The Dame Barbara Windsor Dementia Goals Programme was launched by the UK Government to accelerate the development and delivery of new treatments for dementia. We present the recommendations from the Scientific Advisory B...The Dame Barbara Windsor Dementia Goals Programme was launched by the UK Government to accelerate the development and delivery of new treatments for dementia. We present the recommendations from the Scientific Advisory Board, to enable timely access to therapies for the wider population, reducing health system burden while improving patient outcomes. The recommendations focus on three areas: (i) establishing a new dynamic national patient registry for clinical trial recruitment; (ii) the use of biomarkers to improve early and accurate diagnosis; and (iii) a framework for end-to-end implementation across the landscape of healthcare, research and regulators. A Brain Aging Registry for Biomarkers, Access to trials, Research and Adoption would support recruitment, monitoring, and personalized care. Embedding digital and biomarker innovations into routine care would improve personalized and equitable dementia services, with earlier diagnosis and more effective prevention. Robust patient and public involvement is required, to ensure transparency, trustworthiness, and meaningful participation.
Ceron C, Casquero-Veiga M, Lamanna-Rama N
… +20 more, Fernández-Nueda I, Fernández-Pena A, Olazagoitia N, Sobrino G, Herraiz A, González MI, Muñoz-Hernando M, Ruperti-Repilado A, Romero-Sanz E, Morcillo MÁ, Pérez-Medina C, Moro MA, Villaverde G, Rubio J, Fernandez-Ferro J, Desco M, Herranz F, Salinas B, Fuster V, Cortes-Canteli M
Alzheimers Dement
· 2026 Jul · PMID 42394416
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INTRODUCTION: A subset of Alzheimer's disease (AD) patients exhibits a procoagulant state that remains undiagnosed despite available treatments. We developed positron emission tomography (PET) strategies to in vivo detec...INTRODUCTION: A subset of Alzheimer's disease (AD) patients exhibits a procoagulant state that remains undiagnosed despite available treatments. We developed positron emission tomography (PET) strategies to in vivo detect cerebral microthrombi in TgCRND8 mice. METHODS: PET was performed with a fibrin-binding probe (FBP) in TgCRND8 and wild-type mice using a zirconium-89-radiolabeled and a click-chemistry pre-targeted gallium-68 radiotracer. Platelet content was assessed in post mortem brain tissue from AD patients and TgCRND8 mice, and evaluated by PET using a CD41 pre-targeted gallium-68 nanoradiotracer. RESULTS: Cerebral FBP uptake differentiated TgCRND8 from wild-type mice, particularly ex vivo and with advancing age. Cerebral fibrin burden correlated with platelet content in AD patients, and elevated cerebral platelet burden in TgCRND8 mice was confirmed in post mortem tissue and in vivo by PET. DISCUSSION: Our findings support PET-based detection of AD-associated cerebral microthrombi and the development of imaging biomarkers to stratify AD patients by procoagulant status and inform personalized therapies.
Alzheimers Dement
· 2026 Jul · PMID 42394394
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INTRODUCTION: Secondary prevention treatments for Alzheimer's disease (AD) that are currently in late-stage clinical trials may preserve productivity and workforce participation. METHODS: Using the nationally representat...INTRODUCTION: Secondary prevention treatments for Alzheimer's disease (AD) that are currently in late-stage clinical trials may preserve productivity and workforce participation. METHODS: Using the nationally representative Health and Retirement Study waves from 1996 to 2020, we estimated changes in labor force participation, annual earnings, and social assistance payments between incident cases of cognitively impaired and statistically matched cognitively normal individuals. RESULTS: Among 20,717 respondents (aged 50 to 79), 5232 developed mild cognitive impairment or mild dementia. Disease onset was associated with a five-percentage-point (p.p.) reduction in workforce participation, annual earnings losses of US$8233 (23%) and US$5616 (18%) for men and women who remained in the labor force, respectively, and an increase of 3.5. p.p. male and 5.6 p.p. female social assistance beneficiaries. DISCUSSION: Onset of cognitive impairment was associated with statistically significant and meaningful reduction in workforce participation and earnings and increased participation in social assistance programs.
Rabichow BE, Nixon L, Tallant LE
… +5 more, Gibson KA, Nascari DG, Barnett JH, Massa N, Fryer JD
Alzheimers Dement
· 2026 Jul · PMID 42394391
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INTRODUCTION: Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear. METHO...INTRODUCTION: Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear. METHODS: We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asyn, mutant tau, or both asyn/tau in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses. RESULTS: Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3 inflammatory glial responses in white-matter fibers. DISCUSSION: Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tau risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.
Liu X, Mao M, Liu C
… +15 more, Ai D, Wang J, Yu T, Han X, Ren Y, Han X, Dong Y, Song L, Tang S, Tian N, Cong L, Xu K, Du Y, Qiu C, Wang Y
Alzheimers Dement
· 2026 Jul · PMID 42387260
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INTRODUCTION: Emerging evidence has linked chronic diseases with structural brain measures; however, the relationship between multimorbidity patterns and brain-age gap is unclear. METHODS: This community-based study invo...INTRODUCTION: Emerging evidence has linked chronic diseases with structural brain measures; however, the relationship between multimorbidity patterns and brain-age gap is unclear. METHODS: This community-based study involved 1151 dementia-free older adults in Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND-China). Multimorbidity was defined as coexistence of two or more chronic diseases. Hierarchical cluster analysis was used to identify five patterns of multimorbidity. We additionally defined cardiometabolic multimorbidity as coexistence of two or more cardiometabolic diseases. The predicted brain age was estimated using DeepBrainNet. Data were analyzed using linear regression models. RESULTS: The number of chronic diseases, multimorbidity, and cardiometabolic multimorbidity were significantly associated with larger brain-age gap (p < 0.05). The multimorbidity clusters comprising cerebrovascular disease and metabolic disorders or biliary tract diseases, dorsopathies, anemia, and hearing problems were significantly correlated with larger brain-age gap (p < 0.05). DISCUSSION: The overall burden and cardiometabolic pattern of multimorbidity are associated with advanced brain aging in dementia-free older adults.
Reuben DB, Stevens AB, Gill TM
… +12 more, Yang M, Volpi E, Lichtenstein ML, Jennings LA, Galloway R, Summapund J, Araujo K, Oyeyemi DM, Cho J, Xu Y, Peduzzi P, Greene EJ
Alzheimers Dement
· 2026 Jul · PMID 42386685
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INTRODUCTION: Greater dementia caregiver self-efficacy (CSE) may have considerable benefits for persons living with dementia (PLWD). The correlates of CSE have received little study. METHODS: Secondary analysis of an 18-...INTRODUCTION: Greater dementia caregiver self-efficacy (CSE) may have considerable benefits for persons living with dementia (PLWD). The correlates of CSE have received little study. METHODS: Secondary analysis of an 18-month randomized pragmatic clinical trial of 2037 community-dwelling PLWD and their caregivers. Baseline and longitudinal analyses were conducted. RESULTS: In cross-sectional multiple regression analyses of baseline data, several factors were significantly associated with lower CSE, including not living with the PLWD, having higher depression scores, distress from PLWD behavioral symptoms, more caregiver strain, and higher PLWD basic activities of daily living functional status. In longitudinal analyses, CSE increased among those with lower baseline CSE, in women more than men, among caregivers with lower baseline depression scores, and among caregivers of PLWD with worse functioning. CONCLUSIONS: CSE is associated with modifiable factors and can be improved with comprehensive dementia care interventions, particularly among those with lower baseline CSE. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03786471, https://clinicaltrials.gov/.
Alzheimers Dement
· 2026 Jul · PMID 42386684
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The recent publication of extension data from post-regulatory trials of amyloid-lowering antibody therapies, such as donanemab and lecanemab, requires clinicians to critically appraise trial designs and analyses in order...The recent publication of extension data from post-regulatory trials of amyloid-lowering antibody therapies, such as donanemab and lecanemab, requires clinicians to critically appraise trial designs and analyses in order to evaluate claims made by authors and sponsors of disease modification. This Perspective outlines the challenges with assessing claims of disease course modification, provides a framework for their evaluation, reviews the different trial designs and analytical approaches used to test or support them, and proposes a practical appraisal checklist for evaluating studies.
Alzheimers Dement
· 2026 Jul · PMID 42386680
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Alzheimer's disease (AD) is a neurodegenerative condition marked by cognitive decline and synaptic issues. Recent studies show primary cilia (PCs), sensory organelles present on the surface of most mammalian cells, act a...Alzheimer's disease (AD) is a neurodegenerative condition marked by cognitive decline and synaptic issues. Recent studies show primary cilia (PCs), sensory organelles present on the surface of most mammalian cells, act as a critical regulators of brain homeostasis and signaling. PCs act as a signaling hubs for pathways like G protein-coupled receptor, Hedgehog, Wnt, and neuroinflammation. When PCs are depleted or dysfunctional, they impair the processing of amyloid precursor protein, tau phosphorylation, synaptic signaling, and neuron-glia communication, leading to tau tangles, neuroinflammation, and amyloid beta plaques that drive AD progression. Beyond their role in signal transduction, PCs also regulate the biogenesis, release, and cargo selection of extracellular vesicles (EVs), and dysfunctional EV-PC crosstalk may contribute to AD progression. Examining PC-derived EVs offers pathway-specific insights into early ciliary and neuroinflammatory issues. This review consolidates evidence on PCs' multifaceted role in AD pathogenesis and suggests their potential as an early biomarker.
Panteleienko L, Banerjee G, Mallon D
… +7 more, Chan E, Fandler-Höfler S, Oliver R, