J. Alzheimers Dis. [JOURNAL]
Sun
200 papers
Beyond language: A structured profile of number processing impairment in logopenic primary progressive aphasia.
Macoir J, Lavoie M, Laforce R
J Alzheimers Dis · 2026 Jul · PMID 42179085 · Full text
BackgroundThe logopenic variant of primary progressive aphasia (lvPPA) is a language-led neurodegenerative syndrome commonly associated with Alzheimer's disease pathology and temporo-parietal degeneration. Although acalc...
BackgroundThe logopenic variant of primary progressive aphasia (lvPPA) is a language-led neurodegenerative syndrome commonly associated with Alzheimer's disease pathology and temporo-parietal degeneration. Although acalculia has been reported in lvPPA, numerical cognition has not been systematically investigated, and the specific profile of impairment remains poorly defined.ObjectiveTo characterize numerical cognition impairment in lvPPA using a comprehensive, theory-driven assessment battery and to examine its clinical relevance for diagnosis and cognitive characterization.MethodsFourteen individuals with lvPPA and twenty-eight demographically matched healthy controls completed the dCALQ, a standardized battery assessing number recognition and comprehension, number production (transcoding), and calculation. Participants also underwent global cognitive screening (Montreal Cognitive Assessment), language assessment (Detection Test for Language Impairments in Adults and the Aged), and measures of working memory and executive functioning. Group comparisons, intra-group domain analyses, correlation analyses, and receiver operating characteristic (ROC) analyses were performed.ResultsIndividuals with lvPPA showed significant impairments across all numerical domains compared with controls, with the most severe deficits in calculation, followed by transcoding, and milder impairment in number recognition and comprehension. Within the lvPPA group, performance differed significantly across domains, revealing a graded pattern of impairment. ROC analyses demonstrated excellent diagnostic accuracy for the dCALQ total score and strong discrimination for the calculation and transcoding domains.ConclusionsNumerical impairment is a robust and systematic feature of lvPPA rather than an incidental finding. The distinct numerical profile identified highlights the contribution of parietal-based cognitive dysfunction and supports the clinical utility of structured numerical assessment for cognitive characterization and diagnosis in dementia syndromes.
Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.
Kim D, Jeong H, Lim HK … +2 more , Ahn SM, Song M
J Alzheimers Dis · 2026 Jul · PMID 42179084 · Publisher ↗
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognit...
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.
The head turning sign "outside the clinic walls" in patients with mild cognitive impairment and dementia.
Aiello EN, Cazzini F, Moreschi A … +10 more , Curti B, De Luca G, Frisco F, Saba S, Patisso V, Maranzano A, Silani V, Ticozzi N, Verde F, Poletti B
J Alzheimers Dis · 2026 May · PMID 42179083 · Publisher ↗
BackgroundIn clinical settings, the head turning sign (HTS) occurs when patients with cognitive complaints turn their head toward the accompanying person seeking assistance. Due to its nature, and unlike other non-canoni...
BackgroundIn clinical settings, the head turning sign (HTS) occurs when patients with cognitive complaints turn their head toward the accompanying person seeking assistance. Due to its nature, and unlike other non-canonical neurological signs of cognitive impairment, the HTS is likely to occur in ecological, daily-life scenarios too. However, this hypothesis has not been tested yet.ObjectiveTo assess the prevalence and clinical correlates of the "ecological HTS" (eHTS) in MCI and dementia due to chronic-degenerative etiologies.MethodsThis retrospective cohort included 112 patients with MCI/dementia due to Alzheimer's disease (AD; = 71), frontotemporal lobar degeneration ( = 6), Lewy body disease ( = 6), chronic cerebrovascular diseases (CVD; = 11), mixed (i.e., AD + CVD; = 15) unspecified non-AD neurodegenerative etiologies ( = 3). We recorded the number of HTSs displayed by patients during the MMSE and inquired accompanying persons whether the HTS occurred in daily life too.ResultsThe overall prevalence of the eHTS in the cohort was 50%; its distribution was independent of demographics, disease severity (i.e., MCI versus dementia), and etiology. Within multiple logistic models, the presence of the eHTS + proved to be predicted both by lower scores on the subtest of the MMSE and by a higher number of HTSs during the execution of the MMSE. Moreover, a trend towards longer disease duration and the occurrence of the eHTS was found.ConclusionsIn MCI and dementia, the HTS is an ecologically valid non-canonical sign, frequently occurs in daily life too, associated with longer disease duration and spatial disorientation.
Visualization of perivascular spaces in Alzheimer's disease using 5.0 T MRI: A preliminary study.
Dong L, Liu C, Lv X … +5 more , Song X, He Y, Shi F, Qian Y, Liu Y
J Alzheimers Dis · 2026 Jul · PMID 42179082 · Publisher ↗
BackgroundPerivascular spaces (PVS) have been associated with neurodegenerative diseases such as Alzheimer's disease (AD); however, the added value of 5.0 T magnetic resonance imaging (MRI) for PVS visualization in AD re...
BackgroundPerivascular spaces (PVS) have been associated with neurodegenerative diseases such as Alzheimer's disease (AD); however, the added value of 5.0 T magnetic resonance imaging (MRI) for PVS visualization in AD remains unclear.ObjectiveThis study aimed to investigate the utility of 5.0 T MRI for PVS in AD patients and healthy controls (HCs).MethodsA total of 186 participants were enrolled, including 62 AD patients and 124 age- and sex-matched HCs. All AD patients underwent paired 3.0 T and 5.0 T MRI scans on the same day, while 62 HCs underwent only 3.0 T MRI and 62 HCs underwent only 5.0 T MRI. Axial T2-weighted imaging was used for PVS assessment. Evaluations included qualitative and quantitative analysis in the basal ganglia (BG) and centrum semiovale (CSO).ResultsIn AD patients, 5.0 T MRI demonstrated significantly higher PVS image quality scores and severity scores in the BG and CSO than 3.0 T MRI (p < 0.05). Quantitatively, 5.0 T MRI detected a greater PVS burden, evidenced by increased number, larger volume, longer length, and higher curvature of PVS in the bilateral BG (p < 0.001), and increased number and volume of PVS in the bilateral CSO (p < 0.05) compared to 3.0 T MRI. Furthermore, when compared to HCs using 5.0 T MRI, AD patients exhibited higher PVS severity scores and greater PVS burden in most regions than HCs (p < 0.05).Conclusions5.0 T high-resolution images provide superior image quality for PVS visualization and reveal more detailed morphological information of PVS in AD patients compared to 3.0 T MRI.
Lipidomics reveals TREM2-associated dysregulation of plasma lipid metabolism in Alzheimer's disease.
Zhang T, He M, Wang Y … +9 more , Gao P, Xia X, Li J, Yin Y, Zhao G, Chen O, Qu M, Tang Y, Qin Q
J Alzheimers Dis · 2026 Jul · PMID 42179069 · Publisher ↗
BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid...
BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid metabolism remains unclear.ObjectiveTo investigate the association between plasma sTREM2 and peripheral lipid profiles in AD and to explore the mechanistic role of TREM2 in peripheral lipid regulation.MethodsWe conducted a cross-sectional study of 59 AD patients and 54 healthy controls and measured plasma biomarkers including sTREM2 as well as performed targeted lipidomics profiling. Mechanistic exploration was performed via plasma and hippocampal lipidomics in knockout and APP/PS1 mice.ResultsPlasma sTREM2 levels were elevated in AD and were negatively correlated with the plasma p-tau217/Aβ ratio and p-tau217. Multivariate analysis revealed a distinct lipidomics signature in AD, in which 30 lipid species were significantly altered. We prioritized significantly altered biomarkers to inform a composite biomarker panel combining sTREM2 with a set of sphingomyelins, phosphatidylinositols, diacylglycerols, fatty acids, and cholesteryl esters, which showed strong discrimination between AD and controls (AUC = 0.93). In a mouse model of APP/PS1, we found that knockout partially normalized plasma sphingomyelins and hexosylceramide levels. Finally, cross-tissue comparisons further suggested that TREM2 exerted distinct effects on peripheral sphingolipid metabolism that were less evident in hippocampal tissue.ConclusionsOur findings associate TREM2 with lipid dysregulation in AD and support development of a plasma sTREM2-lipid panel for patient classification.
Environmental risk and genetic susceptibility in Alzheimer's disease: Impacts on cognitive function and biomarkers.
Kanani K, Ramakrishnan P, Neupane S … +5 more , Misra M, Balmer-Brown K, Halteman S, Warrick T, Alzheimer's Disease Neuroimaging Initiative *
J Alzheimers Dis · 2026 Jul · PMID 42179068 · Publisher ↗
BackgroundAlzheimer's disease (AD) involves interactions among genetic, environmental, and lifestyle factors, yet the contribution of environmental exposures to cognitive decline and biomarker changes remains unclear. De...
BackgroundAlzheimer's disease (AD) involves interactions among genetic, environmental, and lifestyle factors, yet the contribution of environmental exposures to cognitive decline and biomarker changes remains unclear. Detoxification genes such as EPHX1 may influence susceptibility to environmental neurotoxicants.ObjectiveTo evaluate associations between environmental risk, cognitive outcomes, and AD biomarkers, and to examine potential contributions of detoxification genes.MethodsWe analyzed 5101 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) across four study phases. Environmental exposure was summarized using a composite Environmental Risk Score (ERS) derived from Rural-Urban Continuum Codes, Rural-Urban Commuting Area codes, Risk-Screening Environmental Indicators, and occupational exposure. Cognitive outcomes included Mini-Mental State Examination, Clinical Dementia Rating, Montreal Cognitive Assessment, Neuropsychological Test Battery, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Executive Dysfunction Cognitive Assessment. Biomarkers included PET amyloid/tau, MRI hippocampal volume, and cerebrospinal fluid amyloid-β, tau, and neurofilament light chain. Multivariable regression models adjusted for sociodemographic factors and ε4 carrier status.ResultsERS was significantly associated with CDR (β = -1.13E-07; 95% CI -1.98E-07, -2.75E-08; p = 0.00956) but not with other cognitive measures. EPHX1 showed a significant main effect on ADAS-Cog (β = 0.479; 95% CI 0.0305, 0.927; p = 0.0356). ERS × gene interaction terms were not significant. ERS was not associated with amyloid PET SUVR.ConclusionsEnvironmental risk showed limited associations with AD-related outcomes, while EPHX1 demonstrated a significant main effect on cognitive performance. Longitudinal studies are needed to clarify mechanisms linking environmental exposure and AD.
Cerebral blood flow-iron susceptibility decoupling links cognition, amyloid pathology, and neuroinflammation in Alzheimer's disease.
Wang X, Liu T, Guo Y … +6 more , Huang M, Lv C, Huang W, Zhang K, Chen H, Chen F
J Alzheimers Dis · 2026 May · PMID 42179067 · Publisher ↗
BackgroundAlzheimer's disease (AD) is characterized by decreased cerebral blood flow (CBF) and abnormal iron deposition, whereas their relationship remains unclear.ObjectiveTo investigate the spatial pattern of CBF-iron...
BackgroundAlzheimer's disease (AD) is characterized by decreased cerebral blood flow (CBF) and abnormal iron deposition, whereas their relationship remains unclear.ObjectiveTo investigate the spatial pattern of CBF-iron deposition coupling across the AD spectrum and its associations with cognition, plasma biomarkers, and inflammation.Methods34 AD dementia, 86 mild cognitive impairment (MCI), and 26 cognitively normal (CN) were enrolled. Voxel-wise CBF-susceptibility coupling was calculated using three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping (QSM). Whole-brain region-based analyses of CBF, QSM, and CBF-susceptibility coupling were subsequently performed. Correlation and mediation analyses were conducted to evaluate the relationships of CBF-susceptibility coupling with plasma biomarkers, inflammatory factors, and cognitive function.ResultsCBF was significantly reduced in the AD dementia group and MCI group. No significant group differences were observed in QSM susceptibility. The AD dementia group showed significantly lower CBF-susceptibility coupling in multiple brain regions than CN and MCI groups, which was positively correlated with Mini-Mental State Examination (MMSE), Animal Fluency Test scores, and the plasma amyloid-β 42/40 (Aβ/Aβ) ratio. In the MCI group, coupling values were negatively correlated with IL-2 levels. CBF-susceptibility coupling in the bilateral supplementary motor areas of AD patients partially mediated the association between Aβ/Aβ ratio and MMSE.ConclusionsCBF-susceptibility coupling is significantly decreased in AD dementia and appears more sensitive than single-modality measures, and is associated with cognitive decline, amyloid pathology, and inflammation. These findings suggest that disrupted CBF-iron metabolism coupling may be a pathogenic mechanism underlying cognitive impairment in AD, possibly driven by early neuroinflammation.
Amyloid-β suppresses oligodendrocyte differentiation in adult oligodendrocyte precursor cells (OPCs), with inflammatory gene changes distinguishing it from developmental OPCs.
Li D, Dai W, Li X … +5 more , Li H, Li L, Zhao Y, Wang X, Zhang L
J Alzheimers Dis · 2026 May · PMID 42179062 · Publisher ↗
BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs...
BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs oligodendrocyte differentiation and myelination in adult oligodendrocyte precursor cells (OPCs) and to identify molecular correlates via RNA-seq.MethodsOligodendrocyte lineage cells were examined in plaque-associated regions of 8-month-old 5x familial Alzheimer's disease (FAD) mice by immunohistochemistry. Primary OPCs from neonatal and adult rats were cultured with or without amyloid-β oligomers (oAβ) to assess differentiation. Myelination was evaluated in organotypic slice cultures. RNA-seq and qPCR were performed to identify oAβ-induced gene expression changes.ResultsIn 5xFAD mice, Olig2 cells were reduced near plaques, with CC1 mature oligodendrocytes showing a pronounced decrease, while PDGFRα OPCs remained unchanged. In vitro, oAβ inhibited differentiation of both neonatal and adult OPCs, with adult OPCs exhibiting intrinsically slower maturation. Slice cultures revealed selective hypomyelination (reduced myelin basic protein) after oAβ treatment. RNA-seq showed that oAβ induced a distinct transcriptomic profile in adult OPCs, with upregulated genes enriched in immune/inflammatory pathways. Core inflammatory genes Nr4a1 and Tnf were significantly upregulated, validated by qPCR.ConclusionsoAβ plaque pathology is associated with oligodendrocyte maturation blockade. Aβ impairs OPC differentiation in purified cultures accompanied by inflammatory transcriptional changes. These findings highlight oligodendrocyte dysfunction in AD white matter pathology and reveal a specific oAβ response in adult OPCs.
