid41449453,
year = {2025},
author = {Altstiel, LD and Lamendola, M and Luca, W and Malefant, G and Gibbs, E and Kaplan, J and Cashman, N},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103159},
doi = {10.1002/alz70859_103159},
pmid = {41449453},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Drug Development ; Male ; Female ; Middle Aged ; Aged ; Adult ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: Toxic Aβ oligomers (AβO) are implicated in the progression of Alzheimer's disease (AD). PMN310 is a humanized IgG1 monoclonal antibody that binds to a computationally derived three-dimensional epitope specific to misfolded Aβ in AβO. Because PMN310 inhibits toxicity of AβO and does not bind to plaque, thereby potentially limiting risk of ARIA, it is being developed as a therapy for early AD. Results from a single ascending dose study of PMN310 (A Phase 1a Study of PMN310 In Healthy Volunteers NCT06105528) indicate that PK parameters and CSF concentrations of PMN310 were linearly dose-dependent and CSF concentrations were 100-600 times the estimated AβO molar concentration. The plasma half-life (t ½) was approximately 17.5 days and the CSF t ½ was approximately 27 days.

METHODS: PRECISE-AD, NCT06750432, is a placebo-controlled, multiple-ascending dose study of PMN310 to evaluate safety, tolerability, PK, PD, and preliminary efficacy of multiple intravenous infusions of PMN310 in patients with early Alzheimer's disease. The study consists of three staggered dosing arms of 350 mg, 700 mg, 1400 mg. Patients will be randomized 3:1, PMN310: placebo and will receive either PMN310 or placebo once every 28 days for a total of 12 infusions. The study will enroll 128 patients with either Stage 3 or 4 AD. Diagnosis will be determined by clinical criteria, CSF and plasma biomarkers, and Aβ PET. MRI scans will be done at months 2, 4, 6, 9, 12 to detect potential ARIA. Plasma biomarkers (pTau217, pTau 243, GFAP, SNAP25, neurogranin, Aβ42/Aβ40, NfL) will be measured at baseline and at 3-month intervals. Biomarkers in CSF will be measured at baseline, 6, 12 months. Cognitive outcomes (CDR-SB, ADAS-cog, ADAS-ADL IADRS Clinical Impression of Change) will be assessed at baseline, month 6 and month 12.

RESULTS: The proposed study has sufficient power to detect at least one ARIA event. The proposed sample size has sufficient power to provide statistically meaningful insight into effects of PMN310 on biomarkers and clinical outcomes.

CONCLUSIONS: PRECISE-AD will be the first study to examine the effects of a monoclonal antibody directed solely against AβO on biomarkers associated with AD pathology and clinical outcomes.},
}

Humans
*Alzheimer Disease/drug therapy/cerebrospinal fluid
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics
*Amyloid beta-Peptides/cerebrospinal fluid
*Drug Development
Male
Female
Middle Aged
Aged
Adult
Dose-Response Relationship, Drug

@article {pmid41449442,
year = {2025},
author = {Darwish, M and Mason, JW and Stanworth, SW and Feng, X and Dirks, B and Raether, B and Pathak, SS},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105893},
doi = {10.1002/alz70859_105893},
pmid = {41449442},
issn = {1552-5279},
mesh = {Humans ; Double-Blind Method ; Male ; Female ; Electrocardiography/drug effects ; Adult ; Middle Aged ; *Drug Development ; *Long QT Syndrome/chemically induced ; Healthy Volunteers ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: QT interval prolongation is a known adverse event of many psychotropic medications. ACP-204, a potent and selective inverse agonist/antagonist of serotonin 2A (5-HT2A), was developed for the treatment of Alzheimer's disease psychosis to have an improved pharmacological profile and lower risk of QT prolongation. This study evaluates the effect of ACP-204 on corrected QT (QTc) intervals and the relationship between plasma drug concentrations and time-matched change in QTc following single doses in healthy volunteers.

METHOD: QTc intervals were analyzed from randomized, placebo-controlled, double-blind, Phase 1 data in which healthy adult participants were randomized to single ascending oral doses of ACP-204 (10 to 180 mg) or placebo. Data from 12-lead electrocardiogram (ECG) assessments at screening, baseline, and up to 48 hours postdose were used to evaluate changes from baseline in Friderica-corrected QT (ΔQTcF) intervals. Concentration-effect modeling was used to analyze the relationship between plasma drug concentrations and time-matched changes in QTcF. QTc interval assessments were summarized descriptively and categorically.

RESULT: This analysis included 57 participants. A ΔQTcF >30 ms and ≤60 ms was observed in 1 participant in each of the 60, 130, and 180 mg cohorts; 1 participant in the 40 mg cohort had a ΔQTcF >60 ms. The QTcF interval did not exceed 450 ms at any time point for any participant, and no dose-response pattern was observed (Figure 1). The Fridericia heart rate correction met adequacy criterion; 89.5% of participants had QTcF versus RR interval slopes <|0.045|, exceeding the 50% requirement (Figure 2). Changes observed using concentration-effect modeling were small and benign (Figure 3A-B). After subtraction of placebo ΔQTcF, the upper limit of the confidence band remained below 10 ms throughout to the maximum observed concentration of ∼395 ng/mL. Model-predicted average placebo-adjusted ΔQTcF (ΔΔQTcF) at mean Cmax levels for all dose cohorts ranged from 3.17 ms (10 mg) to 0.47 ms (180 mg). The upper limit of the 2-sided 90% CI for ΔΔQTcF at 180 mg was 6.51 ms.

CONCLUSION: No meaningful increases in QTcF were observed in healthy participants after single-dose administration of ACP-204 (10-180 mg); specifically, there was no QTcF prolongation up to 180 mg.},
}

Humans
Double-Blind Method
Male
Female
Electrocardiography/drug effects
Adult
Middle Aged
*Drug Development
*Long QT Syndrome/chemically induced
Healthy Volunteers
Dose-Response Relationship, Drug

@article {pmid41449440,
year = {2025},
author = {Klein, G and Rabinovici, GD and Zetterberg, H and Tonietto, M and Bittner, T and Rukina, D and Alcaraz, F and Hofmann, C and Marchesi, M and Wojtowicz, J and Croney, R and Agnew, D and Abrantes, JA and Stark, FS and Ahlers, S and Delmar, P and Svoboda, H and Wiesel, I and Kulic, L},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104288},
doi = {10.1002/alz70859_104288},
pmid = {41449440},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; *Cognitive Dysfunction/drug therapy ; *Drug Development ; Male ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Female ; Aged ; Amyloid beta-Peptides ; Brain/diagnostic imaging/drug effects ; tau Proteins/cerebrospinal fluid ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: Trontinemab is a novel amyloid-targeting Brainshuttle™ monoclonal antibody specifically engineered for efficient transferrin receptor 1-mediated transport across the blood-brain barrier. It is currently under evaluation in the Phase Ib/IIa Brainshuttle™ AD study (NCT04639050) in participants with mild cognitive impairment due to Alzheimer's disease (AD) or mild-to-moderate AD.

METHOD: The Brainshuttle™ AD study is a randomized, double-blind, placebo-controlled, multiple ascending dose study designed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of trontinemab following intravenous (IV) infusion. The study uses a staggered parallel-group design, with participants recruited to four initial dose cohorts: 0.2 mg/kg (Cohort 1), 0.6 mg/kg (Cohort 2), 1.8 mg/kg (Cohort 3), and 3.6 mg/kg (Cohort 4). A minimum of 10 study participants per dose cohort are randomized in a 4:1 ratio to receive either trontinemab or placebo IV every 4 weeks for a total of seven doses in Part 1 of the study. In a dose-expansion study (Part 2), an additional 60 participants are enrolled in each of Cohorts 3 and 4. Biomarker results, including global and regional amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma will be presented. Plasma and CSF samples are analyzed using the Roche Elecsys NeuroToolKit.

RESULT: An interim analysis (data snapshot: Sep 2, 2024) revealed dose-dependent amyloid plaque lowering and downstream effects on biomarkers across all active doses. Part 1 Cohort 4 exhibited very rapid amyloid depletion: -89 centiloids after 12 weeks (n=13), and -107 centiloids after 28 weeks (n=12). CSF downstream markers including total tau, phosphorylated tau181, and neurogranin were reduced by 30%, 34%, and 29%, respectively by Week 25 in the 3.6 mg/kg dose cohort in Part 1. Updated results from the most recent data snapshot will include available 28-week PET data as well as MRI, CSF, and plasma results from Part 2 of the study.

CONCLUSION: Preliminary results from the ongoing Brainshuttle™ AD study suggest that rapid and deep amyloid reduction can be achieved in most participants at 1.8 and 3.6 mg/kg doses within ≤28 weeks. New biomarker data will be presented to further evaluate trontinemab's continued development as a potential AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy
Double-Blind Method
*Cognitive Dysfunction/drug therapy
*Drug Development
Male
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage
Female
Aged
Amyloid beta-Peptides
Brain/diagnostic imaging/drug effects
tau Proteins/cerebrospinal fluid
Dose-Response Relationship, Drug

@article {pmid41449438,
year = {2025},
author = {Gaster, B and Suchsland, MZ and Liao, JM and McKiddy, S and Fitzpatrick, AL and Belza, B and Raetz, JG},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101395},
doi = {10.1002/alz70858_101395},
pmid = {41449438},
issn = {1552-5279},
mesh = {Humans ; *Dementia/diagnosis/psychology/therapy ; Primary Health Care ; *Cognitive Dysfunction/diagnosis ; Electronic Health Records ; Male ; Female ; Aged ; },
abstract = {BACKGROUND: Primary care providers (PCPs) are at the forefront of evaluating cognitive concerns and detecting mild cognitive impairment and dementia, but they generally lack training and tools to do so.

METHOD: An intervention consisting of education webinars integrated with checklists in the electronic health record (EHR) and a set of exam room tools was developed and implemented across a large primary care system of 14 community-based clinics (94 PCPs). Outcomes from the EHR included the number of cognitive assessments recorded by PCPs in the EHR and the number of patients who received a new diagnosis of mild cognitive impairment or dementia.

RESULT: Over two years of the program, the average number of cognitive assessments entered by quarter into the EHR increased from 6.6 to 42.8 (p = 0.01). In addition, the average number of new diagnoses of mild cognitive impairment or dementia per quarter increased from 17.0 to 37.8 (p = 0.02). See Figures 1 and 2. Referrals to specialty care were reported as being more useful, because they more often included assessments of cognitive function and a review of potential reversible causes of cognitive impairment.

CONCLUSION: An intervention integrating PCP education with workflow tools increased cognitive testing and diagnoses of mild cognitive impairment and dementia in a large primary care health system. Such change is essential for patients to receive improved care for Alzheimer's disease and related dementias.},
}

Humans
*Dementia/diagnosis/psychology/therapy
Primary Health Care
*Cognitive Dysfunction/diagnosis
Electronic Health Records
Male
Female
Aged

@article {pmid41449430,
year = {2025},
author = {Liao, Y and Mu, G and Deng, S and Lu, B and Zheng, M},
title = {Role of TREM2 in neuroinflammation regulation: mechanisms, disease associations, and therapeutic translation advances.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-025-07604-x},
pmid = {41449430},
issn = {1479-5876},
}

@article {pmid41449362,
year = {2025},
author = {Mendes de Leon, CF and Elbejjani, M and Abdulrahim, S and Ghattas, H and El Sammak, A and Nassif, AA and Conrad, F and Nishimura, R and McCall, SJ and Sibai, AM and Chaaya, M},
title = {Cohort profile: the Lebanon Study on Aging and HeAlth (LSAHA).},
journal = {BMC public health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12889-025-25983-0},
pmid = {41449362},
issn = {1471-2458},
support = {R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; R01 AG069016/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: This paper describes the design and cohort profile of the Lebanon Study on Aging and HeAlth (LSAHA), the first population-level study of Alzheimer's Disease and Related Dementias (ADRD) in an Arab country. The burden due to ADRD in the Middle East and North Africa (MENA) region is among the highest in the world, but reliable population-level data on ADRD in the region are lacking. Older adults in Lebanon have experienced prolonged periods of social and economic instability due to political conflicts and chronic government mismanagement. The effects of these destabilizing experiences throughout the life course on ADRD risk and other late-life health outcomes are currently unknown.

METHODS: LSAHA is designed as a prospective cohort study of ADRD in a large sample of adults aged ≥ 60 years in Lebanon [baseline data presented here]. We employed a probability-based multi-stage sampling design in two pre-selected areas, the city of Beirut and district of Zahle, to represent the full range of urban-rural, socio-economic, and religious diversity in Lebanon. Data collection included a standardized survey questionnaire including validated cognitive tests and anthropometric measurements, a household interview, key informant assessments, and a blood sample. Survey weights were computed to account for differential non-response and calibrated for the age- and sex-distribution in the two study areas.

RESULTS: LSAHA enrolled 3,027 participants, 1,510 from Beirut and 1,517 from Zahle, realizing a response rate of 69%. The average age of the sample was 71.7 years and 55.3% was female, 43.1% had primary education or less, while 19.9% had university training. There was a high prevalence of chronic medical conditions, such as hypertension (57.2%), heart disease (32.4%), and diabetes (32.7%). There was also a high prevalence of moderate/severe symptoms of depression (51.4%) and anxiety (34.1%). A substantial percentage reported fair or poor self-rated memory (52.1%) or having worse memory compared to 2 years ago (38.4%).

CONCLUSIONS: We successfully launched a new cohort study of older adults in Lebanon to investigate ADRD and its risk factors. Data from this study will inform clinical care and policy goals in Lebanon and other settings that face a rapidly growing number of older adults with ADRD.},
}

@article {pmid41449323,
year = {2025},
author = {Ikhlas, R and Rashidi-Ranjbar, N and Churchill, NW and Graham, SJ and Schweizer, TA and Fornazzari, LR and Munoz, DG and Fischer, CE},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103663},
doi = {10.1002/alz70856_103663},
pmid = {41449323},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/blood/psychology ; Amyloid beta-Peptides/blood ; Aged ; tau Proteins/blood ; *Cognitive Dysfunction/blood ; Neurofilament Proteins/blood ; Glial Fibrillary Acidic Protein/blood ; Neuropsychological Tests ; Peptide Fragments/blood ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Neuropsychiatric Symptoms (NPS) in Alzheimer's Disease (AD) can exacerbate symptom burden and impair quality of life in patients. It is imperative to gain a better understanding of factors that contribute to NPS manifestation. This study explores the association between NPS scores and blood-based biomarkers implicated in AD including Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NFL), Amyloid Beta 40 (AB40), Amyloid Beta 42 (AB42), and Phosphorylated Tau at Threonine 181 (pTAU181).

METHODS: Individuals with a diagnosis of Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) were included based on data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) database. From 126 participants, 107 had completed the Neuropsychiatric Inventory Questionnaire (NPI-Q) and provided blood samples for measurement of GFAP, NFL, AB40, AB42, and pTAU181 plasma levels. To assess the association between NPS severity scores and blood-based biomarkers, a partial Spearman correlation was conducted; adjusting for age, sex, and education level. A False Discovery Rate (FDR) threshold of 0.05 was applied to all p-values to control for multiple comparisons.

RESULTS: We found significant correlations between several NPS domains and blood-based biomarkers. Apathy scores had a significant positive correlation with pTAU181 (Rs = 0.27, p =  0.04) and NFL plasma levels (Rs =0.30, p =  0.02); Anxiety scores showed a significant positive correlation with GFAP (Rs = 0.28, p =  0.03) and NFL plasma levels (Rs = 0.33, p =  0.006); Euphoria scores were positively correlated with NFL plasma levels (Rs = 0.27, p =  0.05); Appetite, Motor function, and Total NPI severity scores had a significant positive correlation with GFAP plasma levels (Rs = 0.31, p =  0.01; Rs = 0.31, p =  0.01; Rs = 0.29, p =  0.03). No significant findings were observed for AB40 and 42 with any NPS domain.

CONCLUSION: Our findings suggest that certain blood-based biomarkers-pTAU181, NFL, and GFAP- are associated with the development of NPS in Alzheimer's Disease. These biomarkers may help shed light on underlying mechanisms and monitor NPS severity. However, further research in larger cohorts and longitudinal studies is needed to confirm these findings and explore causal relationships.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/blood/psychology
Amyloid beta-Peptides/blood
Aged
tau Proteins/blood
*Cognitive Dysfunction/blood
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood
Neuropsychological Tests
Peptide Fragments/blood
Aged, 80 and over
Middle Aged

@article {pmid41449319,
year = {2025},
author = {Panda, S and Singh, SK and Bashir, B and Pal, B and Vishwas, S and Kaur, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102526},
doi = {10.1002/alz70859_102526},
pmid = {41449319},
issn = {1552-5279},
mesh = {Animals ; Rats ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Neuroprotective Agents/pharmacology ; *Drug Delivery Systems ; Oxidative Stress/drug effects ; *Quercetin/analogs & derivatives/pharmacology/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes. The disease is marked by the accumulation of amyloid-beta plaques and tau tangles, which disrupt neuronal function and lead to cell death. Neuroinflammation, oxidative stress, and synaptic dysfunction further contribute to AD pathology. Various studies evaluate the therapeutic properties of the phytoconstituents like curcumin, piperine, resveratrol, berberine and quercetin for the treatment of AD. Among these phytoconstituents, Isorhamnetin (IH) is reported to have neuroprotective effects against AD by inhibiting the expression of p-JNK, p-p38, and p-NFκB proteins. Studies showed that IH mediates a protective effect against oxidative stress and neuroinflammation. Despite its prospects, the therapeutic use of IH at target sites is limited due to their poor solubility, less bioavailability and poor blood brain barrier (BBB) penetration.

METHOD: To address these limitations, a IH loaded self-emulsifying drug delivery system (SNEDDS) was developed which improved drug loading, stability, bioavailability, and BBB permeability. Further, pharmacodynamic study were conducted using Morris Water Maize test to assess the cognitive performance of rats. Additionally biochemical assessment were performed to measure key markers of AD.

RESULT: The optimized IH-loaded SNEDDS formulation demonstrated a droplet size of 59.46 nm, polydispersity index of 0.3, zeta potential of -19 mV, and 96% drug loading respectively. Pharmacodynamic evaluations showed significant improvements in cognitive and motor functions in rats at high doses. Biochemical analysis revealed that the formulation effectively reduced AChE levels, amyloid-beta, oxidative stress, and neuroinflammation.

CONCLUSION: IH-loaded SNEDDS served as a therapeutic approach in the management of AD.},
}

Animals
Rats
*Alzheimer Disease/drug therapy
*Drug Development
*Neuroprotective Agents/pharmacology
*Drug Delivery Systems
Oxidative Stress/drug effects
*Quercetin/analogs & derivatives/pharmacology/administration & dosage
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Male

@article {pmid41449314,
year = {2025},
author = {Georgiou, E and Grigorova, P and Sen, SE and Miller, AM and O'Connor, A and Kinchin, I and Leroi, I},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101630},
doi = {10.1002/alz70858_101630},
pmid = {41449314},
issn = {1552-5279},
mesh = {Humans ; Ireland ; Feasibility Studies ; *Dementia/therapy/psychology ; *Alzheimer Disease/psychology/therapy/drug therapy ; Retrospective Studies ; Delivery of Health Care ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of cognitive decline, and the recent European approval of disease-modifying therapies (DMTs) like Donanemab and Lecanemab offers new hope for slowing its progression. However, healthcare systems across Europe, including Ireland, are unprepared for their real-world implementation. Challenges include equitable access, infrastructure readiness, and treatment logistics. This study aims to evaluate the feasibility of implementing DMTs across public and private healthcare sectors in Ireland, positioning it as a stepping stone toward broader European readiness.

METHOD: This multi-center observational feasibility study will assess DMT implementation readiness across Irish centers (Dublin, Waterford, Cork, Galway). The study employs patient journey mapping using retrospective and hypothetical data, alongside evaluations of key process measures, including referral timelines, biomarker verification, infusion readiness, and follow-up protocols. Graph-theory modeling will visualize patient pathways and highlight system inefficiencies.

RESULTS: The study is expected to reveal disparities in DMT access, logistical bottlenecks, and enablers for scalable implementation. Graph-based modeling will provide actionable insights to optimize patient pathways and healthcare delivery frameworks. Stakeholder feedback will inform patient-centered approaches and address equity challenges.

CONCLUSION: This feasibility study addresses the critical need for preparedness in integrating DMTs for AD, which were recently approved in Europe but remain underutilized due to systemic barriers. By generating actionable insights and laying the groundwork for national guidelines, this project not only advances Ireland's readiness but also serves as a model for other European countries seeking to adopt transformative therapies for Alzheimer's disease.},
}

Humans
Ireland
Feasibility Studies
*Dementia/therapy/psychology
*Alzheimer Disease/psychology/therapy/drug therapy
Retrospective Studies
Delivery of Health Care

@article {pmid41449308,
year = {2025},
author = {Fogel, A and Walsh, C and Fletcher-Lloyd, N and Ryten, M and Malhotra, P and Nilforooshan, R and Barnaghi, P and , },
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e102593},
doi = {10.1002/alz70858_102593},
pmid = {41449308},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/therapy ; *Activities of Daily Living/psychology ; *Quality of Life/psychology ; Male ; Female ; Longitudinal Studies ; Aged ; Aged, 80 and over ; Mental Status and Dementia Tests ; },
abstract = {BACKGROUND: As the population of people living with dementia (PLWD) increases, the need for scalable, high-quality, and personalised patient care will increase as well. A key consideration during dementia care planning is a patient's ability to perform activities of daily living (ADL), as this not only determines the level of care they require, but also directly impacts their independence and overall quality of life. However, despite considerable variability in trajectories of functional decline across PLWD, clinicians currently rely on experience and generalised statistics to inform care decisions. Thus, there is a need for more tailored approaches that predict how each patient's functional abilities will change over time. A data-driven decision support tool could address this gap by anticipating care needs, improving resource allocation, and supporting patient autonomy and quality of life.

METHOD: Longitudinal, observational data from 118 PLWD (761 assessments total) including clinical assessment, demographic, and medical history information was used. Clinical assessments included the Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Bristol Activities of Daily Living questionnaire (BADL), and comorbidities were classified according to ICD-10 chapters. A regression model was developed to predict functional decline over a 12-month period, as measured by BADL, in PLWD. To support explainability and use of this model in clinical settings, a digital consultation tool was developed.

RESULT: On average, participants declined at a rate of 4.2 (SD 5.7) BADL score-points per year. The best-performing machine learning model was a ridge regression model that predicted BADL scores 12 months in the future with a mean absolute error (MAE) of 4.0 (SD 0.4). Ability to prepare food and drink, presence of a cardiovascular or oncological comorbidity, and language abilities at baseline were found to be most predictive of 12-month functional decline in PLWD.

CONCLUSION: Our model, developed using readily available clinical features, is well-suited for implementation into UK memory clinics. A digital consultation tool was designed to enhance their clinical utility. Given the critical importance of predicting a person's future functional ability during care planning, this tool has the potential to augment care pathways by providing personalised prognostic insights into future care needs.},
}

Humans
*Dementia/psychology/therapy
*Activities of Daily Living/psychology
*Quality of Life/psychology
Male
Female
Longitudinal Studies
Aged
Aged, 80 and over
Mental Status and Dementia Tests

@article {pmid41449307,
year = {2025},
author = {Venkatesh, ML and Tarr, N and Coussoule, A and Scher, NR and Aibel, CR and Udeogu, O and Beltran, J and Mackin, SR and Marshall, GA and Munro, CE and Gatchel, JR},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105838},
doi = {10.1002/alz70857_105838},
pmid = {41449307},
issn = {1552-5279},
mesh = {Humans ; Aged ; Female ; Male ; *Patient Selection ; Aged, 80 and over ; *Dementia/psychology ; *Depression/psychology ; },
abstract = {BACKGROUND: Understanding the relationship between depression and dementia-two leading causes of morbidity and disability-is crucial. However, clinical research in this domain faces challenges related to recruitment and outreach, stigma, risk disclosure, and diversity. The Mood and Memory in Aging Study (MOMENT) at Mass General Brigham (MGB), a 5-year multimodal biomarker observational study of late-life depression and dementia risk, has employed various strategies to enhance recruitment and outreach. We summarize these approaches and discuss future directions for optimizing research in this field.

METHOD: Recruitment occurred in two phases: an initial K23-funded phase, and a second R01-funded phase that aimed to add 50 participants. Non-demented older adults with major or persistent depressive disorder and moderate to severe depressive symptoms were recruited. Strategies included digital platforms (participant databases, website sign-ups), clinician referrals, community outreach via social media, and partnerships with neurology clinical research cores. Participant demographics and engagement metrics from the second recruitment phase were analyzed to assess strategies and effectiveness.

RESULT: The second recruitment phase, initially projected to finish December 2024, concluded one month early due to enhanced efforts in 2024. Expanded methods-tables at clinics and community fairs, a clinical research database of older adults interested in aging and dementia research, recruitment websites, Craigslist/newspaper ads, and referrals from MGB clinics and the Massachusetts Alzheimer's Disease Research Center-together boosted weekly call volume by 36% relative to 2023. Effective methods included clinician referrals (39.42%), recruitment websites (25.96%), clinical research databases (16.34%), ads (8.65%), websites (5.77%), tabling (0.96%). 56 participants were enrolled, with a 22.2% screen-fail rate and a ∼85% retention. Study time commitment, travel, and reluctance to complete neuroimaging were among barriers to recruitment and retention.

CONCLUSION: We employed a multi-faceted strategy integrating clinician referrals, advertisements, and partnership with registries to efficiently meet recruitment milestones. Challenges including limited enrollment of Hispanic/Latino or severely symptomatic individuals, and attitudes towards neuroimaging highlight the need to optimize methods to address health disparities. Future efforts including translation of study documents, expanded database queries, and options for non-imaging participation will improve outcomes and enhance understanding of depression and AD risk.},
}

Humans
Aged
Female
Male
*Patient Selection
Aged, 80 and over
*Dementia/psychology
*Depression/psychology

@article {pmid41449301,
year = {2025},
author = {Moughamian, A and Kile, S and Kim, J and Sengupta, A and Pickett, A and Cheung, J and Urban, T and Zhao, C and Vallee, L and Mukundan, G and Sudat, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102433},
doi = {10.1002/alz70859_102433},
pmid = {41449301},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Aged, 80 and over ; *Cognitive Dysfunction/drug therapy ; Middle Aged ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Lecanemab was the first disease modifying therapy for Alzheimer's disease to receive full FDA approval but is associated with the serious side-effect of ARIA (amyloid related imaging abnormalities). Due to the novelty of lecanemab and ARIA, uncertainty exists regarding the frequency and severity of ARIA in clinical practice. Here we summarize our experience with lecanemab in a community-based healthcare system.

