J. Alzheimers Dis. [JOURNAL]
Sun
200 papers
Exploring the repurposing potential of β-adrenergic receptor agonists for cognitive function: Evidence from the PharmLines Initiative Retrospective Cohort Study.
Alghamdi A, Combrtg E, Balafas S … +4 more , Bos JHJ, Van Munster BC, Schmidt M, Hak E
J Alzheimers Dis · 2026 Jun · PMID 42261707 · Publisher ↗
BackgroundPreclinical studies suggest β-adrenergic receptor agonists may exert neuroprotective effects, but evidence in human populations is limited.ObjectiveTo examine the association between β-adrenergic receptor agoni...
BackgroundPreclinical studies suggest β-adrenergic receptor agonists may exert neuroprotective effects, but evidence in human populations is limited.ObjectiveTo examine the association between β-adrenergic receptor agonist use and cognitive performance in older adults.MethodsThis retrospective cohort study linked Dutch pharmacy dispensing records (IADB.nl) with Lifelines cohort data. Participants aged ≥50 years with ≥1 prescription for β-adrenergic receptor agonists or reference medications (COPD/cardiovascular) within 365 days prior to baseline cognitive testing were included. Cognitive function was assessed using the Cogstate Brief Battery. Linear mixed models adjusted for demographic, clinical, and lifestyle factors evaluated longitudinal changes.ResultsA total of 3179 participants were included (249 β-adrenergic receptor agonist users, 2930 reference). The exposed group was younger (mean age 58.6 ± 7.4 years versus 63.7 ± 9 years) and included a higher proportion of females (68.2% versus 58.6%) compared with the referent group. At baseline, groups were similar in most cognitive domains, except for slightly higher attention (COG2) scores in the reference group (p = 0.010). Over time, psychomotor speed (COG1), attention (COG2), and visual learning (COG4) remained stable across groups. Working memory (COG3) declined significantly in both groups, with a steeper decline in the reference cohort (p = 0.048).ConclusionsIn this exploratory cohort study, β-adrenergic receptor agonist use was not associated with broad cognitive benefits, though a modest attenuation of working memory decline was observed. These results highlight the need for larger, prospective studies to clarify whether specific subgroups or drug formulations may offer cognitive advantages.
Semaglutide showed limited improvements in patients with Alzheimer's disease: Revisiting the evoke and evoke + clinical trials.
Hölscher C
J Alzheimers Dis · 2026 Jun · PMID 42261705 · Publisher ↗
BackgroundSemaglutide is a glucagon-like peptide-1 analog that is on the market to treat type 2 diabetes and weight loss (Ozempic, Wegovy). Two phase 3 clinical trials have been conducted, Evoke and Evoke+, testing the d...
BackgroundSemaglutide is a glucagon-like peptide-1 analog that is on the market to treat type 2 diabetes and weight loss (Ozempic, Wegovy). Two phase 3 clinical trials have been conducted, Evoke and Evoke+, testing the drug in patients with Alzheimer's disease. The trial management presented results of the intermediate readout at week 104 of the CDR-SB scores, which were negative. On the basis of that, the management decided to declare the trials a failure. However, data from week 130 and 156 had not been statistically analyzed.ObjectiveWhen evaluating time points 130 and 156, several results show a separation between drug group and placebo group with semaglutide showing better results.MethodsUsing the means, converting the SEMs to SDs and numbers of patients per group, I analyzed the results using the Welch T-test (two-tailed), which does not assume equal SD.ResultsThe ADCS-ADL-MCI test, Evoke trial, week 130, did show a significant difference, p = 0.0039. Other test such as the ADAS-cog-13 results show trends towards improvement by semaglutide at week 156. Cerebrospinal fluid biomarker analyses showed significant differences in some AD markers, too.ConclusionsThe results did show some limited drug effects at later time points of the trials. However, Semaglutide has been designed to stay in the blood for a long time and therefore does not cross the blood-brain barrier readily. Novel GLP-1 type drugs that can cross the blood-brain barrier easily may show superior protective effects in AD patients.
Blood-based biomarkers for dementia with Lewy bodies.
Acquaviva J, Delic V, Bellacicco N … +1 more , Choi YB
J Alzheimers Dis · 2026 Jun · PMID 42261703 · Publisher ↗
Dementia with Lewy bodies (DLB), a synucleinopathy, is the second most common form of dementia after Alzheimer's disease (AD). Yet, DLB is often more aggressive and clinically challenging to diagnose due to overlapping s...