Neurovascular unit failure as the opening chapter of dementia pathogenesis.
Hattori Y
J Alzheimers Dis · 2026 May · PMID 42178678 · Publisher ↗
Neurovascular dysfunction is increasingly recognized as a central feature of dementia pathogenesis in the early or even preclinical stage, rather than merely a downstream effect of amyloid-tau neurodegeneration. Based on...
Neurovascular dysfunction is increasingly recognized as a central feature of dementia pathogenesis in the early or even preclinical stage, rather than merely a downstream effect of amyloid-tau neurodegeneration. Based on multimodal clinical evidence showing that cerebrovascular dysregulation can precede amyloid-β accumulation, this commentary emphasizes three converging lines: (1) hippocampal blood-brain barrier breakdown as an early, potentially amyloid-/tau-independent event, (2) vascular-first/parallel two-hit frameworks linking vascular risk factors to subsequent proteinopathy, and (3) early neurovascular coupling failure and chronic hypoperfusion as upstream drivers. Integrating blood-brain barrier and hemodynamic biomarkers may facilitate earlier biological subtyping and prevention.
A systematic review on the effects of hypercaloric diet in animal models of Alzheimer's disease.
Carbone E, Scibetta S, Cappella M … +13 more , Crestini A, Perrone F, Hallulli M, Rosa P, Rivabene R, Maiolo F, Simonelli V, Ricceri L, Di Bari MA, De Luca G, Vanacore N, Lacorte E, Piscopo P
J Alzheimers Dis · 2026 May · PMID 42169623 · Publisher ↗
BackgroundAccording to several published studies, a hypercaloric diet (HD) could be considered a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To fully understand the molecular pathways...
BackgroundAccording to several published studies, a hypercaloric diet (HD) could be considered a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To fully understand the molecular pathways involved, HD has been investigated in several animal models.ObjectiveThe aim of this systematic review (SR) is to provide an overview of recent published data on the effects of HD on animal models of AD to gain insight into the molecular mechanisms potentially involved and to highlight current knowledge gaps for future studies.MethodsStructured bibliographic searches were carried out on PubMed, the Cochrane Library, and ISI Web of Knowledge. The SR was conducted following the Cochrane Handbook and the PRISMA statement. Studies enrolling only wild-type models or not using standard diet (SD) as control were excluded, as were non-original publications. Included studies were assessed for risk of bias using SYRCLE's tool.ResultsA total of 77 studies met inclusion criteria. Most reported significant behavioral differences in HD-exposed mice (Morris Water Maze, Open Field, Y-maze), though with considerable variability due to protocol heterogeneity. A significant increase in tau and amyloid deposition was observed after HD exposure, and most studies reported negatively affected learning and memory. However, nearly half found no significant differences between HD and SD groups, likely reflecting heterogeneity in diet duration and type, animal age, and strain susceptibility. Methodological quality varied widely, with many studies omitting randomization, blinding, or sex-stratified analyses.ConclusionsDespite variability, evidence suggests HD worsens behavioral performance and increases tau and amyloid expression in mouse brain, representing a risk factor for dementia. More rigorous, standardized, and sex-balanced preclinical studies are needed, and findings support dietary interventions as early non-pharmacological strategies in AD prevention.
Attitudes toward preventive neurology care: A cross-sectional survey study.
Clute-Reinig N, Helfman S, Lakis J … +3 more , Epstein L, Niotis K, Isaacson R
J Alzheimers Dis · 2026 May · PMID 42163712 · Publisher ↗
BackgroundUp to 45% of dementia cases due to Alzheimer's disease may be preventable, but implementation of risk-reduction programs have lagged in the United States.ObjectiveThe objective of this study was to understand w...
BackgroundUp to 45% of dementia cases due to Alzheimer's disease may be preventable, but implementation of risk-reduction programs have lagged in the United States.ObjectiveThe objective of this study was to understand whether belief in effectiveness, or interest in implementing risk-reducing interventions among healthcare consumers and providers are driving this lag.MethodsA survey was administered online using both directed and free-response questions. Directed questions were translated from Likert scales to numeric, while free-response questions were multi-operator coded and analyzed for themes.ResultsA total of 2054 full or partial responses were recorded; a majority of consumer respondents identified as White, Female, and between the ages of 51 and 79. Consumers were more interested in lifestyle than pharmaceutical interventions (Likert mean 4.5 versus 3.5, p < 0.0001), and were most interested in personalized risk reduction plans (mean 4.82, p < 0.001). Healthcare providers had higher belief in lifestyle interventions than pharmaceutical interventions (means 3.86 and 2.81, p < 0.0001), and they showed interest in medical education, referral networks, and blood biomarker testing (mean 4.15; 69%/58% of responses). Free response coding suggested that healthcare providers want to provide preventive neurology services but want guidance and education.ConclusionsBoth healthcare consumers and providers show interest in preventive neurology offerings. Our data suggest there is substantial demand for this type of care and that measures should be taken to increase clinical preventive neurology capacity.
