Chen Y, Duggan MR, Timsina J
… +16 more, Xu Y, Western D, Gong K, Liu M, Budde J, Schindler SE, Morris JC, Holtzman DM, Benzinger TLS, Gordon BA, Moqri M, Knight Alzheimer Disease Research Center (Knight‐ADRC), Ibanez L, Walker KA, Cruchaga C, Ali M
Alzheimers Dement
· 2026 Jun · PMID 42325000
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INTRODUCTION: Cerebral amyloidosis is a defining feature of Alzheimer's disease (AD), yet the molecular heterogeneity among amyloidbeta-positive (Aβ+) individuals remains poorly defined. We aimed to map the proteomic cor...INTRODUCTION: Cerebral amyloidosis is a defining feature of Alzheimer's disease (AD), yet the molecular heterogeneity among amyloidbeta-positive (Aβ+) individuals remains poorly defined. We aimed to map the proteomic correlates of cerebral amyloidosis and link them to clinical variability within Aβ+ individuals. METHODS: We integrated quantitative amyloid PET with large-scale plasma proteomics (∼7000 proteins; SomaScan version 4.1) in Knight Alzheimer's Disease Research Center and Bio-Hermes cohorts (n = 1429). Proteome-wide association analyses identified proteins associated with amyloid load, followed by unsupervised clustering and pathway enrichment analyses. RESULTS: We identified 454 amyloid-associated proteins, of which 54 replicated cross-cohort. A derived 54-protein proteomic score correlated with amyloid burden, AD biomarkers, and clinical severity. Pathway analyses of clinically distinct protein clusters revealed coordinated enrichment of intracellular signaling, immune, and proteostasis modules. DISCUSSION: These findings delineate the circulating proteomic signature of cerebral amyloidosis and support plasma proteomics as a complementary approach to phosphorylated tau at threonine 217 and amyloid PET for biological stratification and characterization of disease heterogeneity in AD.
Carriere L, Minyo M, Bass D
… +4 more, Possin KL, Samper-Ternent R, Salinas J, Deaner N
Alzheimers Dement
· 2026 Jun · PMID 42324989
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Over half of dementia cases remain undiagnosed, with persistent disparities across racial, ethnic, and socioeconomic groups. Dementia care navigation (DCN) has demonstrated value in post-diagnosis settings. If implemente...Over half of dementia cases remain undiagnosed, with persistent disparities across racial, ethnic, and socioeconomic groups. Dementia care navigation (DCN) has demonstrated value in post-diagnosis settings. If implemented earlier, DCN could address diagnostic delays and care gaps. We define the diagnostic window as the period from initial symptom awareness through diagnosis and early care planning. Drawing on deliberations from the Alzheimer's Association Dementia Care Navigation Roundtable, we present a pre-diagnosis DCN framework organized across six domains and describe navigator roles across three phases: pre-evaluation, diagnostic assessment, and immediate post-diagnosis and transition. We address special considerations, including people without a care partner and those with unmet care needs. The framework complements federal initiatives such as the Guiding an Improved Dementia Experience (GUIDE) Model and the National Alzheimer's Project Act and identifies existing reimbursement pathways for pre-diagnostic navigation activities. Generating evidence to refine these models across diverse settings will be essential to inform policy action and system-level integration.
Maust DT, Davis RC, Strominger J
… +7 more, Marcus SC, Kim HM, Caverly T, Blow FC, Wallner LP, Krein S, Vordenberg SE
Alzheimers Dement
· 2026 Jun · PMID 42324490
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INTRODUCTION: Central nervous system (CNS) -active polypharmacy, defined as concurrent use of antidepressants, antipsychotics, anti-seizure medications, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists...INTRODUCTION: Central nervous system (CNS) -active polypharmacy, defined as concurrent use of antidepressants, antipsychotics, anti-seizure medications, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, opioids, or skeletal muscle relaxants for ≥ 31 consecutive days, poses significant risks patients with dementia. METHODS: Among community-dwelling patients in Medicare plans aged ≥ 65 with dementia and Medicare Part D coverage in 2021, we determined the rate of CNS-active polypharmacy initiation as well as medication and prescribing clinician characteristics. RESULTS: Among beneficiaries with dementia (n = 1,214,928, mean age 81.6 years), 7.8% (n = 94,190) experienced incident polypharmacy. Antidepressants were the most frequent class (92.3%), and quetiapine (30.9%), gabapentin (29.0%), and trazodone (28.3%) the top individual medications. At the time of initiation, 43.8% of patients were prescribed all CNS-active medications by a single clinician; primary care clinicians accounted for most polypharmacy prescriptions. DISCUSSION: Interventions to address polypharmacy should focus on development of guidelines targeting individual prescribers to help clarify appropriate use of CNS-active medications.