Dementia with Lewy bodies (DLB), a synucleinopathy, is the second most common form of dementia after Alzheimer's disease (AD). Yet, DLB is often more aggressive and clinically challenging to diagnose due to overlapping symptoms with AD and Parkinson's disease dementia. Reliable biomarkers are necessary, since a definitive diagnosis of DLB currently requires postmortem tissue analysis. Blood-based biomarkers represent a minimally invasive and cost-effective avenue for earlier and more accurate diagnosis. This review integrates current evidence on blood biomarkers for DLB, at times extrapolated from other synucleinopathies, with a focus on α-synuclein and its derivatives, including extracellular vesicle-associated α-synuclein, seeding amplification assays, and autoantibodies. Additional biomarkers such as phosphorylated tau and amyloid-β highlight the frequent co-pathology with AD, while markers of neurodegeneration, neuroinflammation, and oxidative stress, heart-type fatty acid-binding protein, proteomic profiling, lipid, and other metabolites offer complementary diagnostic and prognostic potential. Although no single blood biomarker currently provides definitive diagnostic, differential, and prognostic accuracy for DLB, the studies reviewed here provide converging evidence that combined blood-based biomarker panels may offer meaningful clinical promise in facilitating earlier detection, guiding prognosis, and improving the design of targeted therapeutic trials for DLB.
The relationship between infection and the development of Alzheimer's disease: A scoping review.
Lopes Cardoso I, Guimarães MI, Tubiana E … +1 more , Gavinha S
J Alzheimers Dis · 2026 Jun · PMID 42261695 · Publisher ↗
BackgroundAlzheimer's disease is the leading cause of dementia and constitutes a major public health problem. Recent research suggests that certain chronic infections, particularly periodontal infections, may play a role...
BackgroundAlzheimer's disease is the leading cause of dementia and constitutes a major public health problem. Recent research suggests that certain chronic infections, particularly periodontal infections, may play a role in the development or progression of this disease. Among the bacteria involved in periodontal disease, has attracted particular attention from researchers.ObjectiveIn this way, the aim of this thesis, conducted in the form of a scoping review, was to analyze existing scientific data on the relationship between infection and Alzheimer's disease.MethodsTo achieve this, a literature search was conducted in several scientific databases leading to the selection of fourteen studies that met the inclusion criteria.ResultsSome of the selected studies have shown the presence of or its virulence factors in the brain tissues of patients with Alzheimer's disease. Experimental studies also indicate that this bacterium can promote certain mechanisms involved in neurodegeneration, namely inflammation and accumulation of amyloid-β.ConclusionsSelected studies point to the existence of an association between exposure to periodontal bacteria and an increased risk of developing Alzheimer's disease.
Reflections on rural community characteristics by an outreach, recruitment, and engagement team.
Vassilaki M, Smith SM, Loftin TM … +7 more , Mohamed EA, Rethemeier N, Coburn RP, Graff-Radford J, Petersen RC, Boeve BF, Lunde AM
J Alzheimers Dis · 2026 Jun · PMID 42261694 · Full text
Rural populations are underrepresented in cognitive impairment research and have limited resources for education about brain and cognitive health, Alzheimer's disease and related dementias, or caregiving. As our Outreach...
Rural populations are underrepresented in cognitive impairment research and have limited resources for education about brain and cognitive health, Alzheimer's disease and related dementias, or caregiving. As our Outreach, Recruitment, and Engagement team aimed to expand activities into more rural communities, we also wanted to better understand the characteristics of the communities surrounding our center and gain insight into the social exposome of the areas. The goal of the manuscript is to reflect on our experience and share measures that were useful in this effort, which can be further enriched and adjusted by other outreach teams.
Nocturnal vagus nerve stimulation enhances cognitive functions in patients with early Alzheimer's disease.
Broncel A, Konopacki J, David TB … +3 more , Galecki P, Ben-Menachem E, Krawczyk M
J Alzheimers Dis · 2026 Jun · PMID 42261688 · Publisher ↗
BackgroundAuricular transcutaneous vagus nerve stimulation (atVNS) has been proposed as a non-invasive neuromodulation approach for cognitive disorders, including Alzheimer's disease (AD). Sleep represents a physiologica...