An aging hallmark, Alzheimer's disease, and nexus.
Gabrielli AP, Weidling I, Lysaker CR … +5 more , Novikova L, Ranjan A, Wang X, Wilkins HM, Swerdlow RH
J Alzheimers Dis · 2026 May · PMID 42163711 · Publisher ↗
BackgroundThe commonality of Alzheimer's disease (AD) in the elderly suggests connections between aging and AD biology. biology is also tied to AD.ObjectiveWe sought to link three aging hallmarks (loss of proteostasis,...
BackgroundThe commonality of Alzheimer's disease (AD) in the elderly suggests connections between aging and AD biology. biology is also tied to AD.ObjectiveWe sought to link three aging hallmarks (loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing) to biology.MethodsWe altered SH-SY5Y cell proteostasis directly via heat shock, integrated stress response inhibition (ISRIB), or autophagy inhibition (chloroquine), and indirectly by perturbing mitochondria (mtDNA depletion; oligomycin). We also exposed induced pluripotent stem cell-derived neurons to ISRIB and chloroquine. Conversely, we mitigated protein stress with rapamycin. We assessed intervention impact on expression.ResultsIncreasing protein stress elevated and decreasing protein stress lowered expression. In SH-SY5Y cells rapamycin blocked oligomycin-induced mTOR 2448 phosphorylation, Akt 473 phosphorylation, and expression. In chloroquine-treated neurons rapamycin reduced mTOR phosphorylation and expression.DiscussionProtein stress initiates expression and facilitates mitochondrial dysfunction's impact on by engaging the mTOR pathway. Our findings link aging and AD biology.
Periodontal diseases and all-cause dementia risk: Genetic instrument analyses in half a million UK Biobank participants.
Gao C, Iles MM, Bunce D … +6 more , Wu B, Luo H, Pavitt S, Wu J, Bishop DT, Kang J
J Alzheimers Dis · 2026 Jul · PMID 42163709 · Full text
BackgroundNumerous studies suggest that periodontal diseases might be associated with the development of dementia, but the causality is inconclusive.ObjectiveThis study aims to explore the casual effect of periodontal di...
BackgroundNumerous studies suggest that periodontal diseases might be associated with the development of dementia, but the causality is inconclusive.ObjectiveThis study aims to explore the casual effect of periodontal diseases on all-cause dementia.MethodsThe UK Biobank (UKB) data (n = ∼500,000) has been implemented, where participants were divided into two independent groups (2/3train and 1/3test). The exposure is the self-reported periodontal diseases, and the outcome is all-cause dementia measured by both clinical diagnoses based on ICD10 and ICD9 codes, and self-reported dementia. Four sets of genetic instruments were developed based on four different thresholds (main approach: p < 5 × 10; alternative approach I: p < 5 × 10; alternative approach II: p < 10; and alternative approach III: the best-fit p-value threshold calculated by polygenic risk score). The causal association between periodontal diseases and dementia was assessed by inverse-variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimate models.ResultsThe number of genetic instruments included in these four approaches varied from 3 to 1020, after passing the MR assumption checks. Most MR results suggested no causal association between periodontal diseases and dementia except the IVW model from main approach (coefficient beta: -0.816, 95% confidence interval, CI (-1.617, -0.015)) and the weighted median model from alternative approach II (beta: 0.077 95%CI (0.006, 0.149)) suggested potential causal relationship between periodontal diseases and dementia.ConclusionsThe results showed inconsistent evidence of causal link between periodontal diseases and dementia using UKB. Future studies are needed with clinically defined periodontal diseases to better understand the causal link.
Development and validation of a novel single molecular immunology assay for detection of p-Tau181.
Liu M, Li X, Fang H … +1 more , Miao D
J Alzheimers Dis · 2026 May · PMID 42163499 · Publisher ↗
BackgroundAlzheimer's disease (AD) presents a major public health challenge. Current diagnostic methods for these disorders are often costly, invasive, and not widely accessible. The recently revised NIA-AA criteria high...