METHOD: Data collection was approved by the Sutter Health IRB. All subjects were screened at a memory clinic. Eligibility for treatment was determined by the FDA labelling and Appropriate Use Recommendations were followed with a few exceptions. We present data on patients who received lecanemab between July 2023 and June 2024 since these patients received at least 6 months of lecanemab treatment, the highest risk time for ARIA.

RESULT: 210 patients were treated; the mean age was 75, 52% female, 70% mild cognitive impairment and 30% mild dementia. 37% were ApoE4 non-carriers, 56% ApoE4 heterozygotes and 6% ApoE4 homozygotes. 36% of patients experienced infusions reactions (91% mild, 8% moderate and 1% severe). Lecanemab was discontinued in 14% of patients. There were 5 deaths, none attributed to lecanemab treatment. There were 33 cases (15.7%) of ARIA including ARIA-E, ARIA-H and ARIA-E with ARIA-H. 29 (13.8%) had ARIA-H and 16 (7.6%) had ARIA-E. ARIA occurred in 8 of 78 ApoE4 non-carriers, 19 of 118 ApoE4 heterozygotes and 5 of 13 ApoE4 homozygotes. 8 cases of severe radiographic ARIA occurred (4 ApoE4 homozygotes, 3 ApoE4 heterozygotes and 1 ApoE4 non-carrier). 3 cases of ARIA were symptomatic. A majority of ARIA occurred in the posterior cortex and ARIA-H often occurred in the same region of ARIA-E.

CONCLUSION: Our data show that lecanemab can be safely delivered in a large community-based healthcare system. Compared to the phase 3 CLARITY-AD trial, we report higher rates of infusions related reactions but lower rates of ARIA. Our cohort contains fewer ApoE4 homozygotes (6%) compared to CLARITY-AD (16%) which likely reduces our ARIA rates. However, we observe lower rates of ARIA in ApoE4 non-carriers and ApoE4 heterozygotes compared to CLARITY-AD, supporting that lecanemab can be safely administered in a community setting.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/drug therapy
*Drug Development
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Aged, 80 and over
*Cognitive Dysfunction/drug therapy
Middle Aged
Apolipoprotein E4/genetics

@article {pmid41449296,
year = {2025},
author = {Lorincz-Comi, NJ and Cheng, F and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Pieper, AA and Haines, JL and Mina, C},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103217},
doi = {10.1002/alz70859_103217},
pmid = {41449296},
issn = {1552-5279},
mesh = {Humans ; *Genome-Wide Association Study ; *Alzheimer Disease/genetics/drug therapy ; Polymorphism, Single Nucleotide/genetics ; *Drug Development ; Neurons/drug effects/metabolism ; Proteomics ; },
abstract = {BACKGROUND: Progress toward identifying repurposed medicines to target Alzheimer's disease (AD)-associated genes has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies (GWAS). Gene-based association tests provide a more statistically powerful alternative to standard inference based on detecting AD-associated single nucleotide polymorphisms (SNPs), yet current approaches fail to leverage functional information from disease-relevant tissues.

METHOD: We developed a gene-based association test (GenT) which can integrate summary multi-omic data with large GWAS data to efficiently screen the genome for evidence of gene candidacy as an AD drug target. We leveraged brain cortex transcriptomic (eQTL) and proteomic (pQTL) data from ROSMAP, MetaBrain, and GTEx cohorts, as well as the largest AD GWAS to date, applying GenT to up to 18,273 genes. We experimentally evaluated one candidate in vitro using AD patient-derived iPSC neurons.

RESULT: We identified 151 druggable and potentially causal genes (e.g., RIPK2, NTRK1, RIOK1) associated with AD which were not within 1Mb of any known AD target from SNP-based inference in GWAS. 103 were identified using eQTLs (e.g., ACE, BIN1, TNKS) and 74 by pQTLs (e.g., CR1, ABO, CLU), of which 26 were shared by both. Over 95% of candidate targets were replicated using SNP-based causal inference from fine-mapping with SuSiE. Experimental assays demonstrated that the NTRK1 protein inhibitor GW441756 significantly reduced tau hyper-phosphorylation (including p-tau181 and p-tau217) in AD patient-derived iPSC neurons, thus providing mechanistic support for our predictions.

CONCLUSION: Our findings underscore the power and efficiency of gene-based association testing, integrating multi-omic information as a strategic and efficient tool for informed drug target discovery and validation based on human genetic and genomic data for AD and AD-related dementia if broadly applied. These findings additionally highlight the limitations of standard inference based on detecting disease-associated SNPs in GWAS, for which there is generally significantly less power than in gene-based testing.},
}

Humans
*Genome-Wide Association Study
*Alzheimer Disease/genetics/drug therapy
Polymorphism, Single Nucleotide/genetics
*Drug Development
Neurons/drug effects/metabolism
Proteomics

@article {pmid41449284,
year = {2025},
author = {Sinclair, LI and Morisaki, M and Henley, PP and Dempster, E and Ballard, CG and Lin, JT and Love, S},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105622},
doi = {10.1002/alz70857_105622},
pmid = {41449284},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/genetics/complications/pathology/psychology ; Aged ; *Depression/genetics/complications ; Aged, 80 and over ; *Brain/metabolism/pathology ; Microglia/metabolism ; United Kingdom ; },
abstract = {BACKGROUND: Depression in individuals with Alzheimer's disease (AD) is common, distressing, does not respond to currently available antidepressants and is inadequately understood. We aimed to identify patterns of differential gene expression in depression in AD compared to AD without depression, including the influence of depression genetic risk on gene expression.

METHOD: We identified individuals with AD +depression (n = 95) and AD without depression (n = 25) with tissue available from UK brain banks. Exclusion criteria included; other disorders known to affect cognition; major psychiatric disorder; significant depression prior to AD diagnosis; and a primary neuropathological diagnosis of a non-AD dementia. Depression was defined as a clinical diagnosis or GDS/CESD >7. Fill in genotyping was performed using UKBiobank axiom array and imputed using the Michigan Imputation server. PRS-depression was calculated using LDpred2. In the AD +depression group only the top (n = 29) and bottom tertile (n = 30) of PRS-depression were measured using microarray. Tissue from the superior frontal gyrus (SFG) and the anterior insula (AIns) was gently homogenised, FACS sorted into neuronal and microglial fractions and gene expression measured using a ClariomS Pico microarray, prior to analysis in TAC console (ThermoFisher). Covariates included age, sex, braak stage, postmortem delay, and RIN. Our a-priori power analysis found 30 per group gives 90% power to detect a 2-fold gene expression change. Our primary outcome was gene expression in neurons comparing AD +depression to AD no depression.

RESULT: Following quality control, microarray data was available for AIns microglia (n = 53), AIns neurons (n = 61), STG microglia (n = 61) and STG neurons (n = 65). No individual genes had an FDR adjusted p value <0.05. Gene set enrichment analysis (GSEA) in R identified significantly upregulated and downregulated pathways in both brain regions and cell types, as well as in most of the PRS comparisons in the secondary analysis. More pathways were differentially expressed in microglia than in neurons e.g. in the AIC microglia, 8 pathways were significantly upregulated and 25 downregulated in AD+ depression vs AD no depression.

CONCLUSION: Although no individual gene reached significance, by using GSEA we have identified pathways which may contribute to the development of depression in AD, particularly in microglia.},
}

Humans
Male
Female
*Alzheimer Disease/genetics/complications/pathology/psychology
Aged
*Depression/genetics/complications
Aged, 80 and over
*Brain/metabolism/pathology
Microglia/metabolism
United Kingdom

@article {pmid41449232,
year = {2025},
author = {Liu, M and Hu, HY and Fu, Y and Chi, HC and Huang, LY and Tan, L and Hu, H},
title = {Proteins Associated with Cognition in Amyloid-beta Positive Elders Based on Cerebrospinal Fluid Proteomics.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {327},
pmid = {41449232},
issn = {1559-1182},
support = {82271475//National Natural Science Foundation of China/ ; 82201587//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; *Proteomics/methods ; Male ; Female ; Aged ; *Cognition/physiology ; Cognitive Dysfunction/cerebrospinal fluid ; Alzheimer Disease/cerebrospinal fluid ; Aged, 80 and over ; Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid ; Disease Progression ; },
abstract = {In the pathogenesis of Alzheimer's disease (AD), amyloid-beta (Aβ) is widely recognized as a core pathological hallmark and an upstream factor contributing to cognitive decline. However, not all individuals with Aβ pathology inevitably develop cognitive impairment or progress to AD. To date, the key proteins associated with cognitive progression in Aβ-positive (A +) individuals have not been fully identified. This study aimed to identify such proteins in A + participants, defined by cerebrospinal fluid (CSF) Aβ42 levels and Aβ positron emission tomography (PET) imaging, using CSF proteomics. We analyzed 6,361 CSF proteins from 490 A + participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Baseline differences in protein expression were examined between the A + with AD dementia group and the A + non-demented group, which included cognitively normal (CN) and mild cognitive impairment (MCI) participants. Associations between dysregulated proteins and both cognitive progression and diagnostic conversion were investigated using linear mixed-effect (LME) and Cox proportional-hazard models, with a mean follow-up of 3.65 years. Functional enrichment was assessed through Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. We identified 61 dysregulated proteins, including 47 upregulated and 14 downregulated, in the A + with AD dementia group compared with the A + non-demented group. Of these, 39 key proteins (significantly associated with all five cognitive scales and diagnostic conversion) and 14 candidate proteins (associated with at least one cognitive measure) were linked to cognitive progression. Notably, 14-3-3 proteins (YWHAG, YWHAZ, YWHAB) were strongly associated with cognitive decline, particularly in the early stage of AD, and YWHAG, MMP10, and NEFH were associated with a higher risk of cognitive diagnostic conversion than classical CSF AD biomarkers. GO enrichment analysis revealed that these dysregulated proteins were significantly enriched in pathways related to cognition, learning, or memory. These findings may provide potential targets for early diagnosis and therapeutic intervention in AD.},
}

Humans
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
*Proteomics/methods
Male
Female
Aged
*Cognition/physiology
Cognitive Dysfunction/cerebrospinal fluid
Alzheimer Disease/cerebrospinal fluid
Aged, 80 and over
Positron-Emission Tomography
Biomarkers/cerebrospinal fluid
Disease Progression

@article {pmid41449192,
year = {2025},
author = {Zhang, F and Yang, W and Sun, R and Duan, X and Yang, Y and Wang, A and Tian, Y},
title = {Cytokine-Microglia Interactions in Neuroinflammation: Mechanisms, Disease Dynamics, and Therapeutic Strategies.},
journal = {Antioxidants & redox signaling},
volume = {},
number = {},
pages = {},
doi = {10.1177/15230864251401591},
pmid = {41449192},
issn = {1557-7716},
abstract = {Neuroinflammation contributes to the onset and progression of a variety of central nervous system (CNS) diseases, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, intracerebral hemorrhage, and neurodevelopmental disorders related diseases. Microglia are essential for the neurodevelopment of a healthy brain and the integrity of the blood-brain barrier. Activation of microglia is the brain's defense mechanism against damaged tissues and harmful pathogens. However, their activation can trigger neuroinflammation, which can exacerbate or induce damage to the CNS. Cytokines are small proteins that can act in either an autocrine or paracrine manner. Cytokines are highly expressed in microglia and are potential mediators of neuroinflammation. We review the recent research progress on the role of cytokines such as interleukin-1 (IL-1β), tumor necrosis factor-α , IL-6, IL-4, and transforming growth factor-β in regulating neuroinflammation in various CNS diseases. Understanding how these cytokines affect microglia-mediated neuroinflammation will provide important therapeutic insights for preventing and managing CNS dysfunction, with potential clinical relevance for developing targeted anti-inflammatory therapies and biomarker-based diagnostic strategies. Antioxid. Redox Signal. 00, 000-000.},
}

@article {pmid41449139,
year = {2025},
author = {Marco, M and Tella, SD and Wright, LM},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105557},
doi = {10.1002/alz70857_105557},
pmid = {41449139},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/psychology/physiopathology ; *Cognitive Dysfunction/psychology/physiopathology ; Neuropsychological Tests ; Aged ; },
abstract = {BACKGROUND: We ran a meta-analysis to characterise clustering and switching abilities of adults with mild cognitive impairment and Alzheimer's dementia (MCI/AD), during their Category Fluency (CF) performance.

METHOD: A bibliographical search was carried out in Web of Knowledge, MEDLINE, CINAHL Plus, APA PsycArticles, APA PsycINFO and Academic Search Complete databases, via Web of Science, Pubmed, Ebsco Host and Ovid. The search string included the terms "fluency", "cluster*" and a third one taken from a set of alternatives defining the conditions of interest (i.e., MCI/AD). A total of 428 unique entries were shortlisted. After screening and eligibility-checking procedures, 29 studies were retained for inclusion. Mean cluster size (MCS) and number of switches (NOS) were extracted as outcomes. Random-effect meta-analysis models were run using ProMeta3, to compare MCI/AD individuals and cognitively-healthy controls. Age, education, Mini Mental State Examination-equivalent (MMSE) scores, category type and standard CF counts were included as moderators.

RESULT: The meta-analysis of MCS included 2,066 controls and 1,672 MCI/AD individuals, and revealed that this latter cohort generated significantly smaller clusters (G = 0.30, p < 0.001). No publication bias was found (Egger's test's: p = 0.068), but the analyses were influenced by significant study-to-study heterogeneity (Q = 82.14, p < 0.001). No moderator analysis reached statistical significance. The meta-analysis of NOS included 3,632 controls and 1,778 MCI/AD individuals, and revealed that this latter cohort made significantly fewer switches (G = 0.85, p < 0.001). Further analyses indicated no evidence of publication bias (Egger's test's: p = 0.737), but significant study-to-study heterogeneity (Q = 203.34, p < 0.001). Standard CF counts and MMSE scores were reported as significant moderators, both as negative predictors of effect size.

CONCLUSION: CF MCS and NOS are significantly reduced among individuals with MCI/AD. Clustering is thought to be driven by automatic semantic processing, while switching is considered the controlled component of CF. People who generate larger clusters are able to retrieve more exemplars of a subcategory, while those who make more switches can identify (and "exploit") more thematic directions during the test. This highlights the role of both semantic knowledge and semantic control in CF decline in individuals with MCI/AD. Quantifying MCS and NOS can support the assessment of semantic processing when CF is administered.},
}

Humans
*Alzheimer Disease/psychology/physiopathology
*Cognitive Dysfunction/psychology/physiopathology
Neuropsychological Tests
Aged

@article {pmid41449132,
year = {2025},
author = {Bregman, N and Nathan, T and Shir, D and Hay-Levy, M and Trabulus, N and Bar-David, A and Wolpe, G and Abu-Awad, A and Alcalay, Y and Ash, E and Shiner, T},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102792},
doi = {10.1002/alz70859_102792},
pmid = {41449132},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides ; tau Proteins/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; *Drug Development ; Middle Aged ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Mental Status and Dementia Tests ; Apolipoprotein E4/genetics ; Treatment Outcome ; Follow-Up Studies ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a significant impact on patients and healthcare systems. Lecanemab, a monoclonal antibody targeting amyloid beta, has recently been approved for early-stage AD, offering potential for disease modification. This report examines the demographic characteristics, treatment responses, and safety profile of early-stage AD patients treated with Lecanemab at the Tel Aviv Medical Center (TLVMC), focusing on 6-month follow-up outcomes.

METHOD: Since November 2023, Lecanemab has been administered to early-stage AD patients at TLVMC. Data collected included baseline demographics, ApoE4 status, CSF biomarkers (t-tau, p-tau181, Aβ42), plasma p-tau181 levels, and Mini-Mental State Examination (MMSE) scores. Patients were monitored for amyloid-related imaging abnormalities (ARIA), and cognitive outcomes were assessed at 6 months. This report summarizes data for patients who completed the 6-month follow-up by January 2025.

RESULT: By January 2025, 45 out of 85 patients had completed the 6-month visit. The mean age was 73 years (SD = 7.2), with 53% women and 51% ApoEε4 carriers. Mean baseline CSF biomarker levels (pg/ml): t-tau = 580 (SD = 268), p-tau181 = 194 (SD = 461), and Aβ42 = 333 (SD = 166). Plasma p-tau181 levels (n=27) had a mean value of 32.3 pg/ml (SD = 10.5). The mean baseline MMSE score was 24.02 (SD = 2.59). Plasma p-tau181 levels were significantly correlated with baseline MMSE scores (r = -0.429, p = 0.023). At 6 months, the mean MMSE score decreased to 22.48 (SD = 3.92), a significant decline of 1.47 points from baseline (p = 0.009). Younger patients (<75 years) showed a statistically significant decline in MMSE score (p = 0.007), while older patients (≥75 years) did not. Seven patients (15.5%) developed asymptomatic ARIA-H during the first 6 months.

CONCLUSION: This 6-month follow-up highlights Lecanemab's potential to preserve cognitive function in early-stage AD, with a lower incidence of ARIA than reported in trials. These findings emphasize the importance of real-world evidence in shaping clinical practice for disease-modifying therapies.},
}

Humans
Female
Male
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Aged
Amyloid beta-Peptides
tau Proteins/cerebrospinal fluid/blood
Biomarkers/cerebrospinal fluid/blood
*Drug Development
Middle Aged
Aged, 80 and over
*Antibodies, Monoclonal, Humanized/therapeutic use
Mental Status and Dementia Tests
Apolipoprotein E4/genetics
Treatment Outcome
Follow-Up Studies

@article {pmid41449130,
year = {2025},
author = {Mares, JA and Guo, J and Nuriel, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103473},
doi = {10.1002/alz70856_103473},
pmid = {41449130},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging ; Male ; *Apolipoprotein E4/genetics ; Female ; Magnetic Resonance Imaging ; *Biomarkers ; Aged ; Positron-Emission Tomography ; Neuroimaging ; *Brain/diagnostic imaging/pathology ; *Cognitive Dysfunction/genetics/diagnostic imaging ; tau Proteins/metabolism ; Heterozygote ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Carriers of the apolipoprotein E ε4 (APOE4) allele are at an increased risk of developing Alzheimer's disease (AD) and display an earlier age of onset compared to non-carriers who develop the disease. While researchers have extensively characterized the impact of APOE4 on the susceptibility of AD, little is known about the differences in disease etiology and presentation in APOE4 carriers vs. non-carriers.

METHOD: In order to investigate these differences, we performed a broad analysis of neuroimaging biomarkers in APOE4 carriers vs. non-carriers present in the ADNI cohort. We also have analyzed this data using a novel deep learning method called DeepContrast, which uses artificial intelligence to identify functional brain activity signatures in structural MRI scans.

RESULT: We observed differences between APOE4 carriers vs. non-carriers in several neuroimaging readouts, including Ab-PET, Tau-PET, FDG-PET, structural MRI, and FLAIR MRI. These differences were variable based on sex and age. Interestingly, when we compared cognitively unimpaired ADNI participants who converted to MCI or AD to those who did not, we observed APOE4-dependent differences that may point to specific pathologies that mediate MCI/AD conversion in APOE4 carriers vs. non-carriers. In addition, we also have exciting new data showing distinct differences in APOE4 carriers vs. non-carriers from ADNI using DeepContrast.

CONCLUSION: These observations of pathological heterogeneity between APOE4 carriers vs. non-carriers reveal significant differences in disease pathogenesis between these two groups, which may have important implications with regard to the diagnosis and treatment of AD in different at-risk populations.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging
Male
*Apolipoprotein E4/genetics
Female
Magnetic Resonance Imaging
*Biomarkers
Aged
Positron-Emission Tomography
Neuroimaging
*Brain/diagnostic imaging/pathology
*Cognitive Dysfunction/genetics/diagnostic imaging
tau Proteins/metabolism
Heterozygote
Middle Aged
Aged, 80 and over

@article {pmid41449129,
year = {2025},
author = {Cruzalegui-Bazán, C and Castro-Suarez, P and Vilca-Salas, M and Luna-Peralta, G and Uriol-Alvino, S and Huaccho-Travezaño, H},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105263},
doi = {10.1002/alz70857_105263},
pmid = {41449129},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Cross-Sectional Studies ; Middle Aged ; Peru/epidemiology ; *Cognitive Dysfunction/epidemiology/diagnosis ; Aged, 80 and over ; Nutritional Status ; Mental Status and Dementia Tests ; Exercise ; },
abstract = {BACKGROUND: Cognitive decline, particularly in indigenous populations, is a significant concern for public health. The Shipibo-Konibo community in the Peruvian Amazon faces challenges such as limited access to healthcare and education, which may impact cognitive health. This study aims to develop a predictive model for cognitive function in older adults from this community to inform preventive measures and interventions for Alzheimer's disease and other cognitive disorders.

METHOD: A cross-sectional study was conducted with 79 older adults (aged 60+) from the Shipibo-Konibo community. Data collection was part of the CUMIS (Multidisciplinary University Research and Service Camp), organized by the Society of San Fernando and the Faculty of Medicine at the National University of San Marcos in December 2023. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Diabetes and hypertension were self-reported or confirmed through medical records, physical activity was measured using the International Physical Activity Questionnaire (IPAQ), depressive symptoms were assessed using the Geriatric Depression Scale (GDS), and nutritional status was evaluated using the Mini Nutritional Assessment (MNA). A linear regression model was used to develop a predictive model for cognitive performance, evaluating sociodemographic factors, lifestyle factors, medical history, and nutrition.

RESULT: The predictive model revealed that age negatively impacted cognitive function (p = 0.047), with older participants showing lower MMSE scores and higher GDS stages. Education emerged as the strongest positive predictor (p < 0.001), indicating that higher education levels protect against cognitive decline. Additionally, physical activity significantly enhanced cognitive function (p = 0.0017), and nutritional status showed a positive relationship with cognitive health (p = 0.035). Chronic conditions such as diabetes, hypertension, and substance use (alcohol/tobacco) did not significantly impact cognitive performance. The model explained over 60% of the variance in cognitive function, providing a robust tool for predicting cognitive decline.

CONCLUSION: The study emphasizes that age, education, physical activity, and nutritional status are critical predictors of cognitive function. These findings suggest that interventions promoting education, physical activity, and nutrition could mitigate cognitive decline in older adults, especially in underserved communities like the Shipibo-Konibo. The model offers a valuable tool for personalized care and health interventions aimed at preventing Alzheimer's disease.},
}

Humans
Female
Male
Aged
Cross-Sectional Studies
Middle Aged
Peru/epidemiology
*Cognitive Dysfunction/epidemiology/diagnosis
Aged, 80 and over
Nutritional Status
Mental Status and Dementia Tests
Exercise

@article {pmid41449128,
year = {2025},
author = {Lerch, O and Kala, D and Nedelska, Z and Hadzic, H and Otahal, J and Hort, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102261},
doi = {10.1002/alz70856_102261},
pmid = {41449128},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; Biomarkers ; *Alzheimer Disease/diagnostic imaging/pathology ; *Blood-Brain Barrier/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging ; Hippocampus/diagnostic imaging ; Middle Aged ; Aged, 80 and over ; *Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Blood brain barrier (BBB) dysfunctions is one of is one of the possible mechanisms contributing to onset of Alzheimer's disease (AD), a progressive neurodegenerative disease and a leading cause of dementia worldwide. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is an imaging technique allowing regional assessment of BBB breakdown by estimating local metrics of capillary permeability such as K-trans (volume transfer constant). We used DCE-MRI to examine BBB dysfunction in regions affected early in the course of AD - hippocampus, entorhinal cortex (EC) and basal forebrain (BF) nuclei.

METHOD: A group of 43 participants - 22 biomarker negative cognitively unimpaired (CU) individuals and 21 biomarker positive patients with mild cognitive impairment or dementia due to AD from Czech Brain Aging Study underwent DCE-MRI. K-trans maps were estimated using Patlak algorithm implemented within ROCKETSHIP software toolbox. Segmentations of hippocampal head, body and tail, anterolateral and posteromedial EC and BF nuclei were obtained using in house developed pipeline. Average K-trans values were extracted for each region. Regional differences in BBB permeability between groups were assessed using ANCOVA adjusted for age, sex and ApoE4 positivity.

RESULT: Participants in the AD group had lower mean K-trans in total BF (K-transCU= 0.573 x10[-3]min[-1]; K-transAD= 0.270 x10[-3]min[-1], p =  0.002), anterior-intermediate (K-transCU= 0.833 x10[-3]min[-1]; K-transAD= 0.291 x10[-3]min[-1], p =  0.002) and posterior (K-transCU = 0.536 x10[-3]min[-1]; K-transAD = 0.237 x10[-3]min[-1], p =  0.004) part of nucleus basalis Meynerti. There were no other significant differences between regional BBB permeability in measured structures (p >0.05) CONCLUSION: Our data show regional reduction in BBB permeability BF region but not other regions in patients with MCI due to AD and AD dementia. Regional BBB dysfunction may be one of the factors contributing to early AD related pathological changes in the BF area.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
Biomarkers
*Alzheimer Disease/diagnostic imaging/pathology
*Blood-Brain Barrier/diagnostic imaging
*Cognitive Dysfunction/diagnostic imaging
Hippocampus/diagnostic imaging
Middle Aged
Aged, 80 and over
*Brain/diagnostic imaging

@article {pmid41449127,
year = {2025},
author = {Villar, AA and Villino-Rodríguez, RA and Espinoza-Vinces, C and Pérez-Prol, C and Jimenez-Huete, A and Dominguez, P and Riverol, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102269},
doi = {10.1002/alz70859_102269},
pmid = {41449127},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Drug Development ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIAs) are complications associated with anti-amyloid therapy in Alzheimer's disease (AD). ARIAs include ARIA-edema (ARIA-E) and ARIA-hemorrhage (ARIA-H), which may present asymptomatically or with mild symptoms. Identifying risk factors, such as the ApoE4 genotype, and understanding the clinical course of ARIAs are critical for optimizing treatment outcomes in AD patients undergoing anti-amyloid therapy.