BackgroundAuricular transcutaneous vagus nerve stimulation (atVNS) has been proposed as a non-invasive neuromodulation approach for cognitive disorders, including Alzheimer's disease (AD). Sleep represents a physiological state characterized by enhanced vagal activity and memory consolidation, making it a potentially optimal window for stimulation.ObjectiveTo investigate the cognitive effects of nocturnal atVNS in individuals diagnosed with mild cognitive impairment (MCI) and AD.MethodsParticipants underwent nightly atVNS using a Vguard device, specifically designed for non-invasive stimulation during sleep. Cognitive performance was evaluated using four standardized neuropsychological instruments, including the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog).ResultsRepeated nocturnal atVNS over several months was associated with significant improvements in global cognitive function. Among the administered tests, the ADAS-Cog demonstrated the greatest sensitivity in detecting stimulation-related changes.ConclusionsNocturnal atVNS may constitute a promising therapeutic strategy for enhancing cognition in patients with MCI and AD. By leveraging sleep-related vagal activity, this approach could potentially delay or prevent the progression of MCI to AD and dementia.
A systematic review and meta-analysis of metalloproteinases in patients with Alzheimer's disease and mild cognitive impairment.
McNaugher G, McColgan L, Church M … +5 more , McClean PL, Gibson DS, Murray EK, Coyle S, McGilligan V
J Alzheimers Dis · 2026 Jun · PMID 42249679 · Publisher ↗
BackgroundVarious studies have reported altered expression of metalloproteinases in Alzheimer's disease (AD); however, expression profiles of each metalloproteinase during cognitive decline have not yet been fully charac...
BackgroundVarious studies have reported altered expression of metalloproteinases in Alzheimer's disease (AD); however, expression profiles of each metalloproteinase during cognitive decline have not yet been fully characterized.ObjectiveThe purpose of this systematic review was to generate a comprehensive overview of metalloproteinases and their cognate inhibitors expression in AD and mild cognitive impairment (MCI), across sample matrices, to determine whether metalloproteinases are dysregulated in AD and may have predictive power in individuals with cognitive decline.MethodsAn electronic literature search was conducted in PubMed, EMBASE, Scopus and MEDLINE from inception to December 2024. Sixty-one publications reporting metalloproteinase and inhibitor levels in 8576 patients with AD or MCI, and 7333 controls were included in the systematic review, twenty-one of which were extracted for meta-analysis. Standardized mean difference (SMD) was used to illustrate comparisons, and the Newcastle-Ottawa scale to assess bias.ResultsHigher levels of cerebrospinal fluid (CSF) tissue inhibitor of metalloproteinase-2 (TIMP-2; = 0.0003) were observed in the AD group and in patients with MCI ( = 0.0009) compared to cognitively healthy controls. Following sensitivity analysis, significantly higher levels of CSF MMP-10 ( = 0.0005) and lower plasma TIMP-2 ( = 0.004) were also noted in patients with AD. TIMP-3, across all sample matrices, was decreased in patients with MCI versus controls ( = 0.01).ConclusionsSignificantly altered levels of metalloproteinases and their inhibitors were verified between patients with AD and MCI, representing potential biomarkers and prospective therapeutic targets for cognitive decline. This study was registered with PROSPERO, CRD42024628202.
Abdominal adiposity and Alzheimer's disease imaging markers across sex and race at midlife.
Dolatshahi M, Commean PK, Naghashzadeh M … +21 more , Kassani SH, Rahmani F, Xu Y, Liu J, Mohammadi S, Lloyd L, Nguyen C, Kemper AM, Hantler N, Flores S, Weeks J, Ceriani LK, Sirlin CB, Ippolito JE, Dai W, Mittendorfer B, Schindler SE, Brier MR, Morris JC, Benzinger TLS, Raji CA
J Alzheimers Dis · 2026 Jun · PMID 42249678 · Publisher ↗
BackgroundMidlife obesity is considered one of the top modifiable risk factors for dementia and Alzheimer's disease (AD). However, body mass index (BMI) on its own does not fully represent obesity-associated risks and it...
BackgroundMidlife obesity is considered one of the top modifiable risk factors for dementia and Alzheimer's disease (AD). However, body mass index (BMI) on its own does not fully represent obesity-associated risks and it is crucial to disentangle the role of body adiposity and its localization.ObjectiveTo investigate the relationship of MRI-derived body adiposity metrics with AD-related pathology at midlife.MethodsNinety-seven cognitively normal midlife individuals underwent brain amyloid and tau PET, body MRI, and metabolic and cognitive assessments. Key measures included hepatic fat fraction, visceral (VAT) and subcutaneous adipose tissue (SAT) volumes, and thigh muscle and adiposity. The correlation between adiposity/metabolic measurements and amyloid/tau pathologies was investigated.ResultsThe average age of participants was 49.8 years, 65.3% were female and 53.6% had obesity. Amyloid PET burden in Centiloids correlated with VAT (rho = 0.36, p = 0.002), BMI (rho = 0.33, p = 0.002), SAT (rho = 0.33, p = 0.002), and insulin resistance (IR) (rho = 0.34, p = 0.003) in females and Whites, lower high-density lipoprotein (HDL) cholesterol (rho = -0.36, p = 0.002) irrespective of sex and race, and lower MMSE scores (rho = -0.57, p = 0.043) in only in African-Americans, after correction for age, sex, and education. There was no evidence that HDL nor IR mediated VAT-related amyloid. VAT/SAT ratio was significantly associated with mean cortical tau SUVR (β = 0.138, p = 0.030) after adjustment for age, sex, education, and amyloid.ConclusionsAmong fat depots in our study, visceral fat was more strongly correlated to amyloid pathology, and this association is present even independent from BMI. Also, higher visceral compared to subcutaneous fat is related to higher tau pathology.