BackgroundAlzheimer's disease (AD) presents a major public health challenge. Current diagnostic methods for these disorders are often costly, invasive, and not widely accessible. The recently revised NIA-AA criteria highlight the potential of blood-based biomarkers as a promising non-invasive and cost-effective alternative for diagnosis.ObjectiveTo develop a novel single-molecule immunology assay specifically for the detection of phosphorylated tau at threonine 181 (p-Tau181) protein in blood samples.MethodsA novel single-molecule immunoassay targeting p-Tau181 was developed employing the Lychix Homebrew Kit. This new p-Tau181 assay underwent validation through the analysis of plasma samples from 98 clinically confirmed AD patients and 98 age-matched normal controls (NC), with the aim of assessing its effectiveness in differentiating between these two populations.ResultsInitially, the p-Tau181 immunoassay exhibited high nonspecificity and low discrimination between AD and NC plasma samples, with an AUC of 0.76. Further investigation revealed that false positive signals were caused by enzyme attachment to bead surfaces. By adjusting enzyme concentrations, reaction temperatures, and optimizing the sample diluent, it was ultimately discovered that salt concentration was the key factor in effectively minimizing false signals. With the optimized salt ion concentration, the refined p-Tau181 assay significantly improved its ability to distinguish AD from NC, achieving an AUC of 0.9313. The assay demonstrated improved sensitivity of 84.69% (76.27%-90.50%, 95% CI) and specificity of 87.76% (79.81%-92.85%, 95% CI).ConclusionsThe optimized single-molecule immunoassay p-Tau181 demonstrated significantly improved discrimination between AD and NC populations, underscoring its potential as a valuable diagnostic tool for AD.
Color-modulated olfactory testing using RAPPIT: An innovative tool for early detection of cognitive decline.
Arnhardt S, Singh S, Steinebach K … +5 more , Fuchs R, Diener T, Gasser D, Kornhuber J, Freiherr J
J Alzheimers Dis · 2026 Jul · PMID 42159448 · Full text
BackgroundOlfactory and visual processing are sensitive biomarkers for cognitive impairment; however, unimodal assessments may fail to capture early deficits in higher order cognitive integration. When sensory cues are m...
BackgroundOlfactory and visual processing are sensitive biomarkers for cognitive impairment; however, unimodal assessments may fail to capture early deficits in higher order cognitive integration. When sensory cues are mismatched, multisensory processing induces crossmodal conflict that requires inhibitory control, which is particularly vulnerable in early neurodegeneration.ObjectiveWe developed RAPPIT (Rapid, massively APPlicable Identification Test), a color-modulated olfactory test to assess multisensory interference as an early marker of cognitive decline.MethodsRAPPIT includes 16 physically presented odors, with a digital application for task control and response recording. Answer options are displayed on color backgrounds derived from the MONEX-40 color profile, either congruent or incongruent with the presented odors. A total of 163 participants from the German population completed the assessment. Odor identification accuracy, effects of color congruence (ΔE00), associations with cognitive performance (Montreal Cognitive Assessment, MoCA), hedonic ratings, and depressive symptoms were analyzed.ResultsOdor identification declined with age. Participants aged ≥ 60 years, a group at increased risk for neurodegenerative disorders including Alzheimer's disease, showed reduced performance under incongruent conditions. Performance exhibited a non-linear relationship with color difference (ΔE00), declining at mid-range values. Accuracy was significantly associated with MoCA scores. Hedonic ratings varied with color cues, while no associations were found with depressive symptoms.ConclusionsThese findings demonstrate that differences between congruent and incongruent odor-color conditions capture cognitively relevant interference effects beyond unimodal olfactory or visual performance, supporting the utility of this approach for early detection of cognitive impairment in older adults, in clinical and home settings.
Integrated amyloid, neurodegeneration, and vascular biomarkers estimate the risk of dementia progression in mild cognitive impairment.
Lee WJ, Cho K, Kim GW
J Alzheimers Dis · 2026 May · PMID 42159446 · Publisher ↗
BackgroundProgression from mild cognitive impairment (MCI) to dementia arises from heterogeneous mechanisms involving Alzheimer's disease (AD) pathology and vascular factors.ObjectiveThis study aimed to develop a multimo...
BackgroundProgression from mild cognitive impairment (MCI) to dementia arises from heterogeneous mechanisms involving Alzheimer's disease (AD) pathology and vascular factors.ObjectiveThis study aimed to develop a multimodal biomarker model to estimate the risk of dementia progression and to examine whether carotid atherosclerosis provides independent prognostic value, particularly in amyloid-β (Aβ)-negative MCI.MethodsWe retrospectively analyzed 300 individuals with MCI who underwent baseline [F]florbetapir PET, structural MRI, carotid Doppler ultrasound, cognitive assessments, and APOE genotyping (2018-2021). Participants were followed for a total of 37 months to dementia based on longitudinal cognitive and functional decline, independent of follow-up amyloid PET findings. Aβ positivity was defined using Brain Amyloid Plaque Load criteria. Multivariable logistic regression and receiver operating characteristic analyses were performed.ResultsAmong 189 Aβ-positive individuals, 30.7% (n = 58) progressed to Aβ-positive AD dementia, while 9.0% (n = 10) of 111 Aβ-negative individuals developed non-AD dementia. Independent factors estimating Aβ-positive AD dementia included higher Aβ burden (OR 2.34, p < 0.001), smaller hippocampal volume (OR 0.71, p < 0.001), greater carotid plaque count (OR 1.45, p = 0.001), lower Mini-Mental State Examination (OR 1.11, p = 0.002), and ε4 carriage (OR 1.82, p = 0.021). The integrated model showed excellent performance (AUC 0.903; 95% CI: 0.814-0.968). In Aβ-negative MCI, carotid plaque burden was the primary estimator of non-AD dementia progression.ConclusionsThe prominent prognostic role of carotid plaques in Aβ-negative MCI underscores the vascular contributions to non-amyloid cognitive decline and highlights the importance of evaluating both AD-related and vascular mechanisms in prodromal dementia.