METHOD: A retrospective observational analysis was conducted on data from patients participating in clinical trials involving anti-amyloid antibodies (Aducanumab, Gantenerumab, Crenezumab). Demographic data, ApoE genotyping, cardiovascular risk factors, treatment initiation dates, and occurrence of ARIAs were recorded. ARIA events were classified as ARIA-E or ARIA-H, and associated symptoms, time of onset, and resolution were documented. Brain MRI was used to monitor ARIA progression and persistence.

RESULT: The study included 52 patients (mean age: 68.6 years; range: 52-85), 42.3% of whom were female. ARIAs were identified in 9 patients, accounting for 15 events: 7 treated with Aducanumab and 2 with Gantenerumab, while none occurred with Crenezumab. Among these, 5 cases involved ARIA-E, 9 involved ARIA-H, and 1 patient exhibited both. Most events were asymptomatic or associated with very mild symptoms, with no treatment discontinuation required. ARIA-E typically resolved spontaneously within 4-8 weeks, while ARIA-H persisted on follow-up MRIs. Events generally occurred between weeks 20 and 39 of treatment, with ARIA-H appearing later in some exceptional cases. A strong correlation with the ApoE4 genotype was observed, as most patients developing ARIAs carried at least one ApoE4 allele.

CONCLUSION: Patients undergoing anti-amyloid therapy are at risk of developing ARIAs, particularly those carrying the ApoE4 genotype. ARIAs are generally asymptomatic, do not necessitate treatment discontinuation, and show differing courses depending on the subtype: ARIA-E resolves spontaneously, while ARIA-H persists. Aducanumab was associated with the highest frequency of ARIA events. These findings underscore the importance of regular MRI monitoring and patient-specific management strategies to mitigate complications and optimize therapy outcomes.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
Retrospective Studies
Middle Aged
Aged, 80 and over
*Drug Development
Magnetic Resonance Imaging
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Brain/diagnostic imaging

@article {pmid41449119,
year = {2025},
author = {Seo, EH and Yoon, HJ and Kim, SG and Choi, KY and Yi, S and Kim, J and Song, HC and Chong, A and Ha, JM and Won, S and Lee, KH},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102275},
doi = {10.1002/alz70856_102275},
pmid = {41449119},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis/diagnostic imaging/psychology ; *Neuropsychological Tests ; Aged ; Biomarkers ; Positron-Emission Tomography ; *Cognitive Dysfunction/diagnosis ; Reproducibility of Results ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Detecting subtle cognitive changes in the very earliest stages of Alzheimer's disease (AD) is a crucial issue. Advancements in computer technology have increasingly integrated into neuropsychological assessments. This study aims to develop a visual memory paradigm on a tablet platform, designed to facilitate the early cognitive detection of AD.

METHOD: The GARD visual memory test is based on the delayed-matching-to-sample paradigm. The test includes three conditions: Color, Shape, and Color-Shape. The development of test followed approach: (1) A cognitive neuroscience paradigm guided the design of an initial item pool. (2) Parallel test sets were developed to minimize learning effects. (3) Extensive user testing and collaboration with experts in elderly user experience. We included 131 cognitively normal (CN) and 71 cognitively impaired (CI) participants from the Gwangju Alzheimer's Disease and Related Dementia (GARD) Cohort in Korea. A battery of neuropsychological test scores and standardized uptake value ratios (SUVR) from amyloid PET scans were collected. We performed ANOVAs, regression, Intraclass correlation (ICC), and Pearson correlation analyses to examine the reliability and validity of the test.

RESULT: All participants completed the visual memory test. All GARD visual memory test scores were significantly influenced by age and education, with no effects of gender observed. For reliability, ICC coefficients were significant across all test scores, ranging from 0.4 to 0.8. Regarding validity, visual memory scores were significantly correlated with paper-and-pencil measures of visual memory and global cognition. Time measurements showed significant correlations with paper-and-pencil psychomotor speed scores (all p < 0.001). All test scores were significantly different between CN and CI (all p < 0.001). Total and color score were negatively correlated, while Time measurements were positively correlated with SUVR.

CONCLUSION: Our preliminary results suggest that the GARD visual memory test is a reliable and valid tool for assessing visuospatial memory and detecting early cognitive changes in AD. The GARD visual memory test shows promise as a sensitive tool for detecting cognitive changes in preclinical AD. Continued development and validation, including pathological biomarker studies and longitudinal research, will further establish its utility in clinical and research settings for early AD detection.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis/diagnostic imaging/psychology
*Neuropsychological Tests
Aged
Biomarkers
Positron-Emission Tomography
*Cognitive Dysfunction/diagnosis
Reproducibility of Results
Middle Aged
Aged, 80 and over

@article {pmid41449117,
year = {2025},
author = {Sharma, A and Gupta, O and Ghosh, V and Arora, H and Gowda, P and Khan, M and Suresh, V},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106948},
doi = {10.1002/alz70857_106948},
pmid = {41449117},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Apathy ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are integral to Alzheimer's disease (AD) yet often go under-recognized, despite their profound impact on disease progression, patient outcomes, and care strategies.

METHOD: A systematic search was conducted in PubMed, EMBASE, SCOPUS, Ovid, and Web of Science up to January 19, 2025. Studies were included if they were original research with a cross-sectional or longitudinal design, involving patients with probable or possible AD diagnosed according to DSM-IV or NINCDS-ADRDA criteria, and reported the prevalence of NPS. The inverse variance method and Freeman-Tukey double arcsine transformation were used for the proportion analysis. For the odds ratio analysis, the inverse variance method (random effects model) was used with tau^2 estimated by the restricted maximum-likelihood estimator (RLE) and confidence intervals (CI) via Q-Profile.

RESULT: In our meta-analysis of neuropsychiatric symptoms in Alzheimer's disease (AD), we analyzed 400 studies with 3,189,267 observations and 306,880 events. The individual symptoms in decreasing order of their proportion were: Apathy (0.4748 [0.3875; 0.5630]), Irritability (0.4120 [0.3612; 0.4636]), Depression/Dysphoria (0.3802 [0.3253; 0.4366]), Agitation (0.3304 [0.2756; 0.3877]), and Anxiety (0.3072 [0.2541; 0.3629]). There was substantial heterogeneity across studies (I^2 = 99.9%). For deriving pooled odds ratios we analyzed 125 studies with a total of 266,938 observations for the odds ratio. None of the individual symptoms had a significant association. Aberrant motor behavior exhibited the highest association with AD (OR = 12.90 [0.63, 262.46]), followed by wandering (OR = 2.70 [0.06, 128.85]), psychosis (OR = 1.81 [0.37, 8.82]), delusions (OR = 1.52 [0.67, 3.44]), and apathy (OR = 1.33 [0.57, 3.12]). Substantial heterogeneity was observed (I[2] = 97.4%).

CONCLUSION: Our meta-analysis reveals that the most prevalent neuropsychiatric symptoms in Alzheimer's disease are apathy, irritability, and depression/dysphoria, with substantial heterogeneity across studies.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Apathy

@article {pmid41449116,
year = {2025},
author = {Clayton, B and Massey, SM and Chu, S and Mason, ER and Bissel, SJ and Bedford, LM and Rizzo, SJS and Mesecar, AD and Kaiser, BL and Lendy, EK and Lamb, BT and Palkowitz, AD and Richardson, TI},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103518},
doi = {10.1002/alz70859_103518},
pmid = {41449116},
issn = {1552-5279},
mesh = {Humans ; *Drug Development ; *Phospholipase C gamma/genetics/metabolism ; *Alzheimer Disease/drug therapy/genetics ; Animals ; Microglia/drug effects/metabolism ; Structure-Activity Relationship ; High-Throughput Screening Assays ; },
abstract = {BACKGROUND: The role of microglia in neuroinflammation is widely recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Genome-wide association studies have identified PLCγ2 as a key contributor, with specific variants conferring either risk or protection. Notably, the protective PLCγ2•P522R variant is associated with increased mRNA expression, protein levels, and innate activity, whereas the risk variant PLCγ2•M28L shows the opposite trend. Based on these findings, we hypothesize that small molecules capable of enhancing PLCγ2 expression or directly activating the protein could mimic the protective effects of the P522R variant. Such an approach may represent a promising therapeutic strategy to mitigate disease progression and cognitive decline in AD patients.

METHOD: We performed high-throughput screening including DNA Encoded Library (DEL) and Affinity Selection Mass Spectrometry (ASMS) using full-length protein to identify novel small molecules which bind to PLCγ2. Target engagement was confirmed using Differential Scanning Fluorimetry (DSF) and Cellular Thermal Shift Assay (CETSA). Structure activity relationship (SAR) studies were performed to synthesize analogs and optimize for binding and cellular pharmacology in IP-One and phagocytosis assays. Top compounds have been studied in vivo to assess pharmacokinetic properties as well as impact on neuroinflammation.

RESULT: Novel PLCγ2 activators have been discovered and preliminary optimization has been completed. These compounds have shown positive results for target engagement, biochemical activity, and cellular pharmacology. In silico predictions indicated the molecule structures are suitable CNS drug discovery program starting points.

CONCLUSION: Activation of PLCγ2 is a novel therapeutic strategy for treatment of AD. We identified structurally distinct molecular scaffolds capable of enzyme activation and cellular activity. Recommendations for use of probe molecules in target validation studies and the development of lead-like molecules for clinical studies will be made.},
}

Humans
*Drug Development
*Phospholipase C gamma/genetics/metabolism
*Alzheimer Disease/drug therapy/genetics
Animals
Microglia/drug effects/metabolism
Structure-Activity Relationship
High-Throughput Screening Assays

@article {pmid41449112,
year = {2025},
author = {Jung, JH and Kong, N and Lee, S},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104595},
doi = {10.1002/alz70857_104595},
pmid = {41449112},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Biomarkers/metabolism ; *Cognitive Dysfunction/metabolism/diagnostic imaging ; Cross-Sectional Studies ; Longitudinal Studies ; *Blood Pressure/physiology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Aging is accompanied by vascular changes, notably arterial stiffness, which is reflected by pulse pressure (PP). Elevated PP has been linked to cardiovascular and cerebrovascular diseases, as well as cognitive decline and dementia. However, its specific role in Alzheimer's disease (AD) development and progression remains underexplored. This study investigates the association between baseline PP and key AD biomarkers-amyloid-beta (Aβ) and tau deposition-and cognitive decline.

METHOD: This study utilized data from 1,690 cognitively unimpaired older adults participating in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Biomarkers were assessed using positron emission tomography (PET) imaging for Aβ and tau (n = 411) deposition. Cognitive function was evaluated using the Preclinical Alzheimer Cognitive Composite (PACC). Cross-sectional analyses were conducted to examine associations, with linear regression adjusted for age, sex, education, and APOE4 status.

RESULT: We revealed that elevated PP was significantly associated with increased global and inferior temporal tau deposition (standardized β = 0.11, p =  0.020; standardized β = 0.12, p =  0.012). Moreover, elevated PP was also associated with higher Aβ deposition (standardized β = 0.06, p =  0.011) and with lower PACC (standardized β = -0.05, p =  0.034). APOE4 status moderated the relationship between PP and tau deposition; in APOE4 carriers, higher PP was strongly associated with tau accumulation, while no significant relationship was observed in non-carriers.

CONCLUSION: These findings underscore the importance of arterial stiffness as a contributor to AD pathology and lower cognition, particularly in individuals with genetic susceptibility. By revealing how PP interacts with APOE4 to influence tau deposition, this study emphasizes the need for targeted interventions addressing vascular health to mitigate AD progression. Future research should further explore mechanisms linking vascular health and AD biomarkers to refine preventative strategies.},
}

Humans
Male
Female
Aged
*tau Proteins/metabolism
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Biomarkers/metabolism
*Cognitive Dysfunction/metabolism/diagnostic imaging
Cross-Sectional Studies
Longitudinal Studies
*Blood Pressure/physiology
Aged, 80 and over

@article {pmid41449110,
year = {2025},
author = {Mittler, B and Wang, Y and Reisman, J and Berlowitz, D and Morin, PJ and Zhang, R and Monfared, AAT and Zhang, Q and Xia, W},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107045},
doi = {10.1002/alz70857_107045},
pmid = {41449110},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis ; *Mental Status and Dementia Tests/statistics & numerical data ; Aged, 80 and over ; Neuropsychological Tests ; Severity of Illness Index ; Veterans ; Disease Progression ; },
abstract = {BACKGROUND: The Functional Assessment Screening Tool (FAST) evaluates functional changes over the course of Alzheimer's disease. This study aimed to evaluate the extent to which FAST scores correspond to cognitive disease staging by the Montreal Cognitive Assessment (MoCA) test.

METHOD: Paired MoCA and FAST scores were analyzed in patients with mild cognitive impairment (MCI) or Alzheimer's dementia (AD) in the Veteran's Affairs Healthcare System (2020-2024). FAST score stage cut-off means, standard deviations (SD), medians, and ranges were generated. Linear and repeated measures mixed effects analysis was performed adjusting for patient demographics.

RESULT: The study sample (N = 405) had a mean age of 77.9 years (95.6% men, 11.1% Black, and 6.2% Hispanic). MoCA cut-offs for Normal, MCI, Mild, Moderate, and Severe AD stages were ≥29, 26,18, 11 and ≤10, respectively. Corresponding mean (SD) and median FAST score cut-offs separating disease stages were: normal (n = 1), 2.0 and 2; MCI (n = 21), 3.3 (1.7) and 3; mild (n = 206), 3.8 (1.5) and 4; moderate (n = 118), 4.8 (1.4) and 5; severe (n = 59), 5.8 (1.0) and 6. FAST tests resulted in score ranges of 1-7 for MCI-moderate stages and 4-7 for severe AD. Of note, more than half the patients (n = 205) scored in the normal/preclinical ranges of FAST (1 or 2); while, only 1 patient scored normal on the MoCA. FAST linear least squares (LS) means were distributed as <3.6, 3.6-<4.0, 4.0-<5.1, 5.1-6.0, >6 for normal, MCI, mild, moderate, and severe stages projected by MoCA cut-offs, respectively (adjusted R-squared=0.25). The LS means from categorical regression were 2.8, 4.2, 4.5, 5.5, and 6.5, normal, MCI, mild, moderate, and severe stages, respectively (adjusted R-squared=0.24). Similarly, LS means from repeated measures analysis found FAST score ranges for normal to severe AD were <3.9, 3.9-<4.2, 4.2-<5.1, 5.1-5.9, and >5.9.

CONCLUSION: This study identified FAST score thresholds corresponding to clinical stages from normal to severe AD according to a regressional crosswalk with MoCA. FAST provides a global functional assessment; however, our data suggest that it may underestimate disease severity relative to MoCA. Nonetheless, FAST is widely used in clinical practice, providing an alternative clinical tool for staging disease progression.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/diagnosis
*Alzheimer Disease/diagnosis
*Mental Status and Dementia Tests/statistics & numerical data
Aged, 80 and over
Neuropsychological Tests
Severity of Illness Index
Veterans
Disease Progression

@article {pmid41449106,
year = {2025},
author = {de Oliveira Alves, J and Salomão, MHQC},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102310},
doi = {10.1002/alz70859_102310},
pmid = {41449106},
issn = {1552-5279},
mesh = {Humans ; *Antipsychotic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; *Drug Development ; Aggression/drug effects ; Psychomotor Agitation/drug therapy ; },
abstract = {BACKGROUND: Dementia affects approximately 47 million people globally. Behavioral and psychological symptoms of dementia (BPSD), such as agitation, aggression, delusions, and hallucinations, are common during the progression of the disease and directly impact the quality of life of patients, families, and caregivers (CALSOLARO, 2021; FRANCHI, 2016). This study analyzes pharmacological management strategies for these cases.

METHOD: A comparative analysis was conducted using three scientific articles from the Medline database that address pharmacological treatment in patients with dementia.

RESULT: Antipsychotics are frequently used to treat agitation, aggression, and psychosis in dementia. Typical antipsychotics: Haloperidol is widely used for delirium but presents a high risk of side effects, such as sedation, extrapyramidal symptoms, and increased mortality, being recommended only in emergencies (CALSOLARO, 2021). Atypical antipsychotics: These are more tolerable, with a lower incidence of extrapyramidal symptoms. Risperidone is effective in managing agitation and aggression (FRANCHI, 2016) and is indicated for moderate to severe Alzheimer's cases (CALSOLARO, 2021). Aripiprazole reduces psychotic symptoms with fewer side effects (MINTZER, 2007), while quetiapine is preferred for patients with Parkinsonian characteristics (CALSOLARO, 2021). However, the prolonged use of atypical antipsychotics is associated with increased mortality and cerebrovascular events (CALSOLARO, 2021). Antidepressants: SSRIs, such as citalopram, may help with agitation but carry the risk of cognitive decline and QT interval prolongation (FRANCHI, 2016). Acetylcholinesterase inhibitors and memantine: Rivastigmine and memantine reduce agitation and aggression; donepezil provides small improvements (FRANCHI, 2016). Analgesics: Paracetamol alleviates pain and reduces neuropsychiatric symptoms, while opioids decrease agitation (FRANCHI, 2016). Anticonvulsants: Carbamazepine showed limited benefits, but its tolerability restricts its use; valproate did not demonstrate efficacy (FRANCHI, 2016).

CONCLUSION: Pharmacological management should be individualized, considering symptoms, comorbidities, and frailty. Medications should be used at the lowest effective dose and for the shortest possible duration to minimize side effects.},
}

Humans
*Antipsychotic Agents/therapeutic use
*Dementia/drug therapy/psychology
*Drug Development
Aggression/drug effects
Psychomotor Agitation/drug therapy

@article {pmid41449105,
year = {2025},
author = {Gambhir, S and Singh, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102577},
doi = {10.1002/alz70859_102577},
pmid = {41449105},
issn = {1552-5279},
mesh = {Humans ; *Drug Development ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy ; Molecular Dynamics Simulation ; Thiadiazoles ; },
abstract = {BACKGROUND: Alzheimer's disease is an advanced neurodegenerative illness that disturbs cognitive and behavior. One of the cores neuropathologic findings of AD is generation of hyper-phosphorylated tau induced neurofibrillary tangles and Glycogen synthase kinase-3β is the main kinase for the same. Tideglusib, a drug which is under second phase of clinical trial, impedes the GSK-3β at therapeutically concentration and has been established to stop phosphorylation of tau.

METHOD: Further, attempts have been made to conduct investigation and achieve advancements on Tideglusib analogues, utilizing scaffold morphing and the designed analogues were further evaluated using varied in silico techniques like pharmacokinetic, molecular docking and molecular simulations studies.

RESULT: The designed molecules showed good interactions with the catalytic dyed residue (Asp228 & Asp32) of GSK-3β having drug like properties. The stability of ligand-protein complex was validated by using molecular dynamics studies in the time interval of 100ns.

CONCLUSION: This design strategy could be used for the lead optimization of GSK-3β Inhibitors and focusing attention on the exciting therapy could thus reap considerable clinical and economic rewards.},
}

Humans
*Drug Development
*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism
Molecular Docking Simulation
*Alzheimer Disease/drug therapy
Molecular Dynamics Simulation
Thiadiazoles

@article {pmid41449103,
year = {2025},
author = {Kim, F and Xi, T and Lee, HJ and Rock, JA and Kim, S and Choung, JJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107781},
doi = {10.1002/alz70859_107781},
pmid = {41449103},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Male ; Female ; Double-Blind Method ; Aged ; *Phosphodiesterase 5 Inhibitors/therapeutic use ; Biomarkers/blood ; tau Proteins/blood ; *Drug Development ; *Sulfonamides/therapeutic use ; Middle Aged ; Treatment Outcome ; Aged, 80 and over ; },
abstract = {BACKGROUND: AR1001 (mirodenafil), a second-generation oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a disease-modifying therapy for Alzheimer's disease (AD). The phase 2 trial (AR1001-ADP2-US01) aimed to evaluate the safety and efficacy of AR1001 in patients with mild to moderate AD. After 26 weeks of once-daily oral dosing, 10 mg and 30 mg AR1001 demonstrated acceptable safety profiles in this population. While there were no significant differences between the treatment groups for the primary endpoint, Alzheimer's Disease Assessment Scale, cognitive subscale 13 (ADAS-Cog-13) at Week 26, plasma ptau-181 and ptau-217 AD biomarkers were significantly reduced in the 30 mg group compared to placebo.

METHOD: In this double-blind, randomized, placebo-controlled, parallel-group trial, 210 patients diagnosed with mild to moderate AD were randomized to receive either placebo, AR1001 10 mg, or AR1001 30 mg. Participants were administered treatment once-daily for 26 weeks. Participants were diagnosed clinically based on 2011 National Institute of Aging and Alzheimer's Associations criteria and were allowed to be on concomitant AD medication such as acetylcholinesterase inhibitors and NMDA receptor antagonists with at least 3 months of stable dose prior to screening. Pre-specified subgroup analyses based on concomitant AD medication were conducted for ADAS-Cog 13 and key plasma biomarkers, including ptau-181 and ptau-217.

RESULT: Sixty-seven and 69 participants were assigned to the placebo and AR1001 30 mg groups, respectively. At baseline, 36 of 67 (51.4%) participants on placebo and 46 of 69 (65.7%) participants on 30 mg AR1001 were on concomitant AD medication. Participants without concomitant AD medication treated with AR1001 30 mg (monotherapy) demonstrated a statistically significant improvement of 4.019 points over baseline at Week 26 (p=0.012) on ADAS-Cog 13. AR1001 30 mg monotherapy group also demonstrated reductions of 1.361 pg/ml in plasma ptau-181 (p=0.023) and 0.426 pg/mL in plasma ptau-217 compared to placebo at Week 26.

CONCLUSION: The subgroup analysis of participants on AR1001 30 mg without concomitant AD medication suggests potential for AR1001 as a monotherapy for the treatment of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/blood
Male
Female
Double-Blind Method
Aged
*Phosphodiesterase 5 Inhibitors/therapeutic use
Biomarkers/blood
tau Proteins/blood
*Drug Development
*Sulfonamides/therapeutic use
Middle Aged
Treatment Outcome
Aged, 80 and over

@article {pmid41449102,
year = {2025},
author = {Li, D and An, B and Salisbury, DL and Lin, FV and Yu, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102229},
doi = {10.1002/alz70856_102229},
pmid = {41449102},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Female ; *Cognitive Dysfunction/blood/therapy ; Male ; Aged ; *Alzheimer Disease/blood/therapy ; tau Proteins/blood ; Brain-Derived Neurotrophic Factor/blood ; Insulin-Like Growth Factor I/metabolism ; Clusterin/blood ; Aged, 80 and over ; Insulin-Like Growth Factor Binding Protein 3/blood ; Glial Fibrillary Acidic Protein/blood ; Amyloid beta-Peptides/blood ; },
abstract = {BACKGROUND: It remains unclear whether blood biomarkers of Alzheimer's disease are surrogate endpoints for non-pharmacological interventions. The ACT Trial blood biomarker study aimed to evaluate neuropathological, neurotrophic, and neuroinflammation biomarkers as surrogate outcomes in older adults with mild cognitive impairment (MCI). This presentation assessed whether any ACT intervention group (ACT, cycling only, SOP only) had significant changes in biomarkers compared to the attention control group over 6 months. Also, we evaluated the effect sizes of interventions on blood biomarkers over 6 months.

METHOD: We collected blood samples from 95, 81, 76, 53, and 39 ACT Trial participants (n = 344) over five time points (baseline, 3, 6, 12, and 18 months). We biochemically analyzed neuropathological biomarkers (plasma Ab42, Ab40, NfL, p-Tau 217), neurotrophic biomarkers (plasma IGF-1, IGFBP-3, and serum free-BDNF), and neuroinflammation biomarkers (plasma GFAP and clusterin). We used mixed effects models to examine whether any intervention group was associated with a significant difference in biomarkers (3 or 6 months compared to baseline [i.e., 0-3 m or 0-6m]) compared to the control group. We also calculated effect size estimates (Cohen's d) for within-group differences in biomarkers.

RESULT: The mean (SD) age of the 102 participants with MCI was 73.83 (6.07) years old, 45.10% (46/102) female, and 34.31% (35/101, 1 missing) APOE4 carriers. There were no significant differences of 0-3 m or 0-6 m in biomarkers of any intervention group compared to that of the control. Most biomarkers had small within-group Cohen's d (less than 0.2) except 0-6 months plasma p-Tau 217 (d=0.27) and 0-6 m serum free-BDNF (d=0.71) in the control group.

CONCLUSION: We did not find a significant effect of interventions on blood biomarkers. Plasma p-Tau 217 and serum free-BDNF had small and moderate effect sizes to detect changes in the control group of older adults with MCI over 6 months, respectively.},
}

Humans
*Biomarkers/blood
Female
*Cognitive Dysfunction/blood/therapy
Male
Aged
*Alzheimer Disease/blood/therapy
tau Proteins/blood
Brain-Derived Neurotrophic Factor/blood
Insulin-Like Growth Factor I/metabolism
Clusterin/blood
Aged, 80 and over
Insulin-Like Growth Factor Binding Protein 3/blood
Glial Fibrillary Acidic Protein/blood
Amyloid beta-Peptides/blood

@article {pmid41449100,
year = {2025},
author = {Lizama, BN and Pandey, K and Cho, E and Caldwell, J and Caro, VD and Duong, DM and Shin, R and Levey, AI and Seyfried, NT and Grundman, M and Teunissen, CE and Caggiano, AO and Hamby, ME},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102120},
doi = {10.1002/alz70859_102120},
pmid = {41449100},
issn = {1552-5279},
mesh = {Humans ; Double-Blind Method ; Male ; Female ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Aged ; *Drug Development ; *Cognitive Dysfunction/drug therapy ; Receptors, sigma ; tau Proteins/blood/cerebrospinal fluid ; Middle Aged ; },
abstract = {BACKGROUND: Participants with Alzheimer's disease (AD) treated with sigma-2 receptor (S2R) modulator zervimesine (CT1812) exhibited slowing (39% in mITT, 95% in a pre-specified plasma-pTau217 subgroup (below-median at baseline)) of cognitive decline (ADAS-Cog11) compared to placebo in the SHINE trial (NCT03507790, COG0201). Given favorable clinical outcomes in the below-median pTau217 subgroup, correlation analysis of the CSF proteome with ADAS-Cog11 was performed to elucidate mechanisms of zervimesine-mediated preservation of cognition.