Poor R-wave progression associates with cerebral amyloid deposition: A potential link between heart and brain.
Sozio SJ, Sahai A, Khalafi M … +15 more , Wang X, Tanzi E, Harvey P, Maloney T, Hojjati SH, Zhou L, Pahlajani S, Butler TA, Glodzik L, Li Y, Razlighi Q, Kim J, Goyal P, Fossati S, Chiang GC
J Alzheimers Dis · 2026 Jul · PMID 42244199 · Publisher ↗
BackgroundAmyloid deposition is a key pathologic hallmark of Alzheimer's disease (AD). Since cardiac amyloidosis also involves abnormal amyloid accumulation, shared proteinopathy mechanisms may underlie both conditions.O...
BackgroundAmyloid deposition is a key pathologic hallmark of Alzheimer's disease (AD). Since cardiac amyloidosis also involves abnormal amyloid accumulation, shared proteinopathy mechanisms may underlie both conditions.ObjectiveWe investigated whether brain amyloidosis on PET imaging is associated with electrocardiogram (EKG) findings of cardiac involvement by AD pathology.MethodsWe included 191 participants (mean age 66 ± 13.0 years) in our analysis, who underwent amyloid PET imaging and EKG within one year. EKG abnormalities (including low QRS voltage, poor R-wave progression (PRWP), bundle branch block, and sinus bradycardia) were assessed for associations with brain amyloid deposition, quantified in Centiloids, and cognitive function. A subset (n = 164) also underwent F-MK6240 tau PET, and the relationship between these EKG abnormalities and tau deposition was also assessed.ResultsPRWP was associated with greater brain amyloid deposition (coefficient = 45 ± 12.15, p < 0.001) and worse cognition on the Clinical Dementia Rating scale (coefficient = 0.22 ± 0.098, p = 0.027). There was a trend for higher likelihood of cortical tau deposition with PRWP (odds ratio = 3.66, p = 0.05). Sinus bradycardia was associated with higher likelihood of cortical tau deposition (odds ratio = 2.81, p = 0.009). Other EKG abnormalities were not significantly associated with brain amyloid/tau deposition or cognition.ConclusionsPRWP and sinus bradycardia were found to be associated with AD pathology in the brain. These findings warrant further investigation into how cardiac electrophysiologic abnormalities may reflect a possible link between brain and cardiac pathologies or AD-associated cardiac dysfunction.
Plasma p-tau217 and p-tau181 in middle-aged adults with mild cognitive impairment: The role of multimorbidity in an age-matched brief report.
Bożek A, Dobosz M, Miśkiewicz M … +4 more , Żurek N, Miodońska M, Zalejska Fiolka J, Krupka Olek M
J Alzheimers Dis · 2026 Jun · PMID 42244196 · Publisher ↗
Mild cognitive impairment (MCI) is an early stage of Alzheimer's disease-related neurodegeneration and may occur in midlife. The objective of the study was to assess associations between plasma p-tau217, p-tau181, cognit...
Mild cognitive impairment (MCI) is an early stage of Alzheimer's disease-related neurodegeneration and may occur in midlife. The objective of the study was to assess associations between plasma p-tau217, p-tau181, cognition, and multimorbidity. We studied 236 MCI patients and 210 controls. Cognition was assessed using the Mini-Mental State Examination and Montreal Cognitive Assessment. Multimorbidity was defined as ≥2 chronic conditions, and comorbidity as coexisting diseases. MCI was associated with lower cognition, higher p-tau levels, and greater multimorbidity. Plasma p-tau217 correlated inversely with cognition. Plasma p-tau reflects early neurodegeneration, with multimorbidity contributing to cognitive decline.
Association of Alzheimer's disease blood-based biomarkers and visit-to-visit blood pressure variability: The HABS-HD study.