Mediation pathways and complementary roles of DTI-ALPS and free water fraction in glymphatic impairment and cognitive decline.
Wei YC, Huang WY, Lin C … +5 more , Chen CK, Hsu CH, Ding CM, Chen YL, Lin CP
J Alzheimers Dis · 2026 May · PMID 42159436 · Publisher ↗
BackgroundGlymphatic system dysfunction is linked to cognitive decline in dementia continuum. Diffusion magnetic resonance imaging markers like the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS)...
BackgroundGlymphatic system dysfunction is linked to cognitive decline in dementia continuum. Diffusion magnetic resonance imaging markers like the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) index and whole-brain free water (FW) fraction allow non-invasive evaluation of glymphatic activity.ObjectiveThis study assessed whether DTI-ALPS and FW fraction are associated with cognitive performance and examined the influence of factors such as education on these relationships across dementia stages.MethodsCognitively normal, mild cognitive impairment, and dementia participants were recruited from both the community and the memory clinic at Chang Gung Memorial Hospital, Keelung. Brain MRI and neuropsychological assessments were performed.ResultsA total of 127 individuals (Clinical Dementia Rating 0, 0.5, 1-3; N = 75, 43, 6) completed the study. Both DTI-ALPS index and FW fraction differed among groups (p < 0.001) and correlated with cognitive performance (DTI-ALPS: β = 0.35; FW: β = -0.50; both p < 0.001). Mediation analysis showed that DTI-ALPS was positively associated with Montreal Cognitive Assessment (total effect b = 21.94, p < 0.001), largely mediated by FW fraction (indirect β = 0.22, 95% CI [0.14-0.33]). After adjusting for age, sex, and education, the total effect remained significant (b = 10.93, p = 0.018), while the direct effect was not (b = 8.15, p = 0.080), and the indirect effect via FW persisted (β = 0.05, 95% CI [0.01-0.13]). Education moderated these associations (DTI-ALPS x education: b = -2.07, p = 0.033; FW x education: b = 5.59, p = 0.034). In addition, sleep-medication use interacted with FW fraction in relation to cognitive performance (FW x sleep-medication: b = -58.87, p = 0.044).ConclusionsDTI-ALPS index and FW fraction provided complementary insights into glymphatic dysfunction linked to cognitive decline. Higher DTI-ALPS values were associated with better cognition, mediated by lower whole-brain FW, but with attenuated effects in individuals with higher education.
(Alzheimer's) dementia in adults with Down syndrome in Germany: Administrative prevalence based on a claims data analysis.
Weitzel M, Walendzik A, Giebel GD … +12 more , Raszke P, Wasem J, Levin J, Nübling G, Wagemann O, Wlasich E, Pantel J, Tesky VA, Schall A, Ruhnke T, Dröge P, Hüer T
J Alzheimers Dis · 2026 Jul · PMID 42138642 · Full text
BackgroundPeople with Down syndrome (DS) have a significantly increased risk of developing early-onset Alzheimer's disease. For example, a longitudinal study by McCarron et al. (2017) found that 97% of a cohort of 77 DS...
BackgroundPeople with Down syndrome (DS) have a significantly increased risk of developing early-onset Alzheimer's disease. For example, a longitudinal study by McCarron et al. (2017) found that 97% of a cohort of 77 DS patients aged 35 years and older developed dementia. Despite this high risk, administrative data on dementia prevalence in this population remain limited.ObjectiveThis study examines whether the diagnosed prevalence is lower than expected based on epidemiological data and explores differences compared to the general population.MethodsA comparative analysis of administrative dementia prevalence (2010-2019) was conducted using claims data for adults with and without DS. Prevalence rates were calculated by age and sex. Chi-square tests were applied to assess significance (p < 0.05), with Cramér's V and Phi as measures of association. Odds ratios were calculated to evaluate group differences.ResultsTotal administrative dementia prevalence was significantly higher in adults with DS (Mean Value (MV) 9.2% ± 1.7% (Standard Deviation (SD))) than those without DS (MV 3.2% ± 0.3% (SD)). Age- and sex-specific analyses also revealed notable differences. For example, in the 56-60 years age group, prevalence was MV 28.7% ± 4.6% (SD) in adults with DS versus MV 0.7% ± 0.1% (SD) in those without DS.ConclusionsAlthough administrative dementia prevalence is higher among adults with DS than those without DS, observed rates appear lower than expected based on existing epidemiological data. This suggests a potential underdiagnosis of dementia in the DS population in Germany.