METHOD: SHINE was a Phase 2 randomized, double-blind, placebo-controlled study. Participants (N=152) received a daily oral dose of zervimesine (100 or 300 mg) or placebo for 6-months (end-of-study). The median baseline plasma-pTau217 concentration (ALZpath, SIMOA) designated participants into subgroups below median (<1 pg/mL, N=69) or above/equal median (≥1 pg/mL, N=69). A proteomics sub-study of 45 participants was performed (tandem-mass tag mass spectrometry, TMT-MS) of baseline and 6-month CSF. CSF from treatment-compliant participants (N=43 mITT, N=17 below-median) were used for further analyses. Pearson correlation analysis was performed with protein change-from-baseline (CFB) to ADAS-Cog11 CFB. Pathway analyses (STRING, Metacore) were performed on correlated proteins (p≤0.01).

RESULT: The previously-reported mITT CSF cognitive correlates were compared to those in the below-median pTau217 subgroup that demonstrated greater cognitive benefit with zervimesine versus placebo. In this subgroup, 106 proteins correlated with ADAS-Cog11 (p≤0.01), exhibiting enrichment in amyloid biology and immune response pathways (p≤0.05). To elucidate the biological underpinnings of robust pharmacodynamic correlates of cognitive improvement, pathway analysis was performed on 62 proteins that correlated with ADAS-Cog11 (p≤0.01) in both mITT and below-median pTau217 subgroup (excluding correlates (p≤0.01) in the subgroup that did not exhibit cognitive benefit with zervimesine). These 62 proteins were enriched in immune response, complement, and synapse biology pathways (FDR≤0.05).

CONCLUSION: In a pre-specified subgroup exhibiting 95% slowing of cognitive impairment with zervimesine, we identified protein correlates of cognition related to amyloid biology, supporting zervimesine mechanism of action. Enriching the mITT analysis with correlates from this biomarker-defined patient population reinforced observations of immune response and synaptic pathways that correlate with cognition in both mITT and below-median pTau217 subgroup. These biomarker findings paired with positive clinical outcomes support the further clinical development of zervimesine for AD.},
}

Humans
Double-Blind Method
Male
Female
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Aged
*Drug Development
*Cognitive Dysfunction/drug therapy
Receptors, sigma
tau Proteins/blood/cerebrospinal fluid
Middle Aged

@article {pmid41449096,
year = {2025},
author = {Tang, M and Kan, GL},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e102598},
doi = {10.1002/alz70858_102598},
pmid = {41449096},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged, 80 and over ; *Dementia/psychology/rehabilitation ; Nursing Homes ; Activities of Daily Living/psychology ; Aged ; *Exercise/psychology ; Hong Kong ; Mental Status and Dementia Tests ; Frail Elderly/psychology ; Cognition ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Physical activity is a promising clinical intervention for slowing the progression of Alzheimer's disease. But it understudied in people with frailty.

METHOD: A rehabilitation bike with immersive familiar VR streets in Hong Kong was provided for this physical activity intervention program. A total of 21 frail nursing home residents (age: mean = 81.17, sd = 9.06) with diagnosed or suspected dementia participated in a 12-week physical activity (PA) intervention program to verify if PA can improve cognition. All participants continued their standard care if any. Cognition (Montreal Cognitive Assessment/MoCA) and physical function (Activities of Daily Living/ADL-BI) were assessed before and after the intervention program.

RESULT: MoCA scores improved significantly following the 12-week physical activity intervention, increasing from a mean of 14.39 (SD 5.59) to 17.61 (SD 7.41), with a mean difference of 3.22 (p <0.001).

CONCLUSION: VR-based physical activity is an effective intervention for improving cognition in frail nursing home residents with diagnosed or suspected dementia. This results demonstrated the potential to slow the progression of AD.},
}

Humans
Male
Female
Aged, 80 and over
*Dementia/psychology/rehabilitation
Nursing Homes
Activities of Daily Living/psychology
Aged
*Exercise/psychology
Hong Kong
Mental Status and Dementia Tests
Frail Elderly/psychology
Cognition
Neuropsychological Tests

@article {pmid41449095,
year = {2025},
author = {Shivers, S and Cohen, O and Zimmer, V and Puca, A and Cisek, E},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101029},
doi = {10.1002/alz70858_101029},
pmid = {41449095},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/therapy ; Quality of Life/psychology ; *Cognitive Behavioral Therapy/methods ; Aged ; Caregivers/psychology ; Female ; Depression/therapy ; Male ; },
abstract = {Community-based organizations (CBOs) meet a plethora of older adult needs in contemporary society including programs for individuals living with Mild Cognitive Impairment, Alzheimer's and other dementias. With an established presence, trust and growing number of caregiving, health promotion and chronic disease management programs in place, CBOs are well positioned to implement evidence-based interventions (EBI) in the real world. With funding by the Administration for Community Living, Alzheimer's Disease Program Initiative, CaringKind, a dementia focused CBO, implemented evidence-based Cognitive Stimulation Therapy (CST) and evaluated program and participant outcomes. CST is a globally practiced small group multi-session EBI with demonstrated impact on cognition, depression and quality of life. Fourteen themed sessions delivered virtually or in-person by trained facilitators actively stimulate cognitive processes through dialogue and multi-sensory based activities. CaringKind's pre/post preliminary program data shows 76% (n = 153) of participants were 'completers' (attending 12+ program sessions); 48% of participants (n = 97) had decreased signs of depression on the Geriatric Depression Scale and 20% (n = 19) moved out of the depressed range; and 56% (n = 57) had increased hope and resilience on the Positive Psychology Outcomes Measure. Participant (n = 37) and proxy report (n = 38) qualitative surveys reveal positive impact on meeting current needs, connecting to peers, and perceived benefit for participant's future. Final data and outcomes will be presented at AAIC 2025. Lessons learned about barriers/facilitators to identify and enroll individuals in real-world dementia programs will be shared, as well as feasibility challenges associated with finding, training and funding qualified staff to deliver sustainable evidence-based programs as a CBO and service provider.},
}

Humans
*Dementia/psychology/therapy
Quality of Life/psychology
*Cognitive Behavioral Therapy/methods
Aged
Caregivers/psychology
Female
Depression/therapy
Male

@article {pmid41449094,
year = {2025},
author = {Aro, OP and Ogunsuyi, OB and Oboh, G},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106225},
doi = {10.1002/alz70859_106225},
pmid = {41449094},
issn = {1552-5279},
mesh = {Animals ; *Drug Development ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cockroaches ; *Brain/metabolism/drug effects ; *Antioxidants/pharmacology ; Streptozocin ; Seeds ; Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Diabetes is a major risk factor for Alzheimer's disease (AD), with shared pathological mechanisms including insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, and impaired brain energy metabolism. Chronic hyperglycemia accelerates cognitive decline by promoting amyloid-beta aggregation and tau hyperphosphorylation. Given the rising global prevalence of diabetes and its impact on neurodegeneration, plant-based interventions with antioxidant and metabolic-modulating properties hold promise for therapeutic development.

METHOD: Cockroaches were divided into six groups: control, STZ-induced, STZ+0.5% raw seeds, STZ+1% raw seeds, STZ+0.5% fermented seeds, and STZ+1% fermented seeds. Brain homogenates were analyzed for glucose, triglyceride, reactive oxygen species (ROS), and total thiol levels, biomarkers linked to metabolic and neurodegenerative disorders.

RESULT: STZ-induced cockroaches exhibited significant (p<0.05) elevations in glucose and ROS levels, along with a decline in total thiol content, indicative of oxidative damage. Treatment with tamarind seeds counteracted these effects, reducing ROS and glucose levels while increasing thiol content, suggesting enhanced antioxidant capacity. Survival rates were also improved in treated groups.

CONCLUSION: Tamarind seed supplementation mitigated metabolic stress and oxidative damage, processes central to both diabetes and AD progression. These findings underscore the therapeutic potential of tamarind seeds in modulating key metabolic and neuroprotective pathways relevant to AD. Further research is needed to explore their impact on amyloid-beta clearance, tau pathology, and neuroinflammatory responses in diabetic neurodegeneration models.},
}

Animals
*Drug Development
Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Cockroaches
*Brain/metabolism/drug effects
*Antioxidants/pharmacology
Streptozocin
Seeds
Alzheimer Disease/metabolism

@article {pmid41449092,
year = {2025},
author = {Valencia, DK and Silverman, W and Hartley, SL and Zaman, S and Brickman, A and Lai, F and Mapstone, M and Krinsky-McHale, SJ and Harp, JP and Lao, PJ and Lott, IT and Rosas, HD and Handen, BL and Christian, BT and Ances, B and Schmitt, FA and Hom, CL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105703},
doi = {10.1002/alz70857_105703},
pmid = {41449092},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Down Syndrome/complications/psychology ; Middle Aged ; Adult ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis ; Positron-Emission Tomography ; Disease Progression ; Prodromal Symptoms ; Biomarkers/blood ; Longitudinal Studies ; },
abstract = {BACKGROUND: 90% of adults with Down syndrome (DS) will develop Alzheimer's dementia (AD) in their lifetime, the majority within 3 years of symptom onset. However, clinicians need to be confident that declines are not temporary or due to treatable causes before diagnosing prodromal AD. The present study investigates the medical, psychiatric, and life factors associated with atypical cognitive decline in DS, a population with genetic risk for AD. We aim to identify factors that contribute to temporary or non-progressing cognitive decline over a three-year period.

METHOD: Thirty-eight adults with DS (ages 43 to 62) from the Alzheimer Biomarker Consortium in Down Syndrome (ABC-DS) were classified as having prodromal AD (MCI-DS) at one or more time points. AD clinical status was determined through a consensus process using only clinical and cognitive data. There were three trajectories based upon longitudinal data: (1) progressors (MCI-DS to dementia), (2) reverters (MCI-DS to cognitively stable), or (3) non-progressors (MCI-DS for 3 time points). Comorbidities and life stressors were collected through study partner interviews. Baseline amyloid PET scans and plasma AD biomarkers are used in the present study.

RESULT: Using chi-square and Kruskal-Wallis tests, non-progressors (n = 6, Mage = 48.67) were younger (p = .032), had lower centiloid values (p = .002) and had higher prevalence of seizure disorder (p = < .001), hearing impairment (p = < .001), and a friend move away (p = .027) than progressors (n = 26, Mage = 52.88). Reverters (n = 6, Mage = 49.17) had a higher incidence of psychotic disorder (p = .028) compared to non-progressors and progressors. Both atypical groups had lower incidence of COVID infection (p = .046), but still had high amyloid load (M=30.50CL and 48.02CL, respectively).

CONCLUSION: In our sample of adults with DS and MCI-DS, 31.6% did not progress to dementia despite having high levels of amyloid PET. Those whose decline plateaued had more medical conditions and life stressors. Those with temporary decline had more psychiatric problems. Primary care physicians need to understand which reversible or treatable factors are most likely to lead to a misdiagnosis of prodromal AD and address them accordingly.},
}

Humans
Female
Male
*Down Syndrome/complications/psychology
Middle Aged
Adult
*Cognitive Dysfunction/diagnosis
*Alzheimer Disease/diagnosis
Positron-Emission Tomography
Disease Progression
Prodromal Symptoms
Biomarkers/blood
Longitudinal Studies

@article {pmid41449091,
year = {2025},
author = {Wang, L and Park, E and He, C and Abbasi, AZ and Rajakumar, RCJ and Huang, S and Fraser, PE and Henderson, JT and Wu, XY},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104173},
doi = {10.1002/alz70859_104173},
pmid = {41449091},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Nanoparticles ; *Drug Development ; Brain/metabolism ; Manganese Compounds ; Blood-Brain Barrier/metabolism ; Humans ; Neuroinflammatory Diseases ; },
abstract = {BACKGROUND: Neuroinflammation plays a causal role in neurodegenerative Alzheimer's disease (AD); it occurs long before clinical onset of AD.[1] Therefore, early detection of neuroinflammation is critical for early intervention before the irreversible neurodegeneration happens. To address this pressing need, our group has developed multifunctional bioreactive nanoparticles, consisting of blood-brain barrier-penetrating terpolymer and MnO2 nanoparticles and conjugated anti-Ab antibody (Ab-TP-MDNP). The system reduced oxidative stress and produced oxygen and paramagnetic Mn[2+] ions, thereby remodeling the brain microenvironment and enabling sensitive detection of early neuroinflammation prior to Ab plague formation in an APP transgenic TgCRND8+ AD mouse model.[2] We also demonstrated its effects on improving vascular functions, Ab elimination, energy metabolism, neuronal activity and cognitive function.[3-4] Built on the foundation of previous findings, we investigate whether the TP-MDNP is able enhance early detection of neuroinflammation regardless of Aß or tau expression and evaluate its therapeutic effect in AD mouse model of tauopathy.

METHOD: Three types of transgenic mouse model of AD, TgCRND8+, PS19 with tauopathy, and APP/PS1 were used in the MRI study. The diagnostic performance of Ab-TP-MDNP in MRI was also compared with PET imaging using F18-florobetaben in TgCRND8+ mice. PS19 mice were treated with IV injection of TP-MDNP for two weeks (2/week, 100 μmol Mn/kg b.w.) and the biomarkers for ROS, neuroinflammation, and p-Tau expression were examined using immunohistochemistry and ELISA.

RESULT: Ab-TP-MDNP enhanced MRI signal significantly outperformed PET imaging by Ab-targeted F18-florobetaben in TgCRND8+ mice of 3 months and 6 months of age. Similar MRI imaging sensitivity was observed in PS19 and APP/PS1 mice with or without conjugated antibody against Ab or tau protein, suggesting the neuroinflammation activated MRI contrast enhancement as a common mechanism. In PS19, TP-MDNP treatment significantly reduced total ROS, CA9 (a hypoxia marker) and p-tau levels.

CONCLUSION: The results suggest that TP-MDNP can enable MRI detection of neuroinflammation and reduce neurodegeneration pathogenetic factors such as ROS, hypoxia, and p-tau in AD mouse brains. References 1. Zhang W, et al. Sig Transduct Target Ther 2023;8, 267. 2. He C, et al. Nano Today. 2020;35:100965. 3. Park E,. et al. Advanced Science. 2023 Apr;10(12):2207238. 4. Park E, et al. Biomaterials. 2025 Jan 24:123142.},
}

Animals
*Alzheimer Disease/drug therapy
Mice
Mice, Transgenic
Disease Models, Animal
*Nanoparticles
*Drug Development
Brain/metabolism
Manganese Compounds
Blood-Brain Barrier/metabolism
Humans
Neuroinflammatory Diseases

@article {pmid41449088,
year = {2025},
author = {Addassi, Y and Taylor, H and McDermott, A and Roberts, M and Bennett, B and Jumbo-Lucioni, P},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102447},
doi = {10.1002/alz70859_102447},
pmid = {41449088},
issn = {1552-5279},
mesh = {Animals ; Male ; Female ; *Alzheimer Disease/drug therapy ; Disease Models, Animal ; *Probiotics/therapeutic use/pharmacology ; Humans ; Animals, Genetically Modified ; *Drug Development ; Lactobacillus plantarum ; Amyloid beta-Protein Precursor/genetics/metabolism ; Locomotion/drug effects ; Drosophila ; Drosophila melanogaster ; Memory/drug effects ; },
abstract = {BACKGROUND: Gut microbiota disruptions have been implicated in Alzheimer's disease (AD) pathogenesis. Lactobacillus probiotics have demonstrated therapeutic potential in AD by modulating the gut microbiome, while Lactobacillus postbiotics, soluble factors secreted by live bacteria, confer similar effects with advantages like longer shelf life, lower cost, and reduced infection risk. Evidence of the benefits of postbiotics in AD is limited. This study compares the effectiveness of Lactobacillus probiotics and postbiotics in mitigating behavioral deficits in a Drosophila model of AD.

METHOD: Flies overexpressing human amyloid β precursor protein and β-site APP cleaving enzyme in neurons served as AD model. Lactobacillus plantarum (Lp) was prepared at 1.0 x 10⁹ CFU/µL in MRS Lactobacilli broth, with the upper 80% of culture supernatant filtered as postbiotic fraction (Lp-PBx). Lp and Lp-PBx were diluted 1:2 in 5% sucrose and administered via capillaries in four 24-hour doses over two weeks. Food intake was recorded. Locomotion and memory were assessed at 14 days. Locomotion was evaluated using a negative geotaxis assay testing flies' ability to cross 8-cm in 10 seconds. Memory was tested through an aversive phototaxic suppression assay, where flies were trained to associate light with an aversive odor. After ten training cycles, flies were tested for dark preference. Data was stratified by sex and analyzed through a two-way ANOVA to test the main effects of genotype, treatment, and their interaction.

RESULT: Untreated AD males (0.48±0.03 vs 0.80±0.03, p<0.0001) and females (0.39±0.04 vs 0.70±0.04, p<0.0001) exhibited significant mobility impairments compared to controls. However, AD flies fed Lp or Lp-PBx showed restored mobility, climbing at speeds comparable to controls. Specifically, AD males fed Lp (0.73±0.03) or Lp-PBx (0.75±0.03) and females fed Lp (0.61±0.04) or Lp-PBx (0.59±0.04) climbed significantly faster than untreated counterparts (males: 0.48±0.03, p<0.0001; females: 0.39±0.04, p<0.05). While food intake in females was unaffected, males fed Lp ate significantly less than those given Lp-PBx (p=0.0216), regardless of genotype. Memory assays are ongoing.

CONCLUSION: In summary, our findings suggest Lp-PBx as a viable alternative to Lp for managing mobility deficits in a Drosophila model of AD. Its palatability facilitates administration, making it a practical therapeutic option.},
}

Animals
Male
Female
*Alzheimer Disease/drug therapy
Disease Models, Animal
*Probiotics/therapeutic use/pharmacology
Humans
Animals, Genetically Modified
*Drug Development
Lactobacillus plantarum
Amyloid beta-Protein Precursor/genetics/metabolism
Locomotion/drug effects
Drosophila
Drosophila melanogaster
Memory/drug effects

@article {pmid41449075,
year = {2025},
author = {Morris, LA and Suzuki, H and Lee, S and Jin, Z and Gazes, Y and Huey, ED and Chen, B and Marin, A and Heibronner, S and Heron, CJL and Vanegas, N},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105243},
doi = {10.1002/alz70857_105243},
pmid = {41449075},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Decision Making/physiology ; *Parkinson Disease/psychology/physiopathology ; *Motivation/physiology ; *Alzheimer Disease/psychology/physiopathology ; Neuropsychological Tests ; *Apathy/physiology ; Middle Aged ; Aged, 80 and over ; Reaction Time ; },
abstract = {BACKGROUND: Loss of motivation is a prominent syndrome accompanying both Alzheimer's and Parkinson's disease. One approach to understanding motivational loss is to examine the processes involved in the expression of goal-directed behaviour. Weighing up rewarding outcomes against the effort costs required to obtain them - effort-based decision-making - is a core computation when deciding to act for outcomes. Whilst a body of evidence points to disruption of this computation in people with altered motivation, which underlying decision parameters drive this disruption, and whether these would generalise across brain disorders has not been examined. In the current study we examined the latent cognitive processes underlying effort-based decision making, across a spectrum of motivation and diagnostic groups.

METHODS: People with Alzheimer's disease (n = 37), Parkinson's disease (n = 52) and healthy controls (n = 21) performed a physical effort-based decision-making task (Apple Gathering Task) and caregiver-rated apathy scores were recorded. Choices made and reaction times were analysed using drift diffusion modeling to uncover latent cognitive processes. Associations between apathy, diagnosis and latent cognitive processes were examined using linear regression models, controlling for age and cognition.

RESULTS: Across all participants, lower motivation was associated with reduced acceptance of offers to work for reward. Specifically, slower overall drift rate, greater decision threshold, decision bias towards rejecting offers and longer non-decision time were significantly associated with reduced motivation. Unrelated to motivation, people with AD were less sensitive to changing effort levels, and had a larger decision threshold than PD and control groups.

CONCLUSION: Loss of motivation in AD and PD is associated with disrupted effort-based decision-making processes, including speed of information accumulation, distance between decision options, information encoding and response execution, and bias to choose to do nothing. In addition, AD more generally is associated with greater decision noise, and reduced ability to integrate effort information on choices. In sum, decision-making tasks are a promising method to investigate the cognitive processes underlying motivational loss in neurodegeneration.},
}

Humans
Male
Female
Aged
*Decision Making/physiology
*Parkinson Disease/psychology/physiopathology
*Motivation/physiology
*Alzheimer Disease/psychology/physiopathology
Neuropsychological Tests
*Apathy/physiology
Middle Aged
Aged, 80 and over
Reaction Time

@article {pmid41449074,
year = {2025},
author = {Galvin, JE and Hamby, ME and Iaci, J and Grundman, M and Caggiano, AO},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106890},
doi = {10.1002/alz70859_106890},
pmid = {41449074},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Lewy Body Disease/drug therapy ; *Drug Development ; Neuropsychological Tests ; Middle Aged ; Double-Blind Method ; Aged, 80 and over ; Treatment Outcome ; Alzheimer Disease/drug therapy ; Activities of Daily Living ; },
abstract = {BACKGROUND: Zervimesine (CT1812) is an experimental oral, small-molecule drug candidate in development for Alzheimer's disease and dementia with Lewy bodies (DLB). Zervimesine is designed to protect neurons by preventing the binding of oligomers of pathogenic proteins including β-amyloid and ɑ-synuclein.

METHOD: The COG1201 'SHIMMER' study is the first study to measure tolerability and clinical effects of zervimesine in adults with DLB. The study enrolled 130 individuals with a clinical diagnosis of DLB and MMSE of 18-27 who were randomized 1:1:1 to receive once-daily oral doses of zervimesine (100 or 300 mg) or placebo for 26 weeks. Among clinical assessments tools, SHIMMER employed the Neuropsychiatric Inventory (NPI), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale and the Unified Parkinson's Disease Rating Scale (UPDRS) Part III.

RESULT: Zervimesine-treated participants experience strong therapeutic responses across behavioral, functional, cognitive, and movement measures in SHIMMER. At the end of the study period, zervimesine-treated DLB (n=88) patients progressed 86% slower than placebo-treated patients (n=42) on the NPI, 52% slower on the ADCS-ADL and 62% slower on the UPDRS Part III. We intend to present for the first time a detailed characterization of the baseline participant characteristics including demographics, baseline scores on outcome measures, concomitant medications, comorbidities and baseline biomarker levels.

CONCLUSION: These data will allow comparison of the SHIMMER population to prior DLB study populations. SHIMMER results support the potential for zervimesine to slow clinical progression in patients with mild-to-moderate DLB. The robust therapeutic response observed across neuropsychiatric, cognitive, motor and functional measures is particularly encouraging. An analysis of participant characteristics will help guide recruitment in future clinical studies of zervimesine and its potential use to treat people with DLB. Cognition Therapeutics conducted COG1201 with University of Miami Miller School of Medicine and the Lewy Body Dementia Association under a grant from the National Institute of Aging (R01AG071643).},
}

Humans
Male
Female
Aged
*Lewy Body Disease/drug therapy
*Drug Development
Neuropsychological Tests
Middle Aged
Double-Blind Method
Aged, 80 and over
Treatment Outcome
Alzheimer Disease/drug therapy
Activities of Daily Living

@article {pmid41449073,
year = {2025},
author = {Xu, P},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102249},
doi = {10.1002/alz70859_102249},
pmid = {41449073},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Development ; Mice ; Disease Models, Animal ; Humans ; Microglia/metabolism/drug effects ; *Brain/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism ; },
abstract = {BACKGROUND: Programmed death ligand 1 (PD-L1) plays a pivotal role in modulating neuroinflammation in Alzheimer's disease (AD), and PD-L1 upregulation is widely observed in the brains of AD patients. This dysregulation hinders Aβ plaque clearance and leads to detrimental microglial activation.

METHOD: To regulate the PD-L1 in the brain, we developed a brain-targeted Nano-ERASER system (BTN-PDL1).

RESULT: BTN-PDL1 can effectively cross the BBB, deplete PD-L1 through a Trim21-mediated proteasomal degradation in microglia and astrocytes, and revive their functions, which can subsequently clear toxic Aβ fibrils and attenuate neuroinflammation. Animal behavior assay revealed that BTN-PDL1 stopped the progression of AD and improved learning and cognitive capacity in 5XFAD mouse model.

CONCLUSION: Since protein malfunction and neuroinflammation prevail in many CNS disease conditions, the success of BTN-PDL1 could also be beneficial for the treatment of AD, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, stroke, and traumatic brain injury.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Drug Development
Mice
Disease Models, Animal
Humans
Microglia/metabolism/drug effects
*Brain/metabolism/drug effects
Amyloid beta-Peptides/metabolism
Blood-Brain Barrier/metabolism

@article {pmid41449072,
year = {2025},
author = {Parra, MAA and Bruno, MA and Duran-Aniotz, C and Slachevsky, A and Behrens, MI and Takada, LT and de Paula, E and Resende, F and Custodio, N and Aguillon, D and Funes, JAÁ and Ibanez, A},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106530},
doi = {10.1002/alz70857_106530},
pmid = {41449072},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis/psychology ; *Neuropsychological Tests/statistics & numerical data ; Aged ; *Cognitive Dysfunction/diagnosis ; Middle Aged ; Cross-Cultural Comparison ; *Memory, Short-Term/physiology ; Colombia ; Reproducibility of Results ; Argentina ; },
abstract = {BACKGROUND: Alzheimer's disease dementia (ADD) is diagnosed based on evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (DSM-5). Jack Jr et al. (2024) acknowledged that clinical judgment remains crucial when biomarkers are discordant with clinical impressions or non-accessible. However, available assessments lack precision in detecting ADD and are influenced by sociocultural factors, thus calling for cross-cultural harmonization strategies (Franzen et al., 2020). The Visual Short-Term Memory Binding Test (VSTMBT) has shown cross-cultural validity across six European countries (Costa et al., 2017; Parra et al., 2019). We investigated whether this and other promising tests are valid across six Latin American Countries.

METHODS: ADD patients (n = 426) and Healthy Controls (n = 869) were recruited from Argentina, Brazil, Chile, Colombia, México and Perú. They were assessed using a comprehensive protocol (Ibanez et al., 2021), which included the VSTMBT, the Craft Story 21 Test (CS21T) and the Benson Complex Figure Test (CBFT). We used General Linear Models (GLM) to compare data across Groups and Countries controlling for confounders. We explored the classification accuracy of these tests using ROC analysis.