Deng J, Li S, Health and Aging Brain Study (HABS-Hd) Study Team
J Alzheimers Dis · 2026 Jun · PMID 42244193 · Publisher ↗
BackgroundThe interplay between Alzheimer's disease (AD) and the cardiovascular system remains poorly understood. While vascular factors influencing AD have been studied, whether AD pathology conversely affects blood pre...
BackgroundThe interplay between Alzheimer's disease (AD) and the cardiovascular system remains poorly understood. While vascular factors influencing AD have been studied, whether AD pathology conversely affects blood pressure regulation is unclear.ObjectiveThis study investigated whether baseline plasma AD biomarkers predict subsequent visit-to-visit blood pressure variability (BPV).MethodsThis prospective analysis included 470 community-based older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort. Multiple linear regression models separately assessed associations between each baseline plasma AD biomarker (Aβ ratio, total tau, p-tau181, NfL) and follow-up BPV, with progressive adjustments for demographics, clinical diagnosis, cardiovascular risk factors, and mean blood pressure. In fully adjusted models, all plasma AD biomarkers were included simultaneously to adjust for potential mutual confounding and identify independent associations. Subgroup and sensitivity analyses were conducted.ResultsIn fully adjusted models, total tau remained independently associated with higher systolic blood pressure variability (β = 3.94, 95%CI: 1.00-6.87, p = 0.009). These associations were particularly prominent in males (β = 5.80, 95% CI: 1.66-9.95, p = 0.007), non-Hispanic White (β = 4.00, 95% CI: 0.12-7.88, p = 0.044), cognitively unimpaired individuals (β = 4.42, 95% CI: 1.14-7.70, p = 0.009), APOE ε4 non-carriers (β = 4.91, 95% CI: 1.42-7.70, p = 0.009), and individuals not using antihypertensive medication (β = 4.29, 95% CI: 0.71-7.87, p = 0.020). Sensitivity analyses confirmed robustness of findings.ConclusionsPlasma total tau independently predicts BPV, especially during pre-clinical AD stages. This finding reveals an important connection between AD pathology and vascular dysregulation, supporting the paradigm of AD as a systemic disorder and providing new directions for early risk identification and intervention.
Longevity and cognitive resilience in a Colombian family carrying the ε2 variant.
Guerrero A, Galvis-Garrido ND, Bocanegra Y … +23 more , Vásquez D, Becerra JC, Zuluaga Y, Baena A, Zubiri V, Alzate D, Osorio L, Hincapié L, Madrigal L, García G, Guzmán C, Restrepo F, Vidal M, Martínez L, Martínez JE, Malotaux V, Tristão-Pereira C, Perez-Corredor P, Vacano GN, Lopera F, Arboleda-Velasquez JF, Quiroz YT, Aguillon D
J Alzheimers Dis · 2026 Jul · PMID 42244184 · Full text
is the strongest genetic risk factor for late-onset Alzheimer's disease. Despite global efforts to promote resilience, delay cognitive decline, and slow aging, ε2, one of the most robust resilience-associated variants,...
is the strongest genetic risk factor for late-onset Alzheimer's disease. Despite global efforts to promote resilience, delay cognitive decline, and slow aging, ε2, one of the most robust resilience-associated variants, remains relatively underexplored in translational research. Exceptional longevity offers a window into cognitive trajectories. We present clinical, cognitive and neuroimaging data from five ε2/ε3 siblings aged 94-105. Cognition ranged from normal to mild dementia. MRI showed less atrophy than expected for advanced age, and FDG-PET revealed preserved metabolism. Findings demonstrate ε2-associated resilience in the oldest-old and offer insight into mechanisms of exceptional cognitive aging with potential translational relevance.
Anti-amyloid immunotherapies in Alzheimer's disease: Are future prescribers prepared? Insights of a French national survey.
Götze K, Auboeuf-Dominguez F, Akroum M … +2 more , Bellosta CT, Paquet C
J Alzheimers Dis · 2026 Jun · PMID 42240184 · Publisher ↗
Anti-amyloid immunotherapies in Alzheimer's disease (AD) are newly authorized for use in the European Union (AD). In a national online survey in 2024, we aimed to assess French practitioners' opinion and knowledge regard...
Anti-amyloid immunotherapies in Alzheimer's disease (AD) are newly authorized for use in the European Union (AD). In a national online survey in 2024, we aimed to assess French practitioners' opinion and knowledge regarding indications and risk management plan. Answers were based on clinical trial criteria. On 303 practitioners, most knew general indications except 19.1% who considered prescribing without AD biomarkers. Side effects were correctly identified, but specific knowledge on amyloid-related imaging abnormalities was lacking. Tertiary memory clinic practitioners had better knowledge on indications (p < 0.001) and side effects (p = 0.033).