Role of endolysosome iron in amyloid-β protein-induced increases in reactive oxygen species, mitochondrial depolarization, and cytotoxicity.
Quansah DNK, Halcrow PW, Kumar N … +2 more , Liang B, Geiger JD
J Alzheimers Dis · 2026 Jul · PMID 42135618 · Publisher ↗
BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized pathologically by the presence of extracellular plaques containing amyloid-β (Aβ) protein, and intraneuronal accumulations of neurotoxic pro...
BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized pathologically by the presence of extracellular plaques containing amyloid-β (Aβ) protein, and intraneuronal accumulations of neurotoxic proteins including Aβ and hyperphosphorylated tau. Also implicated in AD pathophysiology are increased levels of reactive oxygen species (ROS) and iron dyshomeostasis. Ferrous iron (Fe) controls generation of ROS via Fenton-like reactions and Aβ increases levels of intracellular ROS. Endosomes and lysosomes (endolysosomes) are acidic organelles that contain high levels of readily releasable stores of Fe and lysosomotropic insults can trigger Fe release from endolysosomes, which is sufficient to account for increased levels of cytoplasmic Fe and ROS.ObjectiveWe tested the hypothesis that endolysosome stores of Fe were sufficient to control Aβ-induced increases in mitochondrial Fe and ROS, mitochondrial depolarization, and cell death.MethodsUsing SH-SY5Y human neuroblastoma cells, we investigated the effects of Aβ (500 nM) and Aβ (500 nM) peptides on endolysosome and mitochondrial stress responses.ResultsAβ but not Aβ accumulated in and significantly decreased endolysosome Fe levels. Further, Aβ significantly (1) de-acidified endolysosomes, (2) caused endolysosome damage, (3) caused impaired autophagy, (4) increased levels of cytosolic Fe and ROS, (5) increased levels of mitochondrial Fe and ROS, (6) decreased mitochondrial membrane potentials, and (7) significantly increased cell death by apoptosis and ferroptosis. These neurotoxic effects were blocked by the endolysosome-specific iron chelator deferoxamine.ConclusionsEndolysosome stores of Fe appear to be important regulators of Aβ-induced cytotoxicity and targeting these iron stores may lead to new therapeutics against AD-like pathology.
The bidirectional association of epilepsy with Alzheimer's disease and other neurodegenerative dementias: A longitudinal observational study on the UK Biobank.
Fratto E, Buonocore J, Fortunato F … +6 more , Sammarra I, Calomino C, Vescio B, Quattrone A, Gambardella A, Quattrone A
J Alzheimers Dis · 2026 Jul · PMID 42135610 · Publisher ↗
BackgroundConverging evidence supports a bidirectional link between epilepsy and Alzheimer's disease (AD). Limited data are available regarding the association of epilepsy with frontotemporal dementia (FTD) and dementia...
BackgroundConverging evidence supports a bidirectional link between epilepsy and Alzheimer's disease (AD). Limited data are available regarding the association of epilepsy with frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB).ObjectiveTo estimate the bidirectional association between epilepsy and AD, FTD, and DLB in the UK Biobank, a large, multi-source healthcare dataset.MethodsEpilepsy, AD, FTD, and DLB cohorts were extracted. Cox proportional-hazard models were used to compare the AD risk in the epilepsy cohort against matched controls, and the epilepsy risk in the AD cohort against matched controls. Prevalent association of epilepsy with FTD and DLB was assessed using Chi-squared/Fisher test.ResultsHazard-ratio (HR) for AD in the epilepsy population versus controls was 2.5 (1.8-3.4, p < 0.001); HR increased when epilepsy was diagnosed in the sixth-seventh decade and in individuals with epilepsy carrying the ε4 allele. Conversely, HR for epilepsy in AD versus controls was 14.8 (9.7-22.5, p < 0.001). Epilepsy prevalence was higher in the FTD population compared to controls, with prevalence ratio (PR) of 5.3 (2.4-11.8, p = 0.001). Epilepsy PR in DLB versus controls approached but did not achieve statistical significance (2.4, 1.0-5.7, p = 0.068).ConclusionsOur findings reinforce the notion of a bidirectional association between epilepsy and AD, providing proof-of-concept that epilepsy, especially late-onset, may be successfully integrated into AD risk frameworks. Furthermore, we found a high prevalence of epilepsy in the FTD population. Careful stratification of individuals with epilepsy could offer an opportunity to identify those at higher risk of future or covert AD and neurodegeneration.
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