RESULTS: Whole-sample VSTMBT data entered a mixed GLM revealing the traditionally reported Group (ADD vs HC) by condition interaction (F(1,1287) = 4.62, p = 0.032), driven by disproportional Shape-Color Binding deficits. When this test, the CS21T and CBFT immediate recall data entered GLMs with Group and Country as fixed factors and age, sex, education, number of languages, and comorbidities as covariates, the main effects and the interaction proved significant. The three tests revealed significant deficits in ADD relative to HC (all p < 0.05). ROC analysis showed a reliable classification accuracy for a memory composite that combined the three tests (AUC: Argentina=1.0, Brazil=0.99, Chile=0.96, Colombia=0.91), México=0.91, and Perú=0.78).

CONCLUSIONS: The VSTMBT, CS21T and CBFT proved reliable for assessing ADD across six LAC. Although variability was observed across countries, they revealed significant deficits in ADD, which were unaccounted for by relevant confounding factors. The composite score achieved excellent classification accuracy for most countries. The cross-cultural validity of the VSTMBT previously reported across EU countries holds for LAC.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis/psychology
*Neuropsychological Tests/statistics & numerical data
Aged
*Cognitive Dysfunction/diagnosis
Middle Aged
Cross-Cultural Comparison
*Memory, Short-Term/physiology
Colombia
Reproducibility of Results
Argentina

@article {pmid41449071,
year = {2025},
author = {Ghahremani, M and Leon, R and Smith, EE and Ismail, Z},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103819},
doi = {10.1002/alz70856_103819},
pmid = {41449071},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/blood ; Female ; Male ; *tau Proteins/blood ; *Cognitive Dysfunction/blood/diagnosis ; Aged ; *Alzheimer Disease/blood/diagnosis ; Neuropsychological Tests/statistics & numerical data ; Amyloid beta-Peptides/blood ; Aged, 80 and over ; },
abstract = {BACKGROUND: The 2024 NIA-AA revised criteria define Alzheimer's disease (AD) biologically through core biomarkers amyloid-beta (Aβ) and tau. While cognitive function remains central to the clinical evaluation of early-stage dementia, mild neurobehavioral changes may coexist and even precede cognitive decline. Mild behavioral impairment (MBI), marked by late-onset persistent neuropsychiatric symptoms (NPS), has emerged as a potential early indicator of dementia risk. While MBI is associated with well-established Aβ and tau biomarkers, the association with plasma p-tau217, a novel blood-based biomarker with high accuracy for AD-related pathology, remains unexplored. Here, we investigated the association between MBI and plasma p-tau217 levels in older adults with normal cognition or mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative.

METHOD: NPS scores were obtained from the Neuropsychiatric Inventory, with MBI status (MBI+/-) determined over two consecutive visits to operationalize the MBI symptom persistence criterion. Participants without plasma ptau-217 data prior to dementia diagnosis were excluded. Linear regression modeled the association between NPS status and p-tau217 level as a continuous variable outcome. Additionally, logistic regression modeled the association between NPS status and p-tau217 positivity status, using a study-specific cut-off derived using Gaussian mixture modeling. Models adjusted for age, sex, education, and cognitive diagnosis.

RESULT: Plasma p-tau217 levels and NPS status were available in 101 participants (50.5% MCI; mean age 72.0±6.5; 44.6% female). Participants with MBI had significantly higher plasma p-tau217 levels (Beta=36.4%; 95%CI: 2.2-82.0, p = 0.04) (Table 1) and higher odds of being p-tau217 positive (OR=3.06, 95%CI: 1.14-8.70, p = 0.03), relative to MBI- participants (Table 2).

CONCLUSION: Findings add to the evidence base that appropriately measured behavioural symptoms can represent AD proteinopathies, supporting the role of MBI in AD risk stratification. The link between MBI and elevated plasma p-tau217 levels highlights the potential utility of MBI for early AD detection and more efficient clinical trial design by utilizing MBI assessment at screening to identify high-risk individuals for biomarker positivity.},
}

Humans
Biomarkers/blood
Female
Male
*tau Proteins/blood
*Cognitive Dysfunction/blood/diagnosis
Aged
*Alzheimer Disease/blood/diagnosis
Neuropsychological Tests/statistics & numerical data
Amyloid beta-Peptides/blood
Aged, 80 and over

@article {pmid41449069,
year = {2025},
author = {He, XY and Yu, JT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103240},
doi = {10.1002/alz70856_103240},
pmid = {41449069},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Dementia/genetics/diagnosis/metabolism ; Proteomics ; Metabolomics ; *Alzheimer Disease/genetics ; Male ; Longitudinal Studies ; Whole Genome Sequencing ; Female ; Aged ; Mendelian Randomization Analysis ; Machine Learning ; },
abstract = {BACKGROUND: Dementia, a leading cause of global disability, poses significant socioeconomic burdens. Early identification of biomarkers and understanding the molecular mechanisms underlying dementia are crucial for developing effective interventions. Multi-omics approaches offer a comprehensive framework to unravel the complex interplay of genetic, proteomic, metabolomic, and clinical factors in dementia pathogenesis.

METHOD: We conducted a longitudinal multi-omics analysis integrating whole-genome sequencing (WGS), proteomics, metabolomics, and clinical laboratory data from a large cohort (N = 320,226). Single-omics association analyses were performed to identify dementia-related features, followed by cross-omics integration using advanced machine learning models. We employed mediation analysis and Mendelian randomization to assess causal relationships and identify potential drug targets and actionable antecedents.

RESULT: We identified 203 lead genetic variants associated with all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD), implicating 228 candidate genes. Multi-omics network analysis revealed distinct biological modules, such as lipid metabolism dysregulation and synaptic dysfunction in ACD. Longitudinal trajectory analysis demonstrated dynamic changes in blood multi-omics profiles up to 15 years before dementia diagnosis, with specific clusters of proteins and metabolites showing early and sustained elevation. The FT-Transformer model significantly improved dementia risk prediction by integrating multi-omics data, outperforming single-omics models. Mediation analysis identified 258 mediators, with proteins like GDF15, IGFBP2, and NEFL playing key roles in dementia risk. Furthermore, we identified 24 potential drug targets, including 8 proteins with existing drugs in clinical use or trials, and 7 novel targets with favorable safety profiles.

CONCLUSION: This study provides a comprehensive multi-omics framework for understanding the molecular mechanisms of dementia, identifying predictive biomarkers, and uncovering potential therapeutic targets. Our findings highlight the dynamic evolution of multi-omics profiles before dementia onset and offer new avenues for early intervention and drug repurposing.},
}

Humans
*Biomarkers/blood
*Dementia/genetics/diagnosis/metabolism
Proteomics
Metabolomics
*Alzheimer Disease/genetics
Male
Longitudinal Studies
Whole Genome Sequencing
Female
Aged
Mendelian Randomization Analysis
Machine Learning

@article {pmid41449063,
year = {2025},
author = {Kam, AC and Beam, CR and Turkheimer, E and Zandi, E and Martins-Klein, B and Bell, SA and Finkel, D and Davis, DW},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104460},
doi = {10.1002/alz70857_104460},
pmid = {41449063},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/diagnosis ; Biomarkers/blood ; *tau Proteins/blood ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; *Peptide Fragments/blood ; *Memory, Episodic ; },
abstract = {BACKGROUND: Clarifying risk factors for Alzheimer's disease (AD) in midlife permits intervening earlier in the lifespan and delaying conversion to AD. Understanding the relationship between blood-based AD biomarkers and memory functioning during middle age may help clarify whether elevated levels correspond to poor memory performance in later life. Blood-based biomarkers, including amyloid-β42/amyloid-β40 and ptau181, are associated with AD diagnosis, but studies investigating the correlates of these biomarker levels in middle age are scarce (Li et al., 2022; Karikari et al., 2020).

METHOD: Blood-based AD biomarkers and episodic memory scores from the California Verbal Learning Test- 3[rd] Edition (CVLT-3) were collected from 154 midlife twins (78 complete families) as part of the Louisville Twin Study. Pearson correlations and mixed effects regression analysis were used to estimate between-family and within-family associations between AD biomarkers and four CVLT-3 subtests (immediate word recall, short-delay free recall, long-delay free recall, and recognition).

RESULT: Correlations of amyloid-β42/amyloid-β40 and the CVLT3 subtests ranged from -.02 to .04 while correlations with ptau181 ranged from -.09 to -.04. Although no correlations were statistically significant, the pattern of associations between episodic memory and ptau181 at least suggested a reliable negative association. Neither between-family nor within-family correlations were observed.

CONCLUSION: Although AD biomarker levels have been found to correlate with memory functioning in older adult samples, we did not observe these same effects in middle adulthood. Thus, the current results suggest that individual differences in blood-based AD biomarkers may not have predictive utility for observed memory functioning in middle adulthood.},
}

Humans
Male
Female
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/diagnosis
Biomarkers/blood
*tau Proteins/blood
Middle Aged
Neuropsychological Tests/statistics & numerical data
*Peptide Fragments/blood
*Memory, Episodic

@article {pmid41449062,
year = {2025},
author = {Ni, S and Yue, J and Shi, Y},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104171},
doi = {10.1002/alz70856_104171},
pmid = {41449062},
issn = {1552-5279},
mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; Aged ; *tau Proteins/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Biomarkers/metabolism ; *Brain/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Aged, 80 and over ; Carbolines ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: The first-generation tau PET tracer AV-1451 has been widely used to study tau pathology in Alzheimer's disease (AD), but it's high off-target binding in sub-cortical structures has limited our ability to examine possible tau pathology in these structures. With the increasing popularity of second-generation tau PET tracers such as PI-2620 and MK-6240 that exhibit low off-target binding signals in sub-cortical structures, it is important to examine whether their signals can be useful in evaluating the severity of tau pathology of sub-cortical structures in AD.

METHOD: This study utilized tau PET data based on the PI-2620 tracer from the Health and Aging Brain Study: Health Disparities (HABS-HD). Overall, data used in this study are from 1,492 participants with both T1-weighted MRI and tau PET imaging, along with the available clinical and cognitive metrics such as the Consensus Diagnosis (CDX). The cohort included 1097 cognitively unimpaired (CU) and 395 cognitively impaired (CI) participants, which are comprised of 479 Black, 447 Hispanic, and 566 non-Hispanic White subjects. Subcortical regions of interest included key structures from both the left and right hemispheres including the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. Automated segmentation maps were generated from T1-weighted MRI using FreeSurfer and applied to the corresponding PET images to calculate mean standard uptake value ratio (SUVR) values for each subcortical region.

RESULT: Significant differences in tau SUVR values were observed in the caudate (p-value < 1e-2), hippocampus (p-value < 1e-2), and amygdala (p-value < 1e-4) across diagnostic categories in the entire cohort. Ethnic group analyses for CU and CI subjects revealed statistically significant differences in different sub-cortical regions. Among non-Hispanic White participants, differences were significant in the putamen (p-value < 1e-2), hippocampus (p-value < 1e-2), and amygdala (p-value < 1e-5). Significant differences were observed in the caudate (p-value < 1e-2) for Black participants, while the amygdala showed statistically significant differences (p-value < 5e-2) for Hispanic participants.

CONCLUSION: Ethnicity plays an important role on sub-cortical tau PET signal for CU and CI, especially for non-Hispanic White in the amygdala area.

FUNDING SOURCES: RF1AG077578, RF1AG064584, R01EB022744, U19AG078109, P30AG066530.},
}

Humans
Positron-Emission Tomography
Male
Female
Aged
*tau Proteins/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Biomarkers/metabolism
*Brain/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Aged, 80 and over
Carbolines
Middle Aged
Cohort Studies

@article {pmid41449060,
year = {2025},
author = {Feldman, HH and Villain, N and Frisoni, GB and Dubois, B},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107831},
doi = {10.1002/alz70859_107831},
pmid = {41449060},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/pathology ; Biomarkers ; *Drug Development ; Risk Assessment ; },
abstract = {BACKGROUND: The widespread availability of biomarkers of Alzheimer's pathology (BAP) opens new diagnostic considerations for those who have not clinically expressed the disease but who are identified as being at increased risk based on their BAP. The International Working Group (IWG) updated their recommendations within a patient-centered nosographic approach that considers clinical evaluation as a cornerstone with attention to risk and resilience factors, patterns of biomarkers, comorbidities, genetics, and other test results (Dubois B, et al. JAMA Neurol 2024). They stratify risk and tie it to a specific clinical patient journey, including the communication of risk, tailored management of modifiable risk factors, counselling, multidomain lifestyle interventions, and treatment research considerations.

METHOD: For these updated IWG recommendations, an evidence review of available literature between July 1, 2020 and March 2024 was undertaken with a variety of biomarker search terms and AD. The search included a review of papers focused on near term and lifetime risks of progression to AD dementia in cognitively unimpaired people with different BAP patterns.

RESULT: These IWG recommendations provide a risk stratification framework for unimpaired individuals with classification into "Asymptomatic At-Risk" and "Presymptomatic". The majority of cognitively unimpaired individuals with BAP, including those with an amyloid or AD pathophysiological biomarker, will not express clinical AD in their lifetime. The Presymptomatic group includes those with fully penetrant monogenic mutations, Down syndrome, or alternatively patterns of positive amyloid biomarker with neocortical tau PET biomarkers that reach the threshold of near certainty of clinical expression of AD. Prioritizing the testing of preventive disease modifying treatments is identified as urgent for this Presymptomatic group. Furthermore, it is expected that this group will expand as new evidence and patterns of biomarkers reach the necessary thresholds for their inclusion. Management plans can be further tailored to this classification framework.

CONCLUSION: This IWG risk stratification classification recommends against diagnosis of AD based on BAP alone without its clinical expression. This AD classification lends itself to a tailored management approach and specific patient journeys for each of its groups.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/pathology
Biomarkers
*Drug Development
Risk Assessment

@article {pmid41449057,
year = {2025},
author = {Trotier, AF and Randrianaly, JD and Géraudie, A and Jacquot, S and Piguet, F and Bay, S and Lafaye, P and Delatour, B and , },
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103908},
doi = {10.1002/alz70859_103908},
pmid = {41449057},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy ; Blood-Brain Barrier/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism/immunology ; *Drug Development ; Disease Models, Animal ; *Single-Domain Antibodies ; Mice, Transgenic ; Brain/metabolism ; Humans ; *Immunotherapy/methods ; Plaque, Amyloid ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) peptide accumulation, which forms plaques that trigger inflammation, synaptic loss, and neuronal death. Although monoclonal antibodies (mAbs) targeting Aβ aggregates have shown success in reducing plaques, their effect on cognitive decline is limited, potentially due to the challenge posed by the blood-brain barrier (BBB) and brain structure. Camelid nanobodies (VHHs), due to their small size (15 kDa) and single-domain structure, can more effectively penetrate the BBB, diffuse within the brain, and bind difficult-to-reach epitopes, such as those on Aβ plaques or within the intracellular compartment. To enhance the delivery of anti-Aβ VHHs, two strategies were developed: transient BBB opening and brain in situ production via viral vectors. This study aims to develop and assess two novel immunotherapy approaches using the anti-Aβ VHH R3VQ in an AD mouse model.

METHOD: R3VQ was optimized into monomeric, dimeric, and Fc-conjugated formats. In vivo efficacy was evaluated using APP-PS1-KI mice, which develop both intracellular and extracellular Aβ aggregates. The diffusion of R3VQ was assessed through stereotaxic injections of R3VQ variants into the dorsal hippocampus, followed by histological analysis of brain tissue. To transiently open the BBB, microbubbles and low-intensity pulsed ultrasound (LIPU) were used in combination with intravenous (i/V) R3VQ injections, and brain bioavailability was analyzed four hours post-injection. Additionally, AAVr vectors were used to express monomeric or dimeric R3VQ in the brain, and expression was assessed using qPCR and immunofluorescent staining.

RESULT: In vitro assays confirmed that R3VQ effectively recognizes fibrillar and soluble Aβ, inhibiting fibril formation. In vivo, both monomeric and dimeric R3VQ successfully labeled Aβ deposits and diffused widely in the brain compared to conventional IgGs. Preliminary results from the enhanced immunotherapy strategies show that R3VQ can cross the BBB, bind amyloid plaques, and enter neuronal cells following LIPU-induced BBB opening. AAV delivery of R3VQ resulted in robust astrocytic expression in the brain. Ongoing analyses aim to evaluate the therapeutic potential of these approaches.

CONCLUSION: This study explores innovative passive immunotherapy strategies targeting Aβ, with potential to advance AD treatment and deepen understanding of the disease's pathophysiology.},
}

Animals
*Alzheimer Disease/drug therapy
Blood-Brain Barrier/metabolism
Mice
*Amyloid beta-Peptides/metabolism/immunology
*Drug Development
Disease Models, Animal
*Single-Domain Antibodies
Mice, Transgenic
Brain/metabolism
Humans
*Immunotherapy/methods
Plaque, Amyloid

@article {pmid41449052,
year = {2025},
author = {Iqbal, S and Olivares, CB and Rizzo, L and Parker, TD and Wong, C and Underwood, BR and Carpenter, J and Dunne, R and Raymont, V and Reith, A and Mummery, CJ and Karran, EH and Ducotterd, F and Wilcock, G and Cummings, JL and O'Brien, JT and Mursaleen, L and Schneider, LSS and Vandenberghe, R and Reeves, SJ and Malhotra, P},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102227},
doi = {10.1002/alz70859_102227},
pmid = {41449052},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development/methods ; *Drug Repositioning ; },
abstract = {BACKGROUND: Despite recent developments in amyloid-clearing therapies for Alzheimer's Disease (AD), there remains a need for more effective, safe treatments. Funded by the UK National Institute of Health and Care Research, our aim was to establish a robust, systematic, and unbiased drug prioritisation pipeline to identify repurposed drugs with the greatest potential for sustained clinical effect in clinical 'real-world' AD (MMSE >17). These would then be considered for inclusion in a planned multi-arm UK platform trial.

METHOD: We invited the wider AD community to propose compounds by summarising their rationale and evidence in a prespecified drug proposal form. Fourteen proposals were received, and the drug proposers were invited to the first panel meeting. They presented a pre-clinical data focused rationale for each compound to an international expert panel comprised of AD clinicians, scientists, industry professionals, as well as both charity and patient/public representatives. In the context of a platform trial using prespecified primary outcome of cognition (ADAS-Cog, with neuropsychiatric symptoms and everyday activities as secondary outcomes), the panel ranked their top three compounds based on efficacy, biological plausibility, and safety in AD. Ten compounds were taken forward with two subsequently excluded due to lack of data in humans. We compiled extended drug curriculum vitae (CV) for the eight shortlisted compounds. This incorporated practical clinically relevant information and was supplemented by systematic clinical literature review using Repurposing Living Systematic Review (ReLiSyR), a machine learning tool that searches databases and screens studies to identify relevant publications.

RESULT: Drug CVs were reviewed in a second panel meeting. Compound rankings were repeated with previous considerations and also practical clinical factors. The highest ranked compounds were atomoxetine (1[st]), metformin (2[nd]), isosorbide mononitrate and levetiracetam (joint 3[rd]). The pivotal determining factors across the top ranked compounds included scientific evidence of plausible mechanistic pathways in AD as well as evidence of substantial clinical data on safety and tolerability.

CONCLUSION: We present a practical approach to prioritising repurposed drugs to evaluate in the context of clinical AD. We would like to thank our patient and public contributors and the wider investigator team.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development/methods
*Drug Repositioning

@article {pmid41449046,
year = {2025},
author = {Hall, K and Blank, M and Geraci, K and Jaramillo, I and Kahly, O and Miranda, M and Pebler, P and Johnson, DK and Woods, DL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106953},
doi = {10.1002/alz70857_106953},
pmid = {41449046},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Cognitive Dysfunction/diagnosis ; *Neuropsychological Tests ; *Mental Recall/physiology ; *Alzheimer Disease/diagnosis ; *Memory, Episodic ; Middle Aged ; },
abstract = {BACKGROUND: Logical memory (story recall) tasks are frequently used to assess episodic memory and language abilities in older participants to assist in detecting mild cognitive impairment (MCI) and Alzheimer's disease (AD), [1]. Here we describe a logical memory encoding and recall (LM) task from the California Cognitive Assessment Battery (CCAB) [2]. Administration and scoring of this task is automated, and allows for the automatic extraction of speech and language biomarkers (SLBs).

METHOD: PARTICIPANTS: 772 participants (55% female, 66.5 ± 8.5 years) completed the CCAB logical memory task in their homes during normative data collection. Participants underwent two days of identical testing.

TECHNOLOGY: CCAB LM administration is fully automated, with instructions delivered using text-to-speech and responses transcribed and timestamped using consensus automatic speech recognition (CASR). Participants are remotely monitored through the CCAB browser-based interface, which provides an A/V feed and videochat capabilities. Acoustic and phonetic measures are quantified from high quality (48 kHz, 24-bit) recordings obtained with a head-mounted microphone while linguistic SLBs were quantified from CASR generated transcripts. TASK: Participants heard a novel story, and were then asked to immediately recall the story followed, with delayed recall occurring ∼30 min later. Responses were automatically scored for total match count against a scoring set of 49 keyword elements.

RESULT: Analysis of immediate and delayed recall of the LM tasks revealed excellent test-retest values for total match count (r = .77 and r = .79, respectively) with significant effects of vocabulary***, age***, gender**, education**, and race* on both immediate and delayed recall. SLBs such as speech rate and pause ratio showed good reliability (r = .61, r = .58). and significant correlations (r = .32***, r = .42***) with delayed recall performance.

CONCLUSION: The CCAB's logical memory tasks provide automated objective analysis of recall performance and SLBs to assess episodic verbal memory and communication abilities in older adults. References [1] Wechsler, D. (1945). Wechsler memory scale. [2] Woods, D., Pebler, P., Johnson, D. K., Herron, T., Hall, K., Blank, M., … Baldo, J. (2024). The California Cognitive Assessment Battery (CCAB). Frontiers in Human Neuroscience, 17, 1305529.},
}

Humans
Female
Male
Aged
*Cognitive Dysfunction/diagnosis
*Neuropsychological Tests
*Mental Recall/physiology
*Alzheimer Disease/diagnosis
*Memory, Episodic
Middle Aged

@article {pmid41449041,
year = {2025},
author = {Khan, SA and Qamar, Z and Bhardwaj, N and Iqubal, A and Singh, PP and Pervez, S and Baboota, S and Ali, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102657},
doi = {10.1002/alz70859_102657},
pmid = {41449041},
issn = {1552-5279},
mesh = {Animals ; Rats ; Male ; Rats, Wistar ; *Alzheimer Disease/drug therapy/chemically induced ; *Butyrylcholinesterase/administration & dosage/pharmacokinetics ; Scopolamine ; *Drug Development ; Disease Models, Animal ; Brain/drug effects/pathology/metabolism ; Administration, Intranasal ; Antioxidants ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and limited therapeutic options to address both pathology and oxidative damage. Intranasal delivery of nanostructured lipid carriers (NLCs) offers promising approach to enhance brain bioavailability of drugs. This study investigates NLCs loaded with Butyrylcholinesterase (RV) and Kinase Inhibitors (KI) for targeted delivery in AD therapy. Using scopolamine-induced AD-like symptoms model in male Wistar rats, pharmacokinetic, biodistribution, and pharmacodynamic studies, including Novel Object Recognition (NOR) and Elevated Plus Maze (EPM) tests, were conducted alongside immunohistochemistry (IHC), histopathology, and antioxidant assays to evaluate therapeutic efficacy of RV-KI-NLCs.

METHOD: The study aimed to enhance the brain bioavailability of RV and KI using NLCs for intranasal delivery in Alzheimer's disease. NLCs, prepared via a modified emulsification method, were characterized and evaluated in scopolamine-induced AD model rats through pharmacokinetic, biodistribution, and pharmacodynamic studies, including NOR and EPM tests. Immunohistochemistry and histopathological analyses assessed AD biomarkers (BACE1, TNF-α), neuronal integrity, and inflammation, while the DPPH assay confirmed antioxidant potential. RV-KI-NLCs demonstrated significant efficacy in reversing scopolamine-induced AD-like symptoms.

RESULT: Histopathological analysis of hippocampus (CA1) and cortex regions revealed significant neurotoxicity, including cellular disintegration, pyknosis, and vacuolation in the scopolamine-treated negative control group, while no cellular damage was observed in positive control group. Among treatments, RV-KI-NLC formulation exhibited the highest neuroprotective efficacy, followed by KI-NLC and RV-NLC, with all NLC-treated groups significantly mitigating scopolamine-induced damage compared to suspension-treated groups. RV-KI suspension showed moderate improvement, outperforming RV and KI suspensions. Immunohistochemistry demonstrated marked reduction in BACE1, and TNF-α in the RV-KI-NLC-treated group, accompanied by improved neuronal integrity, reduced gliosis, and lower neuroinflammation. DPPH assay confirmed the high antioxidant activity of RV-KI-NLC, indicating strong free radical scavenging potential. These findings aligned with behavioral improvements observed in NOR and EPM tests, highlighting formulation's ability to effectively restore cognitive and behavioral functions.

CONCLUSION: The RV-KI-NLC formulation showed superior neuroprotective effects in scopolamine-induced AD-like symptoms, with significant improvements in neuronal integrity, reduced neuroinflammation, enhanced cognitive function, and strong antioxidant activity, highlighting its potential as a promising therapeutic strategy for AD.},
}

Animals
Rats
Male
Rats, Wistar
*Alzheimer Disease/drug therapy/chemically induced
*Butyrylcholinesterase/administration & dosage/pharmacokinetics
Scopolamine
*Drug Development
Disease Models, Animal
Brain/drug effects/pathology/metabolism
Administration, Intranasal
Antioxidants

@article {pmid41449040,
year = {2025},
author = {Lu, J and Wang, J and Zhang, H and Wu, J and Lin, H and Ma, X and Li, M and Xiao, Z and Ju, Z and Zhou, X and Bao, W and Ding, D and Yen, TC and Zuo, C and Guan, Y and Zhao, Q and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102450},
doi = {10.1002/alz70856_102450},
pmid = {41449040},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/metabolism/blood ; *tau Proteins/metabolism/blood ; *Alzheimer Disease/diagnostic imaging/diagnosis/metabolism/pathology ; Aged ; Disease Progression ; Prognosis ; Longitudinal Studies ; Positron-Emission Tomography ; Cognitive Dysfunction/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Middle Aged ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism/pathology ; },
abstract = {BACKGROUND: Clinical-biological diagnosis of Alzheimer's disease (AD) is gaining increasing recognition. Beyond diagnosis, biological profiles can be of great benefit for disease monitoring and prognosis, although evidence from real-world memory clinics is still limited.