Fluorescence spectroscopy and machine learning methods for detection of Alzheimer's disease from circulating white blood cells.
Tsutsui S, Stepanchuk AA, Stys JP … +4 more , Black SAG, Templeton GW, Greiner R, Stys PK
J Alzheimers Dis · 2026 Jun · PMID 42231859 · Publisher ↗
BackgroundAlzheimer's disease (AD) is the most common cause of dementia whose prevalence is projected to increase significantly in the coming decades. The recent advent of disease modifying therapies is a welcome develop...
BackgroundAlzheimer's disease (AD) is the most common cause of dementia whose prevalence is projected to increase significantly in the coming decades. The recent advent of disease modifying therapies is a welcome development; however, it is also now apparent that early treatment maximizes the benefits of these drugs. Therefore, it is important to develop reliable methods of disease detection, preferably from an easily accessible matrix such as blood.ObjectiveTo develop a method for detecting AD from circulating white blood cells using spectral confocal microscopy.MethodsUsing K114-stained wild type and 5xFAD transgenic mouse cortical sections as proof-of-principle, spectral imaging of K114 fluorescence coupled with a signal processing/machine learning pipeline (spectral wavelet decomposition, dimensionality reduction, support vector machine classifier) can reliably distinguish non-plaque background parenchyma in the two strains. We then performed immunoprecipitation of Aβ from peripheral blood mononuclear cells (PBMCs) obtained from non-neurological controls and histopathologically-proven AD cases. We spectrally imaged the immunobeads labeled with K114, then used similar machine learning methods to classify control versus AD samples.ResultsNormal-appearing non-plaque 5xFAD background was reliably distinguished from wild type mouse brain. We could also classify AD with a high degree of reliability (area under the receiver operating curve = 0.95, p = 6.1e-5) and predict neuropathological scores from these blood elements (R = 0.89).ConclusionsOur spectral imaging method, together with automated machine learning analysis of spectral micrographs, using readily obtainable PBMCs from blood, represents a potentially useful approach for detection of AD in living subjects.
A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive, metabolic, and neuroimaging outcomes of a pilot randomized controlled trial.
Rashidi-Ranjbar N, Churchill NW, Jerkic M … +12 more , Zomorrodi R, Rotstein O, Schneider R, Andreazza AC, Rajji TK, Graham SJ, Munoz DG, Fornazzari L, Lim L, Norris M, Schweizer TA, Fischer CE
J Alzheimers Dis · 2026 Jun · PMID 42231857 · Publisher ↗
BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicat...
BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).MethodsWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.ResultsAdherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.
Secoisolariciresinol diglucoside ameliorates Alzheimer-like lesions by increasing MKP-1.
Chen M, Xie Q, Yi F … +7 more , Ma J, Lu S, Ouyang H, Qin Y, Yang S, Wei W, Liu Y
J Alzheimers Dis · 2026 Jul · PMID 42231856 · Publisher ↗
BackgroundSecoisolariciresinol diglucoside (SDG), a phytoestrogen, has been demonstrated to exert anti-inflammatory and neuroprotective effects. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) serves as a c...
BackgroundSecoisolariciresinol diglucoside (SDG), a phytoestrogen, has been demonstrated to exert anti-inflammatory and neuroprotective effects. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) serves as a critical negative regulator of MAPK signaling pathways, and the MAPK signaling pathways play a significant role in the pathogenesis of Alzheimer's disease (AD). However, it remains unclear whether SDG ameliorates Alzheimer-like lesions by regulating the MAPK pathway through increasing MKP-1.ObjectiveWe aimed to investigate the impact of SDG on the Alzheimer-like lesions of AD mice and its mechanisms.MethodsThree-month-old 5×FAD mice were treated with SDG (50 mg·kg-1·d-1, i.g.) for 2 months. Learning and spatial memory function was assessed with the behavioral test. Immunofluorescence and Thioflavine-S staining was assessed with the levels of amyloid-β (Aβ) plaques in the cortex and hippocampus. Western blot was performed to evaluate the level of learning memory-related proteins, hyperphosphorylated tau, APP-related proteins, and MAPK phosphorylation. Besides, knockdown of MKP-1 in N2A/APP cells to investigate whether SDG regulates the MAPK signaling pathway by increasing MKP-1.ResultsWe found that SDG significantly enhanced learning and spatial memory while recovering PSD95, PKA-Cα, and synaptophysin levels in 5×FAD mice. SDG reduced Aβ plaques, tau phosphorylation at Ser 199/214/262/396 and Thr 231, alleviated the phosphorylation of MAPKs (JNK, ERK1/2, P38), and increased p-GSK-3β (Ser9), while decreased activation of microglia (Iba-1) and astrocytes (GFAP). Moreover, knockdown of MKP-1 in N2A/APP cells inhibited the regulatory effect of SDG on APP, ERK1/2 and JNK.ConclusionsSDG ameliorates Alzheimer-like lesions may be related with increasing MKP-1.
Connected-speech digital biomarkers for monitoring transcranial pulse stimulation in Alzheimer's disease: A pilot study.
Wiechmann D, Günes A, Kerz E … +3 more , Qiao Y, Köhne M, Sprick U
J Alzheimers Dis · 2026 Jun · PMID 42231842 · Publisher ↗
BackgroundAlzheimer's disease (AD) lacks effective disease-modifying therapies and scalable, ecologically valid biomarkers to monitor treatment response. Transcranial pulse stimulation (TPS) is an emerging non-invasive n...
BackgroundAlzheimer's disease (AD) lacks effective disease-modifying therapies and scalable, ecologically valid biomarkers to monitor treatment response. Transcranial pulse stimulation (TPS) is an emerging non-invasive neuromodulation technique with potential to attenuate cognitive decline. Sensitive digital endpoints are needed to quantify intervention-related changes.ObjectiveTo develop and validate connected-speech-derived digital biomarkers as a longitudinal framework for monitoring TPS treatment response in AD.MethodsIn this open-label, single-arm pilot study, 32 patients with AD were compared to cognitively healthy controls. A three-stage framework was implemented: (1) machine-learning classification using linguistic features to derive a parsimonious biomarker panel; (2) construction of a Speech Composite Index (SCI) calibrated against the CERAD total score (CTS); and (3) longitudinal SCI tracking in a sub-cohort receiving TPS.ResultsThe classifier discriminated AD from controls with an AUROC of 0.879 and an F1-score of 0.825. The SCI showed strong convergent validity with global cognition (CTS: r = 0.76, p < 0.001; MMSE: r = 0.76, p < 0.001) and executive function (Stroop interference: r = -0.51, p = 0.015). Longitudinal modeling demonstrated a significant positive deviation from a CERAD-based progression reference (β_time = 0.057 z-units/month, p = 0.013), indicating relative stabilization of speech performance. Individual trajectories were heterogeneous (range -0.053 to +0.336) without significant demographic associations.ConclusionsConnected-speech-derived digital biomarkers can serve as scalable longitudinal endpoints for neuromodulatory interventions in AD. The SCI captures treatment-related dynamics and may support response stratification. Further validation in larger, sham-controlled multicenter studies is needed to establish clinical utility and specificity to TPS.
Global research landscape of oligodendrocytes in Alzheimer's disease: A bibliometric and knowledge-mapping analysis from 1990 to 2025.
Zhang J, Teng Y, Li Y … +1 more , Zhang M
J Alzheimers Dis · 2026 Jun · PMID 42227745 · Publisher ↗
BackgroundOligodendrocyte (OL) lineage biology is increasingly recognized as a contributor to Alzheimer's disease (AD) pathophysiology, but its global knowledge structure and emerging frontiers remain unclear.ObjectiveTo...
BackgroundOligodendrocyte (OL) lineage biology is increasingly recognized as a contributor to Alzheimer's disease (AD) pathophysiology, but its global knowledge structure and emerging frontiers remain unclear.ObjectiveTo map the development, major contributors, intellectual bases, and research frontiers of OL-related AD research using bibliometric and visualization approaches.MethodsEnglish-language articles and reviews published from 1990 to 2025 were retrieved from the Web of Science Core Collection on January 2, 2026. After deduplication, 1746 records were analyzed. VOSviewer 1.6.20 assessed publication output, contributors, collaborations, and citation networks. CiteSpace 6.1.6 performed keyword co-occurrence, clustering, and burst detection.ResultsAnnual publications increased from 5 in 1990 to 149 in 2025, peaking at 154 in 2024, with acceleration after 2020. The United States led in productivity and impact (684 publications; 54,075 citations). Harvard University was the most productive institution (46 publications), whereas the University of California, Los Angeles had the highest average citation impact among leading institutions (147.20 citations per publication). Acta Neuropathologica was the most productive journal (66 publications; 6548 citations). Mathys et al. was the most influential cornerstone reference. Keyword clustering was robust (Q = 0.701, S = 0.958), identifying "white matter" as the central thematic cluster.ConclusionsOL-related AD research is expanding rapidly and shifting toward white matter-centered, cell state-resolved, and multi-omics paradigms. Future priorities include defining OL and oligodendrocyte precursor cell transcriptional states, clarifying myelin vulnerability and repair mechanisms, and linking OL pathology to amyloid-related processes.
Speech-based machine learning for detecting neuropsychiatric symptoms in Alzheimer's disease.
Chen Y, Huang H, He Y … +7 more , Chen S, Tan Y, Song J, Chen L, Wang X, Lü Y, Yu W
J Alzheimers Dis · 2026 Jun · PMID 42227197 · Publisher ↗
BackgroundNeuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD) and mild cognitive impairment (MCI), yet their detection relies on subjective assessments. Speech features offer a promising objective biom...
BackgroundNeuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD) and mild cognitive impairment (MCI), yet their detection relies on subjective assessments. Speech features offer a promising objective biomarker for NPS, reflecting emotional and cognitive states. However, existing studies are limited in terms of scale and duration.ObjectiveThis study aims to characterize acoustic features associated with NPS in early cognitive decline using Automated Assessment Model-Mini-Mental State Examination framework, and to evaluate machine learning classifiers for identifying indicators of NPS.MethodsSpeech data from 647 clinically diagnosed AD or MCI patients were collected and split into training and test sets in a 6:4 ratio. The training set was used for feature selection and model development, while test set was used for performance evaluation. The Synthetic Minority Over-Sampling Technique was applied to address class imbalance. Twelve machine learning models were trained to classify NPS categories. The best-performing models were evaluated, and SHapley Additive exPlanations (SHAP) were used to analyze feature importance.ResultsThe ExtraTrees model outperformed the others in identifying patterns associated with NPS categories, with cross-validated AUCs ranging from 0.869 to 0.901. SHAP revealed spectral_entropy_std and kurtosis_energy as key features across multiple NPS categories.ConclusionsThis study demonstrates that short speech samples obtained during the MMSE can identify acoustic patterns associated with NPS in clinically diagnosed AD and MCI using machine learning. Given the single-center design and absence of external validation, model outputs should be interpreted as directional signals to raise clinical awareness rather than as definitive diagnostic determinations.
Combining plasma biomarkers and cognitive challenge tests enhances prediction of functional trajectories of decline among older adults with cognitive impairment.
Diane Zheng D, Curiel Cid RE, Ortega A … +14 more , Crenshaw KH, Crocco EA, Vaillancourt D, Armstrong MJ, Wang WE, Asken B, Adjouadi M, Marsiske M, Rosselli M, Barker WW, Smith G, Dekosky ST, Duara R, Loewenstein DA
J Alzheimers Dis · 2026 Jun · PMID 42227192 · Publisher ↗
BackgroundPlasma biomarkers have emerged as promising, less invasive indicators of Alzheimer's disease (AD) pathology. However, biomarkers alone cannot indicate whether actual clinical symptoms are present or progressing...
BackgroundPlasma biomarkers have emerged as promising, less invasive indicators of Alzheimer's disease (AD) pathology. However, biomarkers alone cannot indicate whether actual clinical symptoms are present or progressing. Plasma biomarkers when paired with specific cognitive deficits on brief novel Cognitive Challenge Tests (CCTs), provide excellent sensitivities to underlying AD pathology in preclinical and prodromal stage. There is a lack of data on the extent to which plasma biomarkers and CCTs independently and jointly, predict longitudinal functional decline in the earliest stages of cognitive impairment.ObjectiveTo evaluate whether plasma biomarkers and CCTs independently and in combination predict baseline and longitudinal changes on the Clinical Dementia Rating scale Sum of Boxes (CDR-SOB) among older adults with cognitive impairment without dementia.MethodsOlder adults aged 54 to 98 years diagnosed with cognitive impairment without dementia (n = 159) at baseline were followed annually for a minimum of 3 visits, mean follow-up was 41.5 months (SD 11.9). CDR-SOB trajectory was estimated using latent growth curve modeling. The associations between plasma biomarkers (p-tau217, GFAP, and NfL) and CCTs with baseline levels and longitudinal change in CDR-SOB were evaluated.ResultsAfter adjusting for age, sex, education, Hispanic ethnicity, ɛ4, and amyloid positivity, p-tau217 (β=0.70, SE = 0.23, p < 0.01), and NfL (β=0.03, SE = 0.008, p < 0.001) predicted baseline and longitudinal changes in CDR-SOB, respectively. Deficits in CCTs (β=-0.11, SE = 0.03, p < 0.001) contributed independently to predicting the rate of change on CDR-SOB.ConclusionsIntegrating plasma biomarkers with sensitive CCTs enhances diagnostic accuracy, monitoring, and prognosis during pre-dementia stages.
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