Buée L, Wildsmith KR, Alladi S
… +39 more, Bertucci T, Boche D, Bowles KR, Boxer A, Brummet J, DeVos SL, Diaz K, Dreyer AJ, Duff K, Duran-Aniotz C, Durrant CS, Farrell K, Fontana IC, Franzmeier N, Frost B, Horie K, Kaňovský P, Kao AW, Mahinrad S, Malpetti M, Morris HR, Palleis C, Petrucelli L, Rexach J, Reyderman L, Rommel A, Rowe JB, Sanabria Bohórquez SM, Sato C, Schöll M, Schneider A, de Silva R, Snyder HM, VandeVrede L, Varga AW, Vogel JW, Yeh FL, Yoo AS, Carrillo MC
Alzheimers Dement
· 2026 Jun · PMID 42324487
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The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore adv...The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross-sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker-driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.
Lee M, Meylan S, Shobin E
… +4 more, SpeechDx Consortium, Nisenbaum L, Sukumar A, Kourtis L
Alzheimers Dement
· 2026 Jun · PMID 42318897
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Validated prognostic tools are essential to advance drug development and clinical care in Alzheimer's disease, particularly as the field shifts toward the prevention of cognitive decline. While progress has been made in...Validated prognostic tools are essential to advance drug development and clinical care in Alzheimer's disease, particularly as the field shifts toward the prevention of cognitive decline. While progress has been made in developing blood-based biomarkers for the early detection of amyloid pathology, amyloid positivity alone does not reliably predict progression to symptomatic disease. Digital markers can serve as complementary prognostic tools to inform early intervention strategies. Among digital markers, speech-based markers offer a scalable, non-invasive, and cost-effective approach to predicting and monitoring cognitive decline. However, the development of validated speech-based tools has been constrained by the lack of large, multilingual datasets with longitudinal sampling, deep phenotyping, harmonized clinical and biomarker data, and adequate representation of preclinical populations. SpeechDx is a 3-year, multinational, multilingual observational study (n = 2006) designed to address these gaps and accelerate the development of speech-based tools to inform early risk assessment, enable timely intervention, and guide personalized care.
Viswanathan J, Karamacoska D, Thakur LS
… +16 more, Sawan M, Gomez-Arboledas A, Moreno-Gonzalez I, Shaaban CE, Milani SA, Milinkeviciute G, Loi SM, Wuestefeld A, Govindarajan ST, Low A, Carello-Collar G, Shreshta HL, Kenowsky S, Suemoto CK, Mielke MM, Stites SD
Alzheimers Dement
· 2026 Jun · PMID 42316439
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INTRODUCTION: Women are increasingly entering the dementia research workforce, but they frequently fail to attain senior leadership positions in academia. Discrepancies in academic research outputs were investigated to g...INTRODUCTION: Women are increasingly entering the dementia research workforce, but they frequently fail to attain senior leadership positions in academia. Discrepancies in academic research outputs were investigated to guide equity-focused policy recommendations. METHODS: Bibliometrics was conducted on 400,482 original research articles (2003-2022) followed by surveying the AD/ADRD research community, to quantitatively and qualitatively evaluate discrepancies in publication and authorship trends. In addition, an unsupervised learning algorithm was developed to analyze underlying relationships between author groups. RESULTS: Male author gender was consistently predictive of better publication and citation metrics across all bibliometrics outcomes, with senior male authors outperforming all other subgroups and fewer senior female authors in most research areas. Female survey respondents reported more barriers, but comparable productivity and citation strategies as male authors. DISCUSSION: Multi-pronged approaches by stakeholders across institutions, funders, and journals are necessary to provide career support for early-career scientists working to transition to senior research roles.
García AM, de Leon J, Alladi S
… +11 more, Battista P, Birba A, Cappa SF, Costa Beber B, Jiang J, Kemmerer D, Montembeault M, Orozco-Arroyave JR, Gorno-Tempini ML, Tee BL, Include Network
Alzheimers Dement
· 2026 Jun · PMID 42316425
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Speech and language measures are increasingly recognized as sensitive, scalable, non-invasive markers of diverse brain disorders. Yet, current research is overwhelmingly English-centric, neglecting the world's vast lingu...Speech and language measures are increasingly recognized as sensitive, scalable, non-invasive markers of diverse brain disorders. Yet, current research is overwhelmingly English-centric, neglecting the world's vast linguistic diversity and undermining these markers' global applicability. Here we present the International Network for Cross-Linguistic Research on Brain Health (Include), a multicentric initiative created to address this gap (https://include-network.com/). First, we review the network's origins, mission, and organizational structure. Then, we summarize key milestones achieved during its first 4 years, spanning cross-linguistic empirical studies, harmonized data-governance frameworks, and global dissemination efforts. We further highlight flagship projects demonstrating how linguistic typology and culture shape speech-language markers of neurodegeneration. Finally, we outline critical challenges and opportunities for the field, focusing on language underrepresentation, tool harmonization, regulatory heterogeneity, and expansion beyond neurodegeneration. Together, these efforts position Include as a strategic platform for fostering equitable, globally relevant brain-health research.
Alzheimers Dement
· 2026 Jun · PMID 42316378
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INTRODUCTION: The Clinical Dementia Rating (CDR) scale typically is administered in person, but use of telephone-based, informant-only assessments increased during the coronavirus disease 2019 (COVID-19) pandemic. The co...INTRODUCTION: The Clinical Dementia Rating (CDR) scale typically is administered in person, but use of telephone-based, informant-only assessments increased during the coronavirus disease 2019 (COVID-19) pandemic. The correspondence of informant-only assessments with in-person ratings remains unclear. METHODS: We analyzed 1,140 paired in-person and telephone assessments from the Knight Alzheimer's Disease Research Center Memory and Aging Project conducted within 12 months. Agreement for global CDR and CDR Sum of Boxes (CDR-SB) was examined using kappa statistics, intraclass correlation coefficients (ICCs), and Bland-Altman methods; classification performance of telephone global CDR score ≥ 0.5 was assessed. RESULTS: Agreement for the global CDR was moderate (κ = 0.53, 95% CI: 0.47-0.59). CDR-SB demonstrated moderate reliability (ICC = 0.69, 95% confidence interval [CI]: 0.65-0.73). Telephone CDR-SB scores averaged 0.40 points higher than in-person scores, with wide limits of agreement. Sensitivity was 64.2% and specificity 91.9%. DISCUSSION: Telephone CDR-SB shows moderate concordance with in-person CDR-SB but shows consistent score inflation, which may limit clinical staging utility.
Agrawal S, Yu L, Leurgans SE
… +8 more, Li J, Kapasi A, Agarwal P, Dage JL, Barnes LL, Bennett DA, Boyle P, Schneider JA
Alzheimers Dement
· 2026 Jun · PMID 42309988
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INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker for Alzheimer's disease (AD) progression in clinical studies, yet the role of brain GFAP in AD/AD-related dementias (ADRD) pathologies...INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker for Alzheimer's disease (AD) progression in clinical studies, yet the role of brain GFAP in AD/AD-related dementias (ADRD) pathologies and cognitive decline remains unclear. METHODS: GFAP burden from CA1-subiculum of the hippocampus were quantified. Regression and mixed-effect models, adjusting for demographics and other brain pathologies examined associations between hippocampal GFAP and AD/ADRD pathologies and separately with Alzheimer's dementia and cognitive decline. RESULTS: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis of aging (HS-A), and neurofibrillary tangle density (but not amyloid-beta) were associated with GFAP burden. Hippocampal GFAP was associated with increased odds of Alzheimer's dementia and faster decline in global cognition, episodic memory, semantic memory, and perceptual speed. LATE-NC and tangles explained some but not all the association between hippocampal GFAP and cognitive decline. DISCUSSION: GFAP burden in the hippocampus is related to LATE-NC and tangles but may also be an independent contributor to cognitive decline.
Veitch DP, Miller MJ, Kanoria S
… +20 more, Aisen PS, Beckett LA, Green RC, Harvey DJ, Jack CR, Jagust W, Lee EB, Nho K, Nosheny R, Okonkwo OC, Perrin RJ, Petersen RC, Mindt MR, Saykin AJ, Shaw LM, Toga AW, Tosun D, Landau SM, Weiner MW, Alzheimer's Disease Neuroimaging Initiative
Alzheimers Dement
· 2026 Jun · PMID 42309987
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The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal...The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high-impact studies using ADNI data or biospecimens from 2023 to mid-2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co-pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.
Alzheimers Dement
· 2026 Jun · PMID 42309986
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INTRODUCTION: White matter hyperintensities (WMHs) are a robust marker of brain aging and dementia risk, typically attributed to vascular pathology. However, impaired astrocytic support may also contribute. The locus coe...INTRODUCTION: White matter hyperintensities (WMHs) are a robust marker of brain aging and dementia risk, typically attributed to vascular pathology. However, impaired astrocytic support may also contribute. The locus coeruleus (LC), which degenerates early in aging and Alzheimer's disease, provides widespread noradrenergic projections that regulate astrocytic metabolism via β-adrenergic signaling. METHODS: In a healthy aging cohort (N = 106), we quantified LC volume, WMHs, and voxel-wise (q-WMHs). Associations were tested, controlling for age, cardiovascular risk, and other subcortical nuclei. Spatial partial least squares regression related q-WMH patterns to LC volume, age, and cortical adrenergic receptor expression. RESULTS: LC volume was independently associated with WMH burden and mediated age-related WMH increases. A latent q-WMH pattern aligned with cortical β-adrenergic receptor expression and mediated its association with WMH burden. DISCUSSION: LC degeneration may contribute to regional WMH vulnerability through noradrenergic mechanisms consistent with astrocytic β-adrenergic signaling, highlighting a potential nonvascular pathway influencing white matter integrity.
Mundada NS, Sadeghpour N, McGrew E
… +7 more, Tucker HL, Nasrallah IM, Das SR, Wolk DA, Yushkevich PA, Brown CA, Wisse LEM
Alzheimers Dement
· 2026 Jun · PMID 42309984
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INTRODUCTION: The anterior medial temporal lobe (MTL), including the entorhinal cortex (ERC) and Brodmann area 35 (BA35), is among the earliest cortical sites of tau pathology in Alzheimer's disease (AD), yet conventiona...INTRODUCTION: The anterior medial temporal lobe (MTL), including the entorhinal cortex (ERC) and Brodmann area 35 (BA35), is among the earliest cortical sites of tau pathology in Alzheimer's disease (AD), yet conventional image segmentation methods poorly capture these regions. METHODS: We applied an automated segmentation approach using an extended Automatic Segmentation of Hippocampal Subfields (ASHS) atlas, including anterior MTL subregions, in 448 Pennsylvania Alzheimer's Disease Research Center participants with magnetic resonance imaging, tau positron emission tomography (PET) (n = 199), and/or plasma phosphorylated tau 217 (p-tau217) (n = 377). Amyloid beta (Aβ) positivity was defined using PET or plasma. RESULTS: Tau-PET showed an anterior-posterior gradient, with highest uptake in BA35, ERC, and anterior hippocampus. Increased MTL tau-PET uptake and plasma p-tau217 were associated with cortical thinning localized to BA35 and ERC, even in cognitively unimpaired Aβ-positive individuals. CONCLUSIONS: Anterior MTL subregions, especially BA35, show early vulnerability to tau-related neurodegeneration. Extended anterior MTL parcellation improves localization of early tau-associated structural changes and may facilitate biological staging in preclinical AD.
Alzheimers Dement
· 2026 Jun · PMID 42309982
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Vascular contributions to cognitive impairment and dementia (VCID) are common in older adults and are typically associated with cerebral small vessel disease (cSVD). However, little remains known about non-pharmacologica...Vascular contributions to cognitive impairment and dementia (VCID) are common in older adults and are typically associated with cerebral small vessel disease (cSVD). However, little remains known about non-pharmacological, modifiable lifestyle variables that may build cognitive reserve against cSVD/VCID. To address this gap, we conducted a scoping review of the existing literature on this topic, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified and reviewed over 1000 articles that included keywords associated with cSVD/VCID and cognitive reserve. Only a small number of these articles met our inclusion criteria for testing moderation with CR. Our review comprehensively evaluates and synthesizes results from these studies, which produce a pattern of mixed findings. We discuss the factors that may have contributed to these findings and conclude with a discussion of current gaps in the literature and recommendations for future research to address these knowledge gaps.
López-Teros MT, Yeverino-Castro SG, Yocupicio-Medrano F
… +4 more, Mimenza-Alvarado AJ, Gutiérrez-Robledo LM, Bello-Chavolla OY, Aguilar-Navarro SG
Alzheimers Dement
· 2026 Jun · PMID 42309981
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INTRODUCTION: Healthy aging reflects the maintenance of intrinsic capacity (IC) across five physical and mental domains. Although IC decline has been linked to frailty and mortality, evidence regarding its predictive val...INTRODUCTION: Healthy aging reflects the maintenance of intrinsic capacity (IC) across five physical and mental domains. Although IC decline has been linked to frailty and mortality, evidence regarding its predictive value for dementia remains limited, particularly in low- and middle-income countries. METHODS: Data from 7263 adults aged ≥60 years without baseline dementia from the Mexican Health and Aging Study (2012-2015) were analyzed. IC was assessed across vitality, locomotor, sensory, cognitive, and psychological domains. Dementia was defined as impairment in two or more cognitive domains plus one or more limitation in instrumental activities of daily living. RESULTS: The mean age of the study population was 68.92 ± 6.8 years and 55.4% were women. Dementia incidence over 3 years was 4.15%. Higher baseline IC scores were associated with lower odds of incident dementia (adjusted odds ratio [OR] = 0.62; 95% confidence interval [CI]: 0.41-0.94). DISCUSSION: Our findings support the role of IC as an early, multidimensional marker of cognitive vulnerability.
Alzheimers Dement
· 2026 Jun · PMID 42304169
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INTRODUCTION: Cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimer's disease (AD) pathogenesis. Here, we characterize the susceptibility of the WSB/EiJ genetic context to hu...INTRODUCTION: Cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimer's disease (AD) pathogenesis. Here, we characterize the susceptibility of the WSB/EiJ genetic context to human AD-relevant cerebrovascular phenotypes. METHODS: CAA and parenchymal plaque analysis and in vivo neurovascular imaging were performed on WSB.APP/PS1 brains. Transcriptomics was performed on WSB.APP/PS1 and B6.APP/PS1 brains. B6 and WSB cerebrovascular reactivity was assayed ex vivo. Additional CAA and parenchymal plaque analysis was performed on WSB.APP/PS1 mice with APOE, APOE, or APOE alleles. RESULTS: WSB.APP/PS1 brains exhibited plaque deposition, CAA, transcriptomic overlap with human AD, myelin deficits, cerebrovascular/metabolic uncoupling, and altered cerebrovascular morphology. Aged WSB vasculature retained vasoreactivity but exhibited increased stiffness. Compared to WSB.APOEAPP/PS1, WSB.APOEAPP/PS1 mice had increased CAA and plaque-associated microglial area. DISCUSSION: These data illustrate the utility of the WSB genetic context to model CAA and uncover vascular contributions to AD.
Callow DD, Rani N, Smith JC
… +6 more, Soldan A, Pettigrew C, Spira AP, Albert M, Bakker A, BIOCARD Research Team
Alzheimers Dement
· 2026 Jun · PMID 42304165
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INTRODUCTION: Disturbed sleep and physical inactivity are associated with increased risk for dementia. However, associations with Alzheimer's disease (AD) pathology, and whether these associations differ depending on und...INTRODUCTION: Disturbed sleep and physical inactivity are associated with increased risk for dementia. However, associations with Alzheimer's disease (AD) pathology, and whether these associations differ depending on underlying disease risk, remain unclear. METHODS: We examined associations of actigraphy-derived total volume of physical activity (TVPA), total sleep time (TST), and wake after sleep onset (WASO) with tau burden measured by positron emission tomography (PET) in Braak I-II subregions among 120 cognitively unimpaired older adults. Moderation by APOE ε4 carrier status and amyloid positivity, based on amyloid PET, was examined to evaluate risk-dependent associations. RESULTS: Greater WASO was associated with higher tau burden among APOE ε4 carriers and amyloid beta (Aβ)-positive individuals. TVPA was associated with higher tau burden among Aβ-positive individuals and lower tau burden among Aβ-negative individuals. DISCUSSION: Associations of sleep and physical activity with early tau pathology differ by genetic risk and Aβ status, highlighting the importance of risk stratification.
Wiegand TLT, Rubinski A, Jung LB
… +23 more, Franzmeier N, Arciniega H, Ravanfar P, Dewenter A, Alosco ML, Tripodis Y, Su Y, Protas H, Lin AP, Pasternak O, Chen K, Coleman MJ, Bouix S, Adler CH, Balcer LJ, Bernick C, Cummings JL, Stern RA, Reiman EM, Shenton ME, Ewers M, Koerte IK, DIAGNOSE CTE Research Project
Alzheimers Dement
· 2026 Jun · PMID 42304137
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INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS: We used th...INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS: We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau-PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS: Cortical regions with lower typical GM MWF showed higher tau-PET uptake (β = -0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau-PET covariance (β = -0.238, p < 0.001). Higher typical FC was associated with higher tau-PET covariance (β = 0.447, p < 0.001). DISCUSSION: In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.
Pardo E, Kim T, Wallrabe H
… +8 more, Zengeler KE, Sagar VK, Mingledorff G, Sun X, Periasamy A, Lukens JR, Bloom GS, Norambuena A
Alzheimers Dement
· 2026 Jun · PMID 42304136
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INTRODUCTION: Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is po...INTRODUCTION: Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is poorly understood. We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor. METHODS: Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain. RESULTS: Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons. DISCUSSION: Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.
Osuru HP, Atluri N, Le T
… +5 more, Park J, Jedrusiak M, Dulko E, Illendula M, Lunardi N
Alzheimers Dement
· 2026 Jun · PMID 42298296
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INTRODUCTION: Postoperative delirium (POD) is common in older surgical patients and is clinically associated with an increased risk of long-term cognitive decline and dementia; disrupted BDNF signaling and circadian dysr...INTRODUCTION: Postoperative delirium (POD) is common in older surgical patients and is clinically associated with an increased risk of long-term cognitive decline and dementia; disrupted BDNF signaling and circadian dysregulation are implicated, but their coordinated mechanisms remain unclear. METHODS: Aged male C57BL/6J mice were exposed to anesthesia, surgery, and intensive care unit-like stress (ASI). Hippocampal neuroplasticity, dendritic morphology, epigenetic regulation, and circadian signaling were assessed using molecular assays, imaging, and protein-protein interaction (PPI) network analysis. RESULTS: ASI reduced brain-derived neurotrophic factor (BDNF)-activity-regulated cytoskeleton-associated protein signaling, dendritic structural complexity, and attention, with accompanying histone hypoacetylation, an increased 5-methylcytosine/5-hydroxymethylcytosine ratio, and disruption of network hubs centered on BDNF and circadian regulators. Suberoylanilide hydroxamic acid mitigated these effects and improved short-term cognitive performance. DISCUSSION: Perioperative stress is associated with an epigenetically repressed, synaptically impaired hippocampal state linked to delirium-like behavior and cognitive vulnerability. Targeting chromatin accessibility and BDNF-circadian coupling with histone deacetylase inhibition may mitigate acute cognitive consequences following surgery.
Guo Y, Wang R, Sindi S
… +2 more, Middleton LT, Kivipelto M
Alzheimers Dement
· 2026 Jun · PMID 42298291
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INTRODUCTION: The relationship between sleep, other dementia risk factors, and dementia remains unclear. We aim to explore these associations using a two-sample Mendelian randomization (MR) approach. METHODS: We identifi...INTRODUCTION: The relationship between sleep, other dementia risk factors, and dementia remains unclear. We aim to explore these associations using a two-sample Mendelian randomization (MR) approach. METHODS: We identified genetic instrumental variables for sleep characteristics from the UK Biobank and obtained summary-level genetic association data for dementia outcomes, including Alzheimer's disease (AD), from the FinnGen consortium. We applied inverse-variance weighted (IVW) MR to examine the associations between sleep characteristics and dementia outcomes. Multivariable MR was subsequently employed to assess the influence of additional dementia-relevant factors on these relationships. RESULTS: Genetic variants for insomnia, among the sleep characteristics, were associated with elevated AD risk (odds ratio [OR]= 3.02, 95% confidence interval [CI]: 1.28-7.10, p = 0.01). Yet this association was largely attenuated after adjusting for education and low-density lipoprotein (LDL). DISCUSSION: These findings indicate that the association between insomnia and AD is complex and indirect, potentially operating through social-behavioral factors (education) and biological pathways such as LDL cholesterol.