METHOD: 211 subjects with cognitive concerns and 31 cognitive unimpaired (CU) volunteers visiting our memory clinic with longitudinal follow-up were enrolled (mean (SD) interval: 1.89 (1.19) years). All participants received AD pathological evaluations (core 1: amyloid-PET or plasma p-tau 217; core 2: Florzolotau tau-PET) at baseline. Biomarkers were assessed by binary amyloid and tau status, and quantitative tau burden in key regions (medial temporal lobe (MTL), neocortical areas (NEO)). Clinical progression served as the primary outcome (increase in CDR or annual MMSE decline ≥ 6). The prognostic values of biomarkers were compared with basic demographic characteristics (a combination of significant risks in Cox Proportional Hazard Models) by receiver operating characteristic analysis.

RESULT: 91 (37.6%) participants were classified as clinical progression (0 CU (0%), 0 SCD (0%), 41 MCI (31.5%) and 50 (56.8%) AD dementia). Only age (older, HR = 1.03, 95%CI 1.01-1.07, P = 0.005) and sex (female, HR = 1.61, 95%CI 1.02-2.52, P = 0.039) showed the significant risks for clinical progression. In the entire cohort, incorporating any of the above biomarkers individually into the basic model (AUC = 0.57) significantly improved the prognostic value (AUC = 0.73-0.80, all P < 0.001), with quantitative tau burden in NEO showing the best added value. Combining both amyloid and tau biomarkers into the basic model further slightly improved the prognosis (AUC = 0.77-0.82), with the one with binary amyloid status plus quantitative tau burden in NEO showing the best added value. In the A+ subcohort, prognostic value was significantly increased by incorporating the quantitative tau burden (MTL: AUC = 0.71, P < 0.001; NEO: AUC = 0.73, P < 0.001) into the basic model (AUC = 0.50), while binary tau status didn't achieve significant improvement (AUC = 0.60, P = 0.125).

CONCLUSION: AD core biomarkers are promising in improving clinical prognosis, among which quantitative tau burden is preferable to binary assessment, especially in the AD continuum.},
}

Humans
Female
Male
*Biomarkers/metabolism/blood
*tau Proteins/metabolism/blood
*Alzheimer Disease/diagnostic imaging/diagnosis/metabolism/pathology
Aged
Disease Progression
Prognosis
Longitudinal Studies
Positron-Emission Tomography
Cognitive Dysfunction/diagnostic imaging
Amyloid beta-Peptides/metabolism
Middle Aged
Aged, 80 and over
Brain/diagnostic imaging/metabolism/pathology

@article {pmid41449039,
year = {2025},
author = {Seo, EH and Yoon, HJ and Kim, SG and Chung, JY and Kim, H and Lee, KH},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104818},
doi = {10.1002/alz70857_104818},
pmid = {41449039},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/psychology ; *Alzheimer Disease/diagnosis/psychology ; Neuropsychological Tests ; Republic of Korea ; Aged, 80 and over ; Cohort Studies ; },
abstract = {BACKGROUND: The use of digital cognitive assessment tools has been rapidly increasing. However, digital literacy-a potential influential factor on performance with such tools-is often overlooked, and existing digital literacy scales are overly complex and time-consuming. To address this gap, we developed a Brief Digital Literacy Scale (BDLS) specifically tailored for older adults to provide a simple pre-assessment tool for digital cognitive evaluations.

METHOD: The BDLS consists of 10 items measuring fundamental digital skills and frequency, scored on a 5-point Likert scale. A total of 202 older adults participated in this study, including individuals with cognitive normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) from the Gwangju Alzheimer's Disease and Related Dementia Cohort in Korea. Internal consistency and exploratory factor analysis (EFA), regression and partial correlation analysis were performed.

RESULT: The BDLS demonstrated excellent internal consistency (α=0.874). EFA revealed a three-factor structure, explaining 70.73% of the total variance: Factor 1: Technical Proficiency, Factor 2: Smart Device Usage, and Factor 3: Digital Usage Frequency and Information Evaluation. Higher BDLS scores were significantly associated with younger age, and longer years of education. Gender differences were not significant, though women showed a trend toward higher scores. BDLS scores showed significant partial correlations (controlling for age, gender, education) with: Boston Naming Test (r = 0.36, p <0.001), Visual Memory Test scores (r = 0.26∼0.37, p <0.01), Psychomotor Speed (r = -0.24, p <0.05). Significant associations were also observed with digital cognitive scores measuring visual memory (r = 0.19∼0.28, p <0.05∼ p <0.001), and processing speed (r = -0.23∼-0.15, p <0.05 ∼ p <0.01). BDLS scores significantly differed across cognitive status groups (F=9.71, p <0.001), with scores decreasing progressively from CN to MCI to AD.

CONCLUSION: Our preliminary results suggest that the BDLS is a reliable and valid tool for assessing digital literacy in older adults. It demonstrates relationships with cognitive performance (both paper-and-pencil and digital format). Notably, BDLS scores were significantly associated with visual memory and naming, highlighting the role of visual information processing and memory in digital literacy. This scale may provide a practical solution for pre-assessment in digital cognitive testing and highlights the importance of considering digital literacy in clinical and research contexts.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/diagnosis/psychology
*Alzheimer Disease/diagnosis/psychology
Neuropsychological Tests
Republic of Korea
Aged, 80 and over
Cohort Studies

@article {pmid41449036,
year = {2025},
author = {Gikelekele, G},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101984},
doi = {10.1002/alz70859_101984},
pmid = {41449036},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/drug therapy/psychology/diagnosis ; Neuropsychological Tests/statistics & numerical data ; *Drug Development ; *Cognition ; Democratic Republic of the Congo/epidemiology ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Many studies in Western countries have examined the association between neuropsychiatric symptoms (NPS) and cognitive functions in dementia, primarily focusing on Alzheimer's disease (AD). However, few studies have evaluated this association in Sub-Saharan African countries. This study examines the association between NPS and cognitive functions in older adults with probable AD in Kinshasa, Congo (DRC).

METHOD: A total of 1432 participants were recruited by convenience sampling in Kinshasa, DRC. They underwent the CSID and the AQ. Out of these, 114 participants were retained, including 56 considered to have probable AD and 58 considered to have normal cognition. The two groups were matched by sex, age, and education level. The Neuropsychiatric Inventory (NPI) was used to determine psychiatric symptoms, and the African Neuropsychology Battery (ANB) for cognitive functions. Descriptive statistics, including means, standard deviations, and frequencies, were conducted. The association between NPS and cognitive function was established using multiple linear regression.

RESULT: The most frequent NPS were irritability (56%), anxiety (46%), sleep disturbance (44%), depression (42%), appetite disorders (35%), aberrant motor behavior (21%), and agitation (19%). A statistically significant association was found between anxiety and the proverb test (95% CI, p=0.03), and between sleep disturbance and visuospatial memory (95% CI, p=0.05). A trend of association was observed between anxiety and visuospatial memory (95% CI, p=0.06).

CONCLUSION: Some NPS are part of the manifestations of AD and are associated with specific cognitive functions. This highlights the importance of using the NPI and ANB in the diagnosis of probable AD.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/drug therapy/psychology/diagnosis
Neuropsychological Tests/statistics & numerical data
*Drug Development
*Cognition
Democratic Republic of the Congo/epidemiology
Aged, 80 and over
Middle Aged

@article {pmid41449034,
year = {2025},
author = {Ortiz, BL and Quagletti, AM and Hebron, L and Miller, BL and Kramer, JH and Rabinovici, GD and Rankin, KP},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106130},
doi = {10.1002/alz70857_106130},
pmid = {41449034},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Empathy ; *Depression/psychology ; *Alzheimer Disease/psychology/complications ; *Emotions ; Aged, 80 and over ; Psychiatric Status Rating Scales ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Emotion sensitivity, including emotion reading and real-life empathy, may be altered in Alzheimer's disease (AD), with some individuals experiencing impairments while others show heightened sensitivity. Depression, common in early AD, may influence empathy and social cognition, yet the impact of depression on emotion sensitivity remains unclear. Clarifying these relationships could inform interventions to support social and emotional well-being in early AD.

METHOD: 252 older adults with early-stage AD (Clinical Dementia Rating 0.5-1; 52% female) self-reported depressive symptoms using the Geriatric Depression Scale (GDS) across five subscales (Dysphoria, Hopelessness, Worry, Withdrawal, Cognitive Concern), and underwent emotion comprehension testing with the Dynamic Affect Recognition Test (DART) and The Awareness of Social Interference Test (TASIT) Emotion Evaluation Test (EET). Informants described participants' empathic functioning using the Interpersonal Reactivity Index (IRI), measuring Perspective-Taking, Fantasy, Empathic Concern, and Personal Distress. Univariate and multivariate regression models examined associations between depressive symptoms and emotion sensitivity, adjusting for age, sex, and education.

RESULT: Regression modeling showed that negative mood (Dysphoria and Hopelessness) hindered emotional connection and cognitive empathy (Empathic Concern: β=-0.65, p <0.05; β=-0.84, p <0.05; Perspective-Taking: β=-0.87, p <0.001; β=-1.39, p <0.05). Greater Withdrawal predicted lower empathic Perspective-Taking (β=-0.62, p <0.05), suggesting social disengagement impairs considering others' viewpoints. Worry and Cognitive Concern predicted greater Emotion Comprehension (β=0.40, p <0.05; β=0.26, p <0.05) but lower Empathic Concern (β=-1.34, p <0.001; β=-0.54, p <0.05), showing that patients with these mood states more accurately identify others emotional expressions while still struggling to engage empathically. Finally, individuals with greater Hopelessness felt more overwhelmed in social interactions (Personal Distress: β=1.23, p <0.05).

CONCLUSION: Depression significantly impacts both emotion reading and real-life empathy in AD, including empathic concern and perspective-taking. Negative mood (dysphoria and hopelessness) hindered emotional connection despite having no effect on emotion reading. Increased mental rumination (worry and concerns about cognition) was linked to reduced empathic engagement, despite heightened emotion comprehension skills. These complex relationships underscore the importance of identifying the specific nature of depressive symptoms when evaluating individuals with early-stage AD, to better implement targeted interventions that preserve social engagement and emotional well-being.},
}

Humans
Female
Male
Aged
*Empathy
*Depression/psychology
*Alzheimer Disease/psychology/complications
*Emotions
Aged, 80 and over
Psychiatric Status Rating Scales
Neuropsychological Tests

@article {pmid41449031,
year = {2025},
author = {de Oliveira Alves, J},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102396},
doi = {10.1002/alz70856_102396},
pmid = {41449031},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Early Diagnosis ; Dementia/diagnosis ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and other dementias pose a significant global challenge, with a projected substantial increase in prevalence over the coming decades (JANNATI, 2024). Early detection of AD, particularly during the preclinical stage, is crucial for implementing effective interventions to slow disease progression (ALTY, 2024). However, traditional cognitive assessment methods, such as the Mini-Mental State Examination (MMSE), have notable limitations, including low sensitivity to mild cognitive changes and susceptibility to demographic factors like age and education level (ALTY, 2022). Furthermore, these tests are often time-consuming and require specialized training for administration (JANNATI, 2024). These challenges underscore the urgent need for more sensitive, rapid, and accessible tools for dementia screening, particularly in primary care settings (ALTY, 2024).

METHOD: This analysis reviewed three studies published within the past five years, retrieved from the Medline database, focusing on novel approaches for early detection of AD. The first study evaluated the efficacy of the Digital Clock and Recall (DCR) test compared to the MMSE in identifying mild cognitive impairment (MCI) and early dementia. The second study investigated TapTalk, a smartphone-based test that combines hand movement and speech analysis with blood biomarkers such as p-tau181 to assess preclinical AD risk. The third study validated the TAS Test, an online tool that integrates motor-cognitive functions and correlates them with p-tau181 levels to classify preclinical AD risk.

RESULT: The studies revealed promising results. The DCR demonstrated higher accuracy and sensitivity than the MMSE in detecting MCI, requiring less than three minutes to administer and being less influenced by demographic factors. TapTalk identified hand movement and speech patterns associated with preclinical AD risk, showing potential as a non-invasive and accessible tool. The TAS Test effectively detected subtle motor changes that may precede cognitive symptoms, highlighting its usefulness in early AD stages.

CONCLUSION: These studies emphasize the potential of digital assessments and biomarkers as innovative, sensitive, and accessible methods for early detection of AD. Their large-scale application could transform dementia screening and enable earlier, more effective interventions, particularly in primary care settings.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/diagnosis
*Cognitive Dysfunction/diagnosis
Neuropsychological Tests
Early Diagnosis
Dementia/diagnosis

@article {pmid41449005,
year = {2025},
author = {Cummings, J and Sharma, S and Andrea, G and Osse, AL and Ortiz, A},
title = {The roles of biomarkers in Alzheimer's disease clinical trials.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00811},
doi = {10.1016/j.neurot.2025.e00811},
pmid = {41449005},
issn = {1878-7479},
abstract = {Biomarkers are essential to guide decision making in Alzheimer's disease (AD) clinical trials where they have a variety of contexts of use (COUs) including diagnosis, risk, pharmacodynamic response, prognosis, prediction, monitoring, and safety. The COU of biomarkers may differ by phase of drug development with Phase 1, 2, and 3 emphasizing different types of information for decision making. A variety of biomarkers are currently serving as pharmacodynamic outcomes in clinical trials including amyloid and tau PET and fluid measures of amyloid, tau, neurodegeneration, inflammation, and synaptic plasticity. Biomarker strategies are integrated throughout drug development programs from collection and assay performance to statistical analysis and data interpretation. Data interrogation approaches using artificial intelligence and machine learning may enhance the value of biomarker observations through integration of multimodal data. Emerging biomarkers that may play a role in future AD trials include proteomics, exosome assays of co-pathology occurring in AD, EEG, ocular measures, and digital biomarkers. Biomarkers inform drug development decision-making including termination of candidate agents without sufficient biomarker effects, resourcing of promising therapies impacting the fundamental features of AD, and accelerating the development of new therapies for those with or at risk for AD.},
}

@article {pmid41448963,
year = {2025},
author = {Dahroug, N and Eltayeb, EAI and Alamin, A and Abdalla, E and Sayed, SBH and Elshabrawi, MN and Abdelrahman, NG},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101645},
doi = {10.1002/alz70858_101645},
pmid = {41448963},
issn = {1552-5279},
mesh = {Humans ; *Quality of Life/psychology ; *Alzheimer Disease/psychology/therapy ; *Wearable Electronic Devices ; *Dementia/psychology/therapy ; Activities of Daily Living ; },
abstract = {BACKGROUND: Alzheimer's disease is marked by progressive cognitive decline, including impairments in spatial awareness and short-term memory. With the global prevalence of dementia, including Alzheimer's disease, expected to rise from 57 million cases in 2019 to nearly 153 million by 2050, innovative solutions are urgently needed. This systematic review aims to explore the role of wearable technology in improving the daily lives of Alzheimer's patients by evaluating its effectiveness.

METHOD: Utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic review on the efficacy of wearable technology in enhancing the quality of life for Alzheimer's patients. A comprehensive search of PubMed, Google Scholar, Cochrane, and Scopus was performed using keywords such as "assistive technology," "wearable device," and "Alzheimer's." We included peer-reviewed studies, published in English between 2015 and 2025, involving human participants diagnosed with Alzheimer's that assessed the impact of wearable devices on quality of life. Data extraction was independently conducted by three reviewers, and quality assessment was completed using the Critical Appraisal Skills Programme (CASP).

RESULT: Out of 13,077 studies, five met the inclusion criteria, with the majority excluded due to lack of relevant outcomes. Qualitative analysis revealed that three studies using SenseCam, a wearable camera employed as a memory aid, demonstrated consistently significant improvements in autobiographical, episodic, and semantic memory over both short- and long-term follow-ups, along with short-term reductions in depressive symptoms and enhancements in activities of daily living. A study with a Bluetooth earpiece that provided task reminders, instructions, and encouragement showed task initiation and completion rates increasing from below 35% to over 90%, indicating improved independence. On the other hand, the Microsoft HoloLens, an augmented reality headset, showed no significant improvements in task performance.

CONCLUSION: This review identified wearable devices as promising tools for enhancing cognitive function, emotional well-being, and daily activities in Alzheimer's care. While some devices significantly improved patients' quality of life, others require further refinement. These findings highlight the transformative potential of wearable technology and emphasize the need for continued research and user-centered design to overcome implementation challenges and optimize integration in both clinical and home settings.},
}

Humans
*Quality of Life/psychology
*Alzheimer Disease/psychology/therapy
*Wearable Electronic Devices
*Dementia/psychology/therapy
Activities of Daily Living

@article {pmid41448961,
year = {2025},
author = {Gomez, ML and Scollard, P and Biber, S and Cuccaro, ML and Mez, J and Choi, SE and Klinedinst, B and Lee, ML and Toga, AW and Sathe, A and Clifton, MJ and Zyski, J and Durant, A and Turner, S and Kukull, WW and Saykin, AJ and Nho, K and Keene, CD and Mukherjee, S and Larson, EB and Soldan, A and Albert, MSS and Beason-Held, LL and Walker, KA and Ferrucci, L and Bilgel, M and Resnick, SM and An, Y and Hassenstab, JJ and Cruchaga, C and Timsina, J and Engelman, CD and Johnson, SC and Mayeux, R and Gifford, KA and Jefferson, AL and Koran, MEI and Liu, D and Pechman, KR and Brickman, A and Lee, AJ and Manly, JJ and Renteria, MA and Vardarajan, BN and Bennett, DAA and Schneider, JA and Barnes, LL and Archer, DB and Crane, PK and Dumitrescu, L and Hohman, TJ and Wilson, JE},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105147},
doi = {10.1002/alz70857_105147},
pmid = {41448961},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics ; Longitudinal Studies ; *Executive Function/physiology ; Neuropsychological Tests/statistics & numerical data ; *Alzheimer Disease/genetics ; Memory/physiology ; Aged, 80 and over ; Language ; },
abstract = {BACKGROUND: Late-life cognitive trajectories display heterogeneity between individuals and across cognitive domains. We aimed to identify latent classes of cognitive trajectories among three cognitive domains (memory, executive function, and language) and to investigate their association with baseline demographic and clinical characteristics.

METHOD: Harmonized data were obtained from 14 longitudinal cohorts of cognitive aging and dementia. Participants were restricted to those with at least 3 observations for each domain (memory, language and executive function). We developed three latent class linear mixed models, whereby each composite domain was modeled as both a linear and quadratic function of age. Separate models were developed with 1 through 5 classes. We assessed goodness of fit through a comparison of class proportions, AIC, BIC, and entropy. Baseline variables were compared across classes, with ANOVA for continuous and Chi-square for categorical variables.

RESULT: We included 38,358 participants (73% non-Hispanic white, 41% male, age=73 ± 9 years, education = 15 ± 4, mild cognitive impairment=19%, Alzheimer's disease = 14%, APOE-ε4=31%, APOE-ε2=13%) (Table 1). Across domains, the 4-class model displayed the best performance (Figure 1) including non-decliners, slow decliners, steady decliners, and rapid decliners. The memory classes deviated from the other two domains with the rapid decliners class displaying poor performance at younger ages with a less precipitous decline, whereas the rapid decline group in the other two domains declined rapidly with age. Across domains, the non-decliners had the highest proportion of non-Hispanic Black, cognitively unimpaired, ε2 carriers, and lowest proportion of ε4 carriers. Slow decliners were older and included more ε2 carriers. Steady decliners had the second highest proportion of AD at baseline and had the highest or second highest proportion of ε4 carriers. Rapid decliners had the highest proportion of AD at baseline, and the highest or second highest proportion of ε4 carriers.

CONCLUSION: While multiple subgroups move from cognitively normal to dementia, our latent class approach highlights subtypes that decline at different times and at different rates. Future work will seek to integrate disease time into models, clarify the stability of the observed subgroups of decliners, and characterize the neuropathological and neuroimaging features that contribute to the distinct etiologies of decline across domains.},
}

Humans
Male
Female
Aged
*Cognitive Dysfunction/genetics
Longitudinal Studies
*Executive Function/physiology
Neuropsychological Tests/statistics & numerical data
*Alzheimer Disease/genetics
Memory/physiology
Aged, 80 and over
Language

@article {pmid41448957,
year = {2025},
author = {Waszak, JL and Gach, G and Hovey, C and Martin, N and Zawada, M},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e102226},
doi = {10.1002/alz70858_102226},
pmid = {41448957},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; *Angiotensin Receptor Antagonists/therapeutic use ; *Dementia/psychology/drug therapy ; Clinical Trials as Topic ; },
abstract = {BACKGROUND: There has been a growing interest in providing pharmacological therapy for the stage in Alzheimer's Disease (AD) where there are no noticeable cognitive symptoms, but pathological changes begin. This stage is defined as Preclinical AD. Monoclonal antibody drugs are being developed to provide disease-modifying effects in Preclinical AD. There is a need for an option that is easily administered, cost-effective, and widely available that can provide potential neuroprotective benefits. Angiotensin II Receptor Blockers (ARBs) are a potential protective therapeutic for Preclinical AD through anti-inflammatory and vasodilatory pathways which can clear Ab in the brain, reducing plaque formation. This review explores what is known about ARBs in AD through various well-known clinical trials while commenting on their potential use as a therapeutic in Preclinical AD.

METHOD: Performed literature searches in databases such as PubMed, NIH Clinical Trials, NEJM, and JAMA using keywords such as "Alzheimer's Disease", "Preclinical", and "ARBs".

RESULT: A select few studies are well-established and published in notable journals that describe the use of ARBs in cognitively normal (CN) older adults and symptomatic AD. The CN studies, Study on Cognition and Prognosis in the Elderly (SCOPE), and ONTARGET/TRANSCEND were among the first studies to investigate the neuroprotective effects of ARBs as secondary endpoints. The symptomatic AD studies "Reducing the pathology of AD through Angiotensin Targeting" (RADAR) and "Candesartan's effects on AD and related biomarkers" (CEDAR) use current methods in exploring the potential efficacy of ARBs in symptomatic AD. CEDAR showed reduced Ab accumulation in groups treated with candesartan.

CONCLUSION: Disease-modifying effects have been observed from monoclonal antibodies in symptomatic AD clinical trials. These are now being tested in Preclinical AD. ARBs may provide additional neuroprotective effects. It is also an appropriate option for those who don't have the economic or geographic means to receive monoclonal antibody infusions. With novel blood biomarkers for tau and Ab, Preclinical AD can be more easily diagnosed in the future. If this is the case, then perhaps prescribing an ARB preliminarily could slow any early pathological process occurring. In addition to a monoclonal antibody, the effects could be even more pronounced.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
*Angiotensin Receptor Antagonists/therapeutic use
*Dementia/psychology/drug therapy
Clinical Trials as Topic

@article {pmid41448956,
year = {2025},
author = {Wilburn, R and Davis, L and Gierzynski, TF and Dinh, J and Hanson, K and Bunker, H and Flores, B and Fox-Fuller, JT and Gadwa, R and Bhaumik, AK and Roberts, JS and Paulson, HL and Rahman-Filipiak, A},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101108},
doi = {10.1002/alz70858_101108},
pmid = {41448956},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Registries ; Surveys and Questionnaires ; *Patient Selection ; Michigan ; *Alzheimer Disease/psychology ; Aged, 80 and over ; *Dementia/psychology ; Middle Aged ; *Biomedical Research ; },
abstract = {BACKGROUND: In the Alzheimer's Disease Research Center (ADRC) network and beyond, registries are commonly established to support representative recruitment into longitudinal cohorts and affiliated studies. While significant attention has focused on how to recruit potential participants into registries, less is known about how to promote registry engagement including matriculation into affiliated studies and attendance at research events. This study aims to identify the barriers and facilitators to participating in Alzheimer's disease (AD) research among diverse older adults in a longstanding AD research registry.

METHOD: An electronic survey was sent to all participants in the Michigan ADRC MiNDSet research registry between November and December 2024. 540 participants (age=71.7±7.7, education = 16.6 ±2.2) responded, 67.2% of whom self-identified as female, 77 % of whom identified as white, 14% of whom identified as Black, and 1.3% of whom identified as Asian. Survey items explored demographic and social factors, reasons for signing up for the registry, and barriers versus facilitators to engaging in studies to which registry members had been referred.

RESULT: The most reported deterrents to enrolling in studies were conflicts of schedule (n = 54) and location of visit (n = 47), while lack of trust (n = 2) or personal benefit (n = 12) did not deter participants. 63.7 % of respondents endorsed having a positive experience in research, with staff empathy, staff competency and the opportunity for feedback identified as thematic incentives in participant free responses. The potential for feedback was the most identified factor contributing to positive participant experience. 97 % of participants were interested in future studies, including Education and Support studies (60%), Diagnostic and Feedback studies (59%), Genetic Treatments (54%), and Non-Pharmacologic Trials (54%).

CONCLUSION: While the sample represents those most engaged in the MADRC registry, preliminary results highlight several tangible targets for studies wishing to recruit diverse older adults into AD research. Logistical flexibility around location and timing of visits may reduce burden and thereby increase willingness to engage in studies. The degree of preparation, organization, communication, and empathy of the study staff can serve as facilitators to engagement. The opportunity to learn individual research results can greatly enhance engagement in research.},
}

Humans
Female
Male
Aged
*Registries
Surveys and Questionnaires
*Patient Selection
Michigan
*Alzheimer Disease/psychology
Aged, 80 and over
*Dementia/psychology
Middle Aged
*Biomedical Research

@article {pmid41448943,
year = {2025},
author = {Patil, VS and Dutta, BJ and Singh, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101945},
doi = {10.1002/alz70859_101945},
pmid = {41448943},
issn = {1552-5279},
mesh = {Animals ; *Dementia, Vascular/drug therapy ; *Drug Development ; Humans ; *Stilbenes/administration & dosage/pharmacology ; Rats ; Administration, Intranasal ; Nanoparticles ; },
abstract = {BACKGROUND: Vascular dementia (VaD), a heterogeneous neurocognitive disorder, arises from cerebrovascular pathology that impairs cerebral blood flow, causing progressive cognitive decline. It is the second most common form of dementia globally, after Alzheimer's disease. Pterostilbene (PTE), a natural stilbene derivative, has shown promise as a therapeutic candidate for VaD due to its antioxidative, anti-inflammatory, and neurogenic properties. However, its clinical utility is limited by poor water solubility and low bioavailability.

METHOD: To address these limitations, a PTE-loaded nanoemulsion (PNE) was developed and converted into a thermoresponsive mucoadhesive nanoemulgel (PNEG) for nasal delivery to facilitate direct brain transport. PNE was formulated using the aqueous microtitration method with medium-chain triglycerides as the oil phase, Tween 80 as the surfactant, and PEG 200 as the co-surfactant. Chitosan and poloxamer 407 were incorporated into PNEG as mucoadhesive and thermoresponsive polymers, respectively. The formulations were characterized for particle size, zeta potential, encapsulation efficiency, morphology, mucoadhesive strength, in vitro drug release, and ex vivo nasal permeation. Cellular toxicity and uptake studies were conducted in RPMI 2650 and SH-SY5Y cell lines, and efficacy was evaluated in a rat model of vascular dementia induced by bilateral common carotid artery occlusion (BCCAO).

RESULT: PNEG demonstrated favorable physicochemical properties, including a particle size of 76.49 ± 0.35 nm, zeta potential of 14.97 ± 3.58 mV, PDI of 0.2704 ± 0.0123, and strong mucoadhesive strength (5.63 g). Transmission electron microscopy revealed a uniform spherical nanoparticle morphology. Cytotoxicity and cellular uptake studies confirmed the safety and efficacy of the formulations. In vivo studies showed significant cognitive improvement in PNE- and PNEG-treated VaD rats, as assessed by the Morris Water Maze and Novel Object Recognition Test. Both formulations reduced oxidative stress, hippocampal apoptosis, and neuroinflammation, with PNEG exhibiting superior efficacy via modulation of the SIRT1/Nrf2/HO-1 pathway.

CONCLUSION: PNEG is a promising therapeutic strategy for vascular dementia, addressing the limitations of conventional formulations and enhancing brain bioavailability. This approach offers potential for improved management of VaD through targeted neuroprotection and cognitive preservation.},
}

Animals
*Dementia, Vascular/drug therapy
*Drug Development
Humans
*Stilbenes/administration & dosage/pharmacology
Rats
Administration, Intranasal
Nanoparticles

@article {pmid41448938,
year = {2025},
author = {Sahelijo, NJ and Goldstein, D and Jun, GR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103575},
doi = {10.1002/alz70856_103575},
pmid = {41448938},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/genetics/diagnosis/blood ; Male ; Female ; Aged ; },
abstract = {BACKGROUND: Genetic subtyping can identify subpopulations at risk for developing Alzheimer Disease (AD), but it cannot detect definitive disease progression. Plasma biomarkers enable a cost-effective, noninvasive approach to early detection of AD disease.

METHOD: We defined genetic subtypes by calculating cell-based polygenic risk scores (cbPRSs) with a suggestive significance (p < 1×10[-5]) in 8,481subjects from the Framingham Heart Study (FHS) using previously described procedures (Sahelijo et al., 2023). We defined high- and low-risk individuals for four cell-specific subtypes using the first and fourth quartiles of the cbPRS distribution in FHS. We analyzed differential expression of 1377 SOMAscan aptamer-based plasma proteins between high- and low-risk individuals in FHS using the LIMMA R software package, adjusting for age and sex. Pathway analysis was conducted for nominally significant differentially expressed proteins (DEP) with p <0.05 using Metascape software. Finally, we validated the identified subtype-specific DEPs using clinically or neuropathologically defined AD diagnosis in autopsied brains from Boston University Alzheimer's Disease Research Center to identify the overlap of the subtype DEP with AD DEP using gene set enrichment analysis (GSEA).

RESULT: Genetic subtypes were defined for two astrocyte and two oligodendrocyte networks with low and high-risk sample sizes ranging from 2,072 to 2,090 subjects in FHS. Differential expression analysis revealed 59 to 91 nominally significant proteins with some overlapping proteins among the subtypes. All four subtypes exhibited enrichment for pathways associated with cytokine regulation and immune response. Top plasma DEP for Ast-M2 was the MMP-8 protein, which was validated in brain DEP for clinical and pathological AD (pAstM2= 4.63×10[-5], pclinicalAD=9.98×10[-5], pPathAD=3.2×10[-3]). Moreover, using GSEA we identified significant enrichment of DEP in clinical AD with Ast-M2 DEP (pAstM2=1.30×10[-2]) and pathological AD with Ast-M10 DEP (pAstM10=3.72×10[-4]).

CONCLUSION: Plasma protein levels from at-risk individuals for cell-based genetic subtypes exhibited considerable enrichment for neuroinflammatory proteins, indicating potential as genetic-subtype-specific biomarkers. These results highlight plasma biomarkers as cost-effective tools for early detection in genetically at-risk individuals of specific brain cell types.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/genetics/diagnosis/blood
Male
Female
Aged

@article {pmid41448920,
year = {2025},
author = {Dhillon, A},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101443},
doi = {10.1002/alz70858_101443},
pmid = {41448920},
issn = {1552-5279},
mesh = {Humans ; *Dementia/epidemiology/therapy/psychology ; Prevalence ; *Alzheimer Disease/epidemiology/therapy/psychology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) accounts for 60-70% of dementia cases. Unlike other types, AD is characterized by amyloid plaques and neurofibrillary tangles causing neurodegeneration (Kalaria, 2018; McKeith et al., 2005). The predictable course begins with memory loss and progresses to severe cognitive impairment. With significant social and economic impact, addressing AD's burden in regions like MENA is crucial for effective public health planning and targeted interventions.

METHODS: A comprehensive literature search was conducted using reputable databases, including PubMed and Scopus. The search parameters were refined with specific keywords and Boolean operators to ensure relevance. A multi-step screening process reviewed titles, abstracts, and full texts to collect relevant information on methodology, sample size, interventions, outcomes, and key findings.

RESULTS: Our literature review found that dementia prevalence, including AD, has risen 3% since 1990 to 777.6 per 100,000 people in MENA by 2019. By 2050, 152 million people will live with dementia globally. MENA shows regional variations: Turkey and Bahrain have higher rates than the UAE and Afghanistan. Dementia costs $10.4-13.9 billion annually in MENA, including healthcare expenses and informal care. Healthcare disparities hinder AD diagnosis and treatment in low-income countries like Yemen and Afghanistan due to limited access to diagnostic tools, trained providers, and cultural stigma. In contrast, GCC nations have advanced early diagnosis and care systems. This highlights the need for policies that expand dementia care infrastructure, improve accessibility to diagnostic tools, and train healthcare providers to address AD management demands in under-resourced areas.

CONCLUSION: The MENA region requires urgent attention to understand dementia and AD causes. It is crucial to investigate public and healthcare professionals' understanding and attitudes towards AD, as well as proposed solutions to address gaps in the region. This study aims to fill this knowledge gap. References: 1. Kalaria, R. N. (2018). The pathology and pathophysiology of vascular dementia. Neuropharmacology, 134, 226-239. 2. McKeith, I. G., et al. (2005). Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology, 65(12), 1863-1872.},
}

Humans
*Dementia/epidemiology/therapy/psychology
Prevalence
*Alzheimer Disease/epidemiology/therapy/psychology

@article {pmid41448919,
year = {2025},
author = {Wang, P and Weiss, I and Zheng, P and Liu, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101773},
doi = {10.1002/alz70859_101773},
pmid = {41448919},
issn = {1552-5279},
mesh = {Animals ; Mice, Transgenic ; *Alzheimer Disease/pathology/genetics/metabolism/drug therapy ; Humans ; *Brain/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Mice ; Microglia/metabolism/pathology ; Disease Models, Animal ; tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) suggested associations between late-onset Alzheimer's Disease (AD) and polymorphisms in several Siglec genes in chromosome 19q13(1,2). In the brain, SIGLEC10 is exclusively and abundantly expressed in microglia. Spatial mRNA analysis from AD brain revealed increased Siglec10 mRNA proximal to Aβ plaques over distant brain tissues. Moreover, SIGLEC10 is progressively elevated in AD tauopathy. However, no data showed causative relationship between SIGLEC10 expression and AD pathogenesis.

METHOD: To examine the potential role for SIGLEC10 in AD pathogenesis, we created a transgenic mice line using human genomic fragment encompassing several SIGLECS including SIGLEC10. The transgene is crossed into mice with targeted deletion of SiglecG, the putative orthologue of human SIGLEC10. The transgenic mice and age-match syngeneic WT control mice were assessed for accumulation of Ab amyloid and pTau neurofilament tangles (NFT) by immunohistochemistry and the contribution of SIGLEC10 is confirmed by using an anti-SIGLEC10 mAb.

RESULT: Flow cytometry of single cell suspension of the brain tissue confirmed the microglia exclusive expression of the human SIGLEC10 among brain cells. Importantly, 9-13 months old SIGLEC10 transgenic mice exhibit marked increase of both NFT (immunostained by anti-phospho-Tau (Ser202, Thr205) antibody AT8) and Aβ plaques (immunostained by anti-beta amyloid Ab1-42 antibody H31L21). To confirm contribution of SIGLEC10 to accumulation both Tau and Aβ pathology, mice were treated with either vehicle or anti-SIGLEC10 antibody for 1 month and compared the accumulation of these protein aggregates in the brain. The results show significant reduction of the pTau aggregates and Aβ plaques by anti-SIGLEC10 mAb.

CONCLUSION: Mice with transgenic expression of unmutated human SIGLEC10 gene cluster in microglia presented with marked increase of both NTF and Aβ plaques at 9 to 13 months. Short-term 4-week anti-Siglec10 treatment significantly reduced both NTF and Aβ plaques in transgenic mice. These data demonstrate a causal relationship between SIGLEC10 and pathogenesis of late onset AD which is not associated with pathogenic mutations in early onset AD, such as APOE4, APP, PS1, PS2 or MAPT. To our knowledge, this is the first mouse model in which a single un-mutated human gene cluster exacerbate both pTau aggregates and Aβ plaques, two critical AD hallmarks.},
}

Animals
Mice, Transgenic
*Alzheimer Disease/pathology/genetics/metabolism/drug therapy
Humans
*Brain/pathology/metabolism
Amyloid beta-Peptides/metabolism
Mice
Microglia/metabolism/pathology
Disease Models, Animal
tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41448909,
year = {2025},
author = {Goulette, O and He, D and Basche, KE and Langhough, RE and Betthauser, TJ and Hermann, BP and Johnson, SC and Mueller, KD},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e107250},
doi = {10.1002/alz70857_107250},
pmid = {41448909},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Brain Injuries, Traumatic/complications/diagnostic imaging/genetics ; Apolipoprotein E4/genetics ; Middle Aged ; Neuropsychological Tests ; tau Proteins/metabolism ; *Alzheimer Disease/genetics/diagnostic imaging/complications ; Positron-Emission Tomography ; Aged, 80 and over ; Longitudinal Studies ; Registries ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: While both traumatic brain injury (TBI) and Alzheimer's disease (AD) are known to impair cognitive, language, and speech abilities, little to no research examines how a history of TBI interacts with AD-related predictors (e.g., amyloid and tau pathology, familial genetic factors) to influence longitudinal changes in cognitive and language outcomes.

METHOD: We included 308 cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) with available amyloid and tau PET imaging, APOE ε4 genetic status, and self-reported TBI history (TBI-=0, TBI+ >=1). Within each of three AD risk groups (i.e., A+, T+, or APOE e4 carriers), we examined TBI history*age interactions in relationship with cognitive-language outcomes using linear mixed-effects models, adjusting for sex, and WRAT-3 score [i.e., outcomes ∼ TBI group * age +sex+ WRAT-3+ (1|ID)]. We examined standardized cognitive measures of executive functioning/set-shifting (i.e., Digit Symbol Coding Test, Trail Making Test B Score), semantic-phonological processing (i.e., animal category fluency, letter fluency [C, F, L]), and connected speech measures from picture description (i.e., Fluency Index, Words per Minute, Correct-Information-Units/total words).

RESULT: In the A+ subset (Ntotal=108, NTBI+=35, NTBI-=73;, Table 1), we found that the TBI+ group exhibited greater average decline in letter fluency (p = 0.036) and the fluency index (i.e., increases in disfluent behavior; p =  0.035) compared to those without TBI (Figure 1). No significant associations were observed between TBI history and longitudinal changes outcomes in the sample of tau+ (Ntotal=73, NTBI+=25, NTBI-=48) and APOE ε4 allele carriers (Ntotal=127, NTBI+=40, NTBI-=87).

CONCLUSION: Our findings suggest that TBI, in combination with early AD amyloid accumulation, may accelerate communication declines, particularly manifesting as reduced letter fluency and increased speech disfluency. Presumably, these results indicate increased challenges in semantic and phonological retrieval due to the compounded impact of TBI and AD pathology in individuals who are cognitively unimpaired. Our study identifies potential early language indicators of decline; future analyses will investigate more complex TBI/biomarker relationships and additional outcomes.},
}

Humans
Male
Female
Aged
*Brain Injuries, Traumatic/complications/diagnostic imaging/genetics
Apolipoprotein E4/genetics
Middle Aged
Neuropsychological Tests
tau Proteins/metabolism
*Alzheimer Disease/genetics/diagnostic imaging/complications
Positron-Emission Tomography
Aged, 80 and over
Longitudinal Studies
Registries
Brain/diagnostic imaging

@article {pmid41448907,
year = {2025},
author = {Hill, JR and Rodriguez, MJ and Gardner, B and Stavig, MD and Golzarri-Arroyo, L and Macagno, ALM and Zoh, RS and Holden, R and Boustani, M},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e104864},
doi = {10.1002/alz70858_104864},
pmid = {41448907},
issn = {1552-5279},
mesh = {Humans ; *Caregivers/psychology ; Male ; Female ; *Social Support ; *Dementia/psychology/nursing ; Aged ; Depression/psychology ; Middle Aged ; *Social Class ; Cost of Illness ; Socioeconomic Factors ; },
abstract = {BACKGROUND: Socioeconomic status (SES) is associated with health disparities across populations, including older adults with Alzheimer's disease and related dementias (AD/ADRD) and their caregivers. How SES affects the severity of behavioral and psychological symptoms of dementia (BPSD), burden, social support, and depressive symptoms among caregivers is underexplored. The aim of the current study was to investigate the relationship between SES and these outcomes.

METHOD: Using baseline data collected from a larger study (N = 144), an ANCOVA was performed to compare BPSD severity, caregiver burden, depressive symptoms, and perceived social support between SES groups (race, education level, household income, employment, and insurance status).

RESULT: The ANCOVA demonstrated no significant overall differences in BPSD severity related to SES measures. Pairwise comparisons revealed caregivers employed full-time reported significantly lower BPSD severity than retired caregivers. Additionally, caregivers who were insured under Medicare plus another form of insurance (e.g. Medicare Advantage) reported significantly lower BPSD severity than caregivers with private insurance. There was a significant difference in caregiver perceived social support between income levels, with caregivers having a household income greater than $75,000 reporting higher social support than those earning less than $75,000. While the ANCOVA comparing burden and depressive symptoms to SES demonstrated no statistical significance, pairwise comparisons demonstrated a) caregivers who attained trade school or associate degrees or attended some undergraduate education reported higher caregiver burden than those who had high school degrees or lower, b) employed caregivers (full- and part-time) had lower burden than unemployed caregivers, c) caregivers with graduate degrees had less severe depressive symptoms than those with bachelor's degrees, and d) caregivers employed full-time had less severe depressive symptoms than unemployed caregivers.

CONCLUSION: Significant differences in BPSD severity and caregiver outcomes were identified between SES groups. Some of these differences reinforce previous findings (e.g. unemployment resulting in higher burden) while others added to the literature (e.g. caregivers employed full-time reporting lower BPSD severity). The effects of SES on BPSD severity and caregiver burden are important to consider when creating interventions. Future studies should focus on exploring these relationships with larger samples and with other groups (e.g. Hispanic/Latino/a ethnicity, other racial identities).},
}

Humans
*Caregivers/psychology
Male
Female
*Social Support
*Dementia/psychology/nursing
Aged
Depression/psychology
Middle Aged
*Social Class
Cost of Illness
Socioeconomic Factors

@article {pmid41448904,
year = {2025},
author = {Aliwa, BO and Shah, J and Nesic-Taylor, O and Nguku, S and Waa, S and Hooker, J and Sokhi, D and Mbugua, S and Musili, L and Maina, RW and Kaleli, H and Muyela, LA and Gitere, AN and Njogu, AN and Merali, Z and Blackmon, K and Udeh-Momoh, CT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103368},
doi = {10.1002/alz70856_103368},
pmid = {41448904},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; Aged ; *Dementia/blood/diagnosis ; Glomerular Filtration Rate/physiology ; *Thyroxine/blood ; Middle Aged ; Aged, 80 and over ; Thyroid Function Tests ; },
abstract = {BACKGROUND: Over 55 million people worldwide live with dementia, with more than 60% residing in low- and middle-income countries. Alzheimer's disease, the most common form of dementia, accounts for 60-70% of cases. Early and accurate diagnosis remains a global challenge, necessitating novel approaches to mitigate the disease burden. Biomarkers hold significant promise in improving diagnostic accuracy and predicting disease progression. Validated biomarkers for the preclinical stages of dementia are crucial for advancing diagnosis and therapeutic strategies. We aimed to identify potential clinical markers for early dementia detection and assess their predictive accuracy in identifying high-risk individuals.

METHOD: We analyzed blood samples from dementia cases (n = 30) and controls (n = 75) for clinical parameters, including renal and liver function tests, lipid profiles, thyroid function tests, glomerular filtration rate (GFR), vitamin B12, and fasting glucose.

RESULT: Dementia cases showed significantly elevated high-density lipoprotein (HDL), free thyroxine (FT4), and vitamin B-12 (P = 0.0002, P = 0.015, and P = 0.004, respectively) compared to controls. We also observed significant reductions in GFR, free triiodothyronine (FT3), and the cholesterol-to-HDL ratio (P = 0.003, P = 0.0002, and P = 0.05, respectively). Logistic regression confirmed associations between HDL (Odds: 10.8, 95% CI: 0.34-5.01, P = 0.04) and FT4 (Odds: 33.78, 95% CI: 0.64-7.20, P = 0.028) with dementia after adjusting for age and sex. Vitamin B-12, FT3, GFR, and the cholesterol-to-HDL ratio were not significantly associated with dementia (P > 0.05). Predictive models demonstrated strong performance (R[2] = 0.47-0.52).

CONCLUSION: Our findings demonstrated the potential of HDL and FT4 as blood-based clinical markers for early detection of cognitive impairment and dementia.},
}

Humans
*Biomarkers/blood
Male
Female
Aged
*Dementia/blood/diagnosis
Glomerular Filtration Rate/physiology
*Thyroxine/blood
Middle Aged
Aged, 80 and over
Thyroid Function Tests

@article {pmid41448900,
year = {2025},
author = {Marin-Díaz, NP and Migeot, J and Rippes, ME and Hernandez, H and Caviedes, A and Hazelton, JL and Oyanedel, L and Franco, TR and Olavarria, L and Ibanez, A and Custodio, N and Montesinos, R and Bruno, MA and Funes, JAA and Slachevsky, A and Duran-Aniotz, C and Gonzalez-Silva, C},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105735},
doi = {10.1002/alz70857_105735},
pmid = {41448900},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Depression/epidemiology ; *Alzheimer Disease/epidemiology/complications/psychology ; *Chronic Pain/epidemiology ; Neuropsychological Tests ; Argentina ; Cohort Studies ; Aged, 80 and over ; Mexico ; Peru ; },
abstract = {BACKGROUND: Chronic pain (CP) and depression frequently co-occur in the elderly, severely impacting individuals with Alzheimer's disease (AD). Their overlapping neurobiological pathways exacerbate each other, accelerating functional decline and worsening cognitive deficits. Untreated CP and depression may even contribute to dementia progression, while adverse social determinants of health (SDH) further compound their effects. However, the triadic relationship between CP, depression, and AD remains poorly understood, particularly in Latin American (LA) populations, where health disparities and environmental factors may shape outcomes. This study explores their interplay in this underrepresented context.

METHOD: A cohort of 320 older adults, including 146 individuals with AD and 174 healthy controls (HC), was recruited from Chile, Argentina, Mexico, and Peru. The sample was sex-balanced, and all participants provided informed consent in accordance with the Declaration of Helsinki. Recruitment was facilitated through the Multicenter Consortium to Expand Dementia Research in Latin America (ReDLat), utilizing standardized protocols across all sites. Data collection encompassed neuropsychological assessments, CP and depression evaluations, SDH measures, and demographic factors. CP was assessed through indicators such as pain frequency, intensity, and symptom severity, while depression was evaluated using validated scales.

RESULT: Structural equation modeling (SEM) revealed that depression significantly mediated the relationship between CP and AD. A marginally significant positive association was identified between depression and CP (p = 0.050), and a strong association was observed between depression and AD (p = 0.001). CP, as represented by pain frequency, intensity, and symptom severity, demonstrated high explanatory power (R[2] = 97.6%). Depression also showed a strong association with dementia risk (R[2] = 96.4%). Furthermore, unfavorable SDH were positively correlated with higher CP and depression scores.

CONCLUSION: These findings underscore the critical role of depression as a mediator in the CP-AD relationship, which is further exacerbated by adverse SDH in older adults from LA. Addressing social disparities and improving access to mental health and pain management services are essential for mitigating dementia risk and improving overall health outcomes in this vulnerable population.},
}

Humans
Male
Female
Aged
*Depression/epidemiology
*Alzheimer Disease/epidemiology/complications/psychology
*Chronic Pain/epidemiology
Neuropsychological Tests
Argentina
Cohort Studies
Aged, 80 and over
Mexico
Peru

@article {pmid41448898,
year = {2025},
author = {Maher, AC and Bartha, R and Culum, I and Finger, E and Geula, C and Goldstein, FC and Huentelman, MJ and Lim, A and Martersteck, A and Mesulam, M and Okonkwo, OC and Paulson, HL and Roberts, AC and Rose, E and Timpo, P and Trammell, AR and Swartz, RH and Ooteghem, KV and Rogalski, EJ and , },
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104075},
doi = {10.1002/alz70857_104075},
pmid = {41448898},
issn = {1552-5279},
mesh = {Humans ; Longitudinal Studies ; Male ; Aged, 80 and over ; Female ; United States ; *Cognitive Dysfunction ; *Aging/physiology ; Canada ; Aged ; *Cognitive Aging/physiology ; Alzheimer Disease ; *Memory, Episodic ; },
abstract = {BACKGROUND: Established in 2021, the SuperAging Research Initiative is a multisite, longitudinal study focused on identifying resilience and resistance factors that promote successful cognitive aging. "SuperAgers" are defined as individuals age 80+ with episodic memory performance that is average or better for individuals 20-30 years younger. The SuperAging Research Initiative aims to advance knowledge of the neurobiology of brain aging, resilience, and resistance against "typical" age-related cognitive decline and pathologic declines seen in Alzheimer's disease and related disorders. The SuperAging Research Initiative is focused on increasing racial-ethnic, geographical, and educational diversity by enrolling 500+ participants across the United States and Canada. The mid-project recruitment and enrollment success, baseline participant characteristics, and initial study findings from the unique cohort are highlighted.

METHOD: Participant enrollment and harmonized data collection is ongoing at five North American sites. The protocol includes behavioral, biological, environmental, genetic, and psychosocial characteristics that may contribute to successful cognitive aging. Two embedded Research Projects provide focused opportunities to extend the depth and breadth of science. Project 1 utilizes state-of-the-art wearable technology to obtain quantitative measurements of daily activity, and Project 2 uses transcriptomic, genetic, and protein profiling to examine immune and inflammatory system parameters.

RESULT: Across sites, >280 participants (ages 80-101 with 6-20 years education) have enrolled in the harmonized protocol using community engaged research (CER) strategies. More than 12 states/provinces are represented. To date, approximately 20% participants identify with a historically underrepresented racial-ethnic group. Sites leveraging existing CER methodology have enrolled a higher percentage of racially diverse participants (30+%). The Project 1 protocol has shown strong feasibility (>90%), yielding high-quality data (>95% data recovery) for a fully remote sensor data collection protocol. Project 2 has begun initial analyses, and estimates to date suggest SuperAgers have similar Alzheimer's disease polygenic risk scores compared to their cognitively-average peers.

CONCLUSION: The prospective, longitudinal study of SuperAgers is feasible and provides a unique opportunity to identify mechanisms conferring cognitive resilience and resistance against "typical" and pathologic age-related cognitive decline. Outcomes may identify novel modifiable factors that promote successful cognitive aging.},
}

Humans
Longitudinal Studies
Male
Aged, 80 and over
Female
United States
*Cognitive Dysfunction
*Aging/physiology
Canada
Aged
*Cognitive Aging/physiology
Alzheimer Disease
*Memory, Episodic

@article {pmid41448897,
year = {2025},
author = {Schlemm, E and Gauthier, S and Magnus, T and Thomalla, G and Rosa-Neto, P and Woo, MS},
title = {Risk of amyloid-related imaging abnormalities associated with anticoagulant therapy in patients with Alzheimer's disease treated with anti-amyloid monoclonal antibodies: a systematic review and meta-analysis.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-337386},
pmid = {41448897},
issn = {1468-330X},
}

@article {pmid41448894,
year = {2025},
author = {Kerr, AV and Dossetor, J and Huynh, J and Hwang, YT},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100668},
doi = {10.1002/alz70858_100668},
pmid = {41448894},
issn = {1552-5279},
mesh = {Humans ; Male ; *Dementia/psychology/drug therapy ; Female ; Surveys and Questionnaires ; Aged ; Middle Aged ; Australia ; Caregivers/psychology ; *Medical Marijuana/therapeutic use ; Adult ; Aged, 80 and over ; Cannabinoids/therapeutic use ; },
abstract = {BACKGROUND: Dementia is a broad term that covers multiple conditions which affect the brain, such as Alzheimer's disease and Frontotemporal dementia. The collection of symptoms caused by these disorders vary and can include disrupted mood, apathy, agitation, aggression, disinhibition, and/or sleep. There has been increasing interest in exploring potential benefits of cannabis-derived medicine in alleviating neuropsychiatric symptoms of dementia. We examined the attitudes towards the use of cannabinoids for symptomatic treatment of dementia among Australian adults diagnosed with different dementia types, their caregivers, and healthy controls.

METHOD: Patients with a diagnosis of dementia, their caregivers, and healthy controls from the FRONTIER research database, at the University of Sydney, completed an online questionnaire assessing attitudes toward medicinal cannabis and cannabinoid use. The questionnaire inquired about the perceived benefits and risks of cannabis use; experience with cannabis use; and interest in participating in a hypothetical clinical trial using medicinal cannabis for the symptomatic treatment of dementia. There were 77 respondents to the questionnaire: 22 dementia patients, 30 study partners, and 25 healthy controls.

RESULT: Of respondents with a diagnosis of dementia, 73% said they would consider participating in a clinical trial exploring the potential therapeutic effects of medicinal cannabis. Out of all participants who completed the survey, 80% said they would consider participating in such a trial. While only 24% of the participants reported previous recreational or medicinal cannabis use, there remains a strong general interest in exploring the potential benefits of cannabinoids through clinical trials.

CONCLUSION: The results from this questionnaire show that there is a strong interest from Australian dementia patients and their caregivers to participate in future clinical trials that would assess the effectiveness of medicinal cannabis in alleviating dementia symptoms. As evidenced by this and other studies, there is growing support for the consideration of cannabis-derived products as medical treatments. We propose that robustly designed clinical trials with clearly defined outcome measures would be of interest and have the potential to expand symptomatic treatment options to those living with dementia.},
}

Humans
Male
*Dementia/psychology/drug therapy
Female
Surveys and Questionnaires
Aged
Middle Aged
Australia
Caregivers/psychology
*Medical Marijuana/therapeutic use
Adult
Aged, 80 and over
Cannabinoids/therapeutic use

@article {pmid41448892,
year = {2025},
author = {Sabbagh, MN and Macfarlane, S and Gabelle, A and Grimmer, T and Jin, K and Chezem, WR and Lopez-Talavera, JC and Missling, CU},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101346},
doi = {10.1002/alz70859_101346},
pmid = {41448892},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; Male ; Double-Blind Method ; Female ; Aged ; Treatment Outcome ; Administration, Oral ; },
abstract = {BACKGROUND: There are no approved oral disease-modifying small molecule therapies for treatment of early Alzheimer's disease (AD). Blarcamesine is an orally bioavailable small molecule that enhances autophagy through SIGMAR1 activation and restoration of cellular homeostasis in early AD.

METHOD: The ATTENTION-AD study was an up to 144-week open-label extension study subsequent the 48-Week Phase IIb/III double-blind placebo-controlled ANAVEX[®]2-73-AD-004 study, to evaluate the safety and efficacy of oral once daily blarcamesine in 508 participants with early AD. Delayed-start analysis was performed to assess the effect of early treatment initiation up to 192 Weeks.

RESULT: The ATTENTION-AD trial confirmed the good efficacy and safety profile of once daily oral blarcamesine and also demonstrated the manageable nature of the most frequent treatment emergent adverse event (TEAE) (dizziness) observed in the preceding ANAVEX[®]2-73-AD-004 trial, which was generally transient in duration (approx. 7-11 days) and mild or moderate in severity (Grade 1 or 2). The titration schedule was adjusted to a slightly longer titration period in the ATTENTION-AD trial, from previous 2-3 weeks to 10 weeks. A markedly lower frequency of the TEAE of dizziness in the respective maintenance phase was observed: from previously 25.2% in the ANAVEX[®]2-73-AD-004 trial to 9.6% in the ATTENTION-AD trial, demonstrating the manageable nature of this TEAE. No severe or life-threatening adverse events were attributed to blarcamesine. No Amyloid Related Imaging Abnormalities (ARIA) adverse events were identified. There were no deaths related to blarcamesine. Efficacy of the cognitive and functional endpoints in the delayed-start analysis of treatment resulted in significant outcomes, ADAS-Cog13 (LS mean difference -3.83, P = 0.0165) and ADCS-ADL (LS mean difference +4.30, P = 0.0206) at Week 192, reflecting importance of early treatment initiation with oral blarcamesine.

CONCLUSION: Blarcamesine significantly reduced clinical decline showing meaningful benefit for early Alzheimer's disease patients. Blarcamesine exhibited a favorable safety profile with no treatment-related deaths and demonstrated no associated neuroimaging adverse events with continued treatment over 4 years. Altogether, these results indicate that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
Male
Double-Blind Method
Female
Aged
Treatment Outcome
Administration, Oral

@article {pmid41448891,
year = {2025},
author = {Scharre, DW and Truelove, J and Kovesci, R and Ramamurthy, A and Thurin, K and Middleton, A and Bouchachi, S},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101678},
doi = {10.1002/alz70858_101678},
pmid = {41448891},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/diagnosis/drug therapy/therapy ; *Cognitive Dysfunction/drug therapy/psychology/diagnosis ; *Alzheimer Disease/drug therapy/psychology ; },
abstract = {Anti-amyloid monoclonal antibodies are approved for use in patients with Mild Cognitive Impairment due to Alzheimer's disease (MCI-AD) or mild AD dementia (ADD). In real world settings, the importance of efficient early-stage identification and careful patient selection, is critical for optimal outcomes and reduction of risks when using anti-amyloid therapies (AAT). We developed, at The Ohio State University, clinical guidelines for prescribing AAT including the identification of appropriate patients, required assessments, treatment, and monitoring. Our guideline selection criteria for appropriate patients require a change in memory or thinking over at least 6 months and a clinical diagnosis of MCI-AD or mild ADD which was operationally defined by specific cognitive assessment score cut offs (SAGE or BrainTest >9, MMSE>19, or MoCA >16), number of cognitive domains impaired (≥1 or ≤4 domains of memory, executive, attention, language, and visuospatial), and functional surveys that require hands-on assistance for one to four instrumental activities of daily living (ADLs) and the ability to perform all basic ADLs. Our guidelines required ruling out other non-Alzheimer's causes of cognitive impairment and verifying amyloid pathology by FDA approved AD biomarkers. Patients were excluded if they were on anticoagulants, unable to have a brain MRI, or with significant psychiatric symptoms making infusions unsafe or impractical. Our guidelines specify every 6-month cognitive and functional assessment monitoring as above with stoppage criteria for ATT including upon progression to moderate ADD stage. After 18 months of therapy, and every 6 months thereafter if they remain on donanemab therapy, our guidelines recommend that amyloid pathology should be reevaluated and if levels are normal, donanemab should be stooped. Lecanemab can be continued until progression to moderate ADD stage. Our guideline includes the FDA prescribing information regarding recommended infusion dosing and timing for lecanemab and donanemab, titration schedule for donanemab, and MRI safety monitoring. We present these clinical guidelines for ATT prescribing as an efficient way to identify appropriate patients and monitor them in real world practice settings. We encourage debate and alternative guidelines that are data-driven following clinical and real-world investigations, with the goal of improving on this guideline we presented.},
}

Humans
*Dementia/psychology/diagnosis/drug therapy/therapy
*Cognitive Dysfunction/drug therapy/psychology/diagnosis
*Alzheimer Disease/drug therapy/psychology

@article {pmid41448890,
year = {2025},
author = {Van Hulle, CA and Wyman, MF and Gleason, CE and Johnson, SC and Asthana, S and Carlsson, CM and Fischer, BL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104698},
doi = {10.1002/alz70857_104698},
pmid = {41448890},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; Neuropsychological Tests/statistics & numerical data ; Middle Aged ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: Mild Behavior Impairment (MBI), a syndrome referring to neuropsychiatric symptoms emerging in mid to late life, is common prior to dementia onset and may have a impact on cognitive decline. Subjective cognitive decline (SCD), the subjective perception of cognitive decline in the absence of objective cognitive impairment, is a potential risk factor for conversion to dementia. Evidence suggests combined SCD and MBI represents greater risk for conversion to cognitive impairment than either alone. For this study we explored the impact of SCD and MBI on cognitive performance in a relatively young, cognitively unimpaired sample.

METHOD: Participants from the Wisconsin Alzheimer's Disease Research Center were included if cognitively unimpaired at baseline. MBI was defined by a study partner endorsing any item on the Neuropsychiatric Inventory Questionnaire at two consecutive study visits. SCD was identified by reporting minor or major memory problems on the question, "How would you rate your memory?" Participants were categorized based on the presence or absence of MBI and SCD in the first four study visits. Cognitive outcomes included the Rey Auditory Verbal Learning Test Immediate and Delayed Recall and Trail Making Tests A and B. Linear mixed effects models were used to test the association between MBI/SCD group and cognitive performance over time. We examined the main effects of MBI/SCD group on overall cognitive performance after removing non-significant interactions.

RESULTS: N = 309 participants (mean age 56.3, range 45-66) provided N = 1,365 observations (see Table 1 for sample characteristics). Participants with SCD were more likely to meet criteria for MBI (χ[2][1] = 8.7, p = .001). The interaction between SCD/MBI group and time was inconsistent across outcomes and did not survive multiple correction (Table 2). Participants in the MBI+/SCD+ group had poorer overall performance on immediate recall while participants experiencing MBI with and without SCD had poorer overall performance on Trails A and B (Table 3).

CONCLUSION: These results suggest MBI alone may function as a marker for impaired executive function in middle aged participants at the earliest stages of disease. When seen in combination with SCD, MBI appears to portend impaired memory. Future work will investigate co-occurring pathology.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/psychology
Aged
Neuropsychological Tests/statistics & numerical data
Middle Aged
Surveys and Questionnaires

@article {pmid41448888,
year = {2025},
author = {Lee, JK and Lee, J and Shin, J and Lee, EJ and Kim, SW and An, SB and Han, H and Jang, G and Kim, B and Park, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101799},
doi = {10.1002/alz70859_101799},
pmid = {41448888},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Amyloid beta-Peptides/metabolism/immunology ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Development ; Microglia/drug effects/metabolism ; Phagocytosis/drug effects ; Disease Models, Animal ; Mice, Transgenic ; Axl Receptor Tyrosine Kinase ; },
abstract = {BACKGROUND: Amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer's disease (AD), and reducing Aβ burden is a key therapeutic strategy. Recent FDA-approved anti-Aβ antibodies, such as Lecanemab and Donanemab, have demonstrated significant reductions in Aβ burden and deceleration of cognitive decline. However, these therapies are associated with adverse events, including antibody-induced neuroinflammation and amyloid-related imaging abnormalities (ARIA). The GAIA platform leverages TAM receptors-Tyro3, Axl and MerTK-to facilitate efferocytosis-driven Aβ clearance without triggering inflammatory responses, addressing limitations of current anti-Aβ immunotherapies. This study evaluates the pharmacokinetic properties and therapeutic efficacy of GAIA-Aβ.

METHOD: GAIA-Aβ was engineered with dual functional domains, a GAS6 domain for TAM receptor binding and Aβ-targeting moiety. Specific binding to oligomeric Aβ (oAβ) and TAM receptors was confirmed using ELISA. TAM receptor-driven phagocytosis and oAβ clearance were evaluated using HMC3, human microglial cell line. Additionally, anti-inflammatory responses were assessed in induced pluripotent stem cell (iPSC)-derived monocytes. Pharmacokinetic properties of GAIA-Aβ were analyzed to determine serum exposure and brain-to-serum ratio. To evaluate the in vivo efficacy, GAIA-Aβ was intravenously administered to 5xFAD mice once weekly (QW) for 8 weeks, and Aβ plaque burden and glial phagocytic activity were assessed using immunohistochemistry.

RESULT: GAIA-Aβ exhibited specific binding to oAβ and activated TAM receptors in a dose-dependent manner. Phagocytosis assays demonstrated effective clearance of oAβ while reducing inflammatory cytokines, indicating successful efferocytosis-mediated activity. Pharmacokinetic analysis revealed that GAIA-Aβ possesses properties comparable to conventional monoclonal antibodies. In 5xFAD mice, GAIA-Aβ treatment led to significant reductions in Aβ plaques and enhanced glial-mediated clearance, particularly via astrocyte engagement.

CONCLUSION: GAIA-Aβ effectively reduces Aβ burden while mitigating neuroinflammation, presenting a favorable safety profile compared to existing anti-Aβ antibodies. These findings highlight the potential of GAIA-Aβ as an improved therapeutic approach for Alzheimer's disease, addressing the limitations of current anti-Aβ immunotherapies.},
}

Animals
Mice
*Amyloid beta-Peptides/metabolism/immunology
*Alzheimer Disease/drug therapy/metabolism
Humans
*Drug Development
Microglia/drug effects/metabolism
Phagocytosis/drug effects
Disease Models, Animal
Mice, Transgenic
Axl Receptor Tyrosine Kinase

@article {pmid41448885,
year = {2025},
author = {Hromas, G and Santiago-Mejias, S and Wang, CP and Fernandez, RA and Maestre, GE and Mejia-Arango, S and Bosque, JGD and Garcia, R and Garcia, DC and Gates, S and Hernandez, P and Valdez, MS and Seidl, AM and Trevino, HA and Toranzo, J and Ayvar, MU and Velarde, AG and Young, VM and Zapata, J and Rascovsky, K and Gonzalez, DA and Seshadri, S and LaRoche, A and Sullivan, AC},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e105625},
doi = {10.1002/alz70857_105625},
pmid = {41448885},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Multilingualism ; *Neuropsychological Tests ; Aged ; Hispanic or Latino ; Texas ; Middle Aged ; Language ; Aged, 80 and over ; *Alzheimer Disease/diagnosis/psychology ; White ; },
abstract = {BACKGROUND: Determining the language of neuropsychological assessment in a bilingual patient population is difficult with implications for test performance and clinical interpretation. We compared two methods of identifying language dominance for neuropsychological testing in a sample of bilingual (English/Spanish) Hispanic/Latine patients in South Texas.

METHOD: Research participants from the South Texas Alzheimer's Disease Research Center (STAC), who identified as bilingual were administered the CLS: Linguistic History Form, which asks individuals to provide a self-rating of their English and Spanish language proficiency, and verbal fluency tasks (F/L fluency in English, and P/M fluency in Spanish) to create a language dominance index (LDI) based on objective test performance.

RESULT: N = 66 participants completed both measures of language proficiency at the time of data extraction (Table 1). Ratios were calculated for each measure to determine a standardized language proficiency score. Scores ≤ 0.49 were classified as Spanish-dominant, scores = 0.5 were classified as purely bilingual, and scores ≥ 0.51 were classified as English-dominant (Figures 1 and 2). Paired samples t-test comparing the language proficiency ratios revealed that both classification methods performed similarly (t(65)=0.175, p = .431). With the CLS, 5 participants were classified as Spanish-dominant, 9 as purely bilingual, and 52 as English-dominant. With the verbal fluency-derived LDI, 9 individuals were classified as Spanish-dominant, 4 as purely bilingual, and 53 as English-dominant.

CONCLUSION: Here, we saw subtle (non-statistically significant) differences in subjective rating of language proficiency and objective measurement of language dominance. CLS classified 13.6% and 7.6% of the sample as bilingual or Spanish-speaking, respectively, while LDI classified 6.1% and 13.6% as bilingual or Spanish-speaking. A high percentage of the sample was classified as English-dominant regardless of measure (80.3% and 78.8%), possibly due to demographic factors (e.g., recruitment site, education level, and country of origin). Future analyses will explore these additional demographic influences as well as cognitive testing outcomes in a larger sample across multiple sites in South Texas.},
}

Humans
Male
Female
*Multilingualism
*Neuropsychological Tests
Aged
Hispanic or Latino
Texas
Middle Aged
Language
Aged, 80 and over
*Alzheimer Disease/diagnosis/psychology
White

@article {pmid41448883,
year = {2025},
author = {Lee, JS and Rhee, HY and Park, KC},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101851},
doi = {10.1002/alz70859_101851},
pmid = {41448883},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy/diet therapy ; Male ; Female ; Double-Blind Method ; Aged ; *Dietary Supplements ; *Drug Development ; *Probiotics/therapeutic use ; Alzheimer Disease ; Neuropsychological Tests ; *Gastrointestinal Microbiome/drug effects ; Middle Aged ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents the symptomatic pre-dementia stage of Alzheimer's disease (AD). Given the increasing prevalence of AD and its socioeconomic burden, delaying the progression of MCI to AD is critical. Modulating the microbiota-gut-brain (MGB) axis has emerged as a promising therapeutic approach. This study aimed to evaluate the efficacy and safety of MT104, a dietary supplement containing Cuscuta seeds and heat-killed probiotics, in regulating the MGB axis in patients with MCI.

METHOD: This multicenter, randomized, double-blind, placebo-controlled study involved participants randomly assigned in a 1:1 ratio to receive MT104 or placebo. Cognitive function was assessed using the Korean-Montreal Cognitive Assessment (K-MoCA) and Korean-Mini Mental State Examination at baseline and after 12 weeks of treatment. Visuospatial and memory functions were evaluated using the Rey Complex Figure Test and Seoul Verbal Learning Test (SVLT). Statistical analyses included t-tests, Mann-Whitney U tests, analysis of covariance (ANCOVA), and ranked ANCOVA.

RESULT: The mean changes in verbal memory function, as measured by SVLT delayed recall, showed clinically significant improvement in the MT104 group compared with the placebo group in the intention-to-treat and per-protocol groups. The global cognition, as measured by the K-MoCA, also significantly improved in the per-protocol group. Additionally, there were no significant findings regarding the safety profile of MT104.

CONCLUSION: MT104 improved memory performance and global cognition in patients with MCI without safety concerns. These findings support the potential of dietary therapeutic strategies to reduce the risk of progression from MCI to AD dementia. Further studies are needed to confirm these results and explore the long-term benefits of MT104.},
}

Humans
*Cognitive Dysfunction/drug therapy/diet therapy
Male
Female
Double-Blind Method
Aged
*Dietary Supplements
*Drug Development
*Probiotics/therapeutic use
Alzheimer Disease
Neuropsychological Tests
*Gastrointestinal Microbiome/drug effects
Middle Aged

@article {pmid41448877,
year = {2025},
author = {Middleton, LE and Grace, L and Vucea-Tirabassi, V and Aiken, C and Bethell, J and Cooke, HA and Keller, H and Liu-Ambrose, T and Norman, M and O'Connell, ME and Stapleton, JE and Waldron, I and Wu, SA and Yous, ML and McAiney, CA},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e105729},
doi = {10.1002/alz70858_105729},
pmid = {41448877},
issn = {1552-5279},
mesh = {Humans ; *Quality of Life/psychology ; *Dementia/psychology/therapy ; *Exercise/psychology ; Nutritional Status ; Life Style ; },
abstract = {BACKGROUND: There is limited research focused on lifestyle interventions among people living with dementia with recent systematic reviews primarily focused on the impact of exercise on cognition. However, functional abilities and quality of life (QoL) are the outcomes most consistently prioritized by people living with dementia, care partners, and healthcare professionals. We conducted a systematic review to understand the impact of two lifestyle interventions (physical activity, nutrition) on the functional abilities, QoL, and nutritional status (nutrition interventions only) of people with dementia living in the community. The findings here focus on the effects of physical activity interventions.

METHOD: Systematic literature searches for peer-reviewed intervention studies were conducted in four databases (MEDLINE, EMBASE, Scopus, CINAHL). Articles were exported to Covidence, where duplicates were removed and two independent reviewers performed study selection, data extraction, and risk of bias assessments. A narrative synthesis was conducted. A meta-analysis is currently ongoing.

RESULT: Fifty-five studies met the inclusion criteria and were included in this review. Data extraction revealed diverse study designs, characteristics and types of physical activity interventions, and measures for functional abilities and QoL. Nine studies measured the QoL of people living with dementia using the self-reported Quality of Life Alzheimer's Disease (QoLAD) tool. Four of these studies showed a significant improvement in the QoLAD. Twenty-five studies reported using the Timed Up and Go Test (TUG) to measure mobility. Fifteen of these studies demonstrated an improvement in the TUG, with nine of the studies revealing significant improvements. Six studies measured functional capacity using the 6-minute walk test. Two of these studies showed a significant improvement in the 6-minute walk test.

CONCLUSION: The results from this review highlight the impact of physical activity interventions on QoL and mobility for people living with dementia. The meta-analysis will provide quantitative estimates for the effects of physical activity interventions on specific outcomes related to functional abilities and QoL. Furthermore, exploring the effectiveness by intervention dose and delivery in subgroup analyses will also allow us to better inform guidelines regarding interventions, programs, and policy related to physical activity interventions. Lastly, we will identify knowledge gaps where research is needed.},
}

Humans
*Quality of Life/psychology
*Dementia/psychology/therapy
*Exercise/psychology
Nutritional Status
Life Style

@article {pmid41448876,
year = {2025},
author = {Charisis, S and Lu, S and Melgarejo, JD and Satizabal, CL and Vasan, RS and Beiser, AS and Seshadri, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102148},
doi = {10.1002/alz70856_102148},
pmid = {41448876},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Biomarkers/blood ; *Alzheimer Disease/blood/epidemiology ; Aged ; Middle Aged ; Incidence ; Cholesterol, LDL/blood ; *Lipoproteins/blood ; Risk Factors ; },
abstract = {BACKGROUND: Proteins involved in lipoprotein metabolism could lie in the causal pathway between cardiovascular health and Alzheimer's disease (AD). The strongest body of evidence exists for Apolipoproteins (Apo) E and J; however, other lipoproteins may be involved. To further explore the physiological links between cardiovascular health and AD risk, we studied the relationships between various blood lipoprotein concentrations and AD incidence in a community-based sample.

METHOD: This analysis included 822 participants ≥60 years of age without prevalent dementia from the Framingham Heart Study. Concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), lipoprotein a (Lp(a)), apolipoprotein B (ApoB), and the ApoB isoform ApoB48 - a specific marker of chylomicron metabolism - were measured by immunoturbidimetric assays and ELISA kits in blood samples obtained from 1985 to 1988. Participants were under surveillance for incident AD until 2020. AD diagnosis was based on standard clinical criteria. The relationships between blood lipoprotein concentrations and AD incidence were explored using Cox proportional hazards regression adjusting for baseline age and sex (Model 1). Additional models were further adjusted for education, vascular risk factors, and APOE genotype (Model 2).

RESULT: Mean baseline age (standard deviation) was 72.5 (3.7) years; 538 (65.5%) participants were women (Table 1). Over a median (interquartile range) of 12.55 (7.34, 15) years of follow-up, 128 participants (99 women) developed AD. A standard deviation unit (SDU) increase in ln(sdLDL-C) concentration was associated with a 21% increase in the risk for incident AD (hazard ratio-HR [95% CI] = 1.21 [1.01, 1.45]), while a SDU increase in ln(ApoB48) concentration was associated with a 22% decrease in the risk for incident AD (HR [95% CI] = 0.78 [0.66, 0.93]) - Model 1 (Table 2). In Model 2, the association with sdLDL-C remained in the same direction but did not reach statistical significance, likely due to the smaller sample size (Table 3).

CONCLUSION: Lower sdLDL-C and higher ApoB48 concentrations were associated with a reduced risk for AD. These findings highlight a potential role of blood lipoprotein markers in AD risk stratification and of lipid modification strategies in dementia prevention.},
}

Humans
Female
Male
*Biomarkers/blood
*Alzheimer Disease/blood/epidemiology
Aged
Middle Aged
Incidence
Cholesterol, LDL/blood
*Lipoproteins/blood
Risk Factors

@article {pmid41448874,
year = {2025},
author = {Wu, CY and Chen, L and Arnold, SE and Dodge, HH},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100939},
doi = {10.1002/alz70859_100939},
pmid = {41448874},
issn = {1552-5279},
mesh = {Humans ; Aged ; Male ; Female ; Single-Blind Method ; *Cognitive Dysfunction/drug therapy/psychology/therapy ; *Drug Development ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {BACKGROUND: With U.S. Food and Drug Administration (FDA)-approved anti-amyloid, partially disease-modifying treatments now available, the ethical justification for randomly assigning patients to placebo has become controversial. The idea of twin-controls (or virtual-controls) has gained significant attention in recent years, with the aim of creating twin patient cohorts that can be used as a surrogate to evaluate the effects of treatment on a personalized level. While promising, the feasibility of digital twins techniques remains largely untested.

METHOD: I-CONECT is a multi-site, single-blind, randomized controlled trial (RCT) examining the effects of conversational interactions on cognition among socially isolated subjects aged ≥ 75 years (normal cognition; mild cognitive impairment). 186 participants were randomized into experimental or control groups. The experimental group engaged in video chats with study staff 4 times/week for 6 months, while the control groups received weekly 10-minute phone calls. The current analysis focused on the efficacy-shown Montreal Cognitive Assessment (MoCA; global cognition) and category fluency animals (CFA; language-based executive function) at 6-month follow-up. Data from the National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) were used to create digital twins for treatment participants through two methods. Method 1 involved twin mapping, matching participants with 1 to 20 twins who had similar demographic, biological, and social factors, and comparing change scores between each participant and their twins. Method 2 used direct modeling by building random forest models to predict change scores as if participants were assigned to a "usual care" control group. Effect sizes were compared between original and twin-controls trials, as well as between the two methods.

RESULT: Approximately 10% of NACC-UDS participants (5,332 out of 50,259) were eligible for I-CONECT. For parallel-group designs, treatment effect sizes on MoCA closely aligned between original (β=1.67) and twin-control (β=1.46-1.97) trials when the Euclidean distance mapping was applied. Similar findings were found in CFA (original trial β=2.56; twin-control trial β=2.31-3.34). For single-case, n-of-1 designs, methods 1 and 2 showed substantial agreement in identifying treatment responders (Cohen's Kappa=1 for MoCA; 0.68 for CFA).

CONCLUSION: Digital twins from publicly available datasets enhance the rigor of RCTs by providing mapped twins as controls for early-phase dementia trials.},
}

Humans
Aged
Male
Female
Single-Blind Method
*Cognitive Dysfunction/drug therapy/psychology/therapy
*Drug Development
Aged, 80 and over
Neuropsychological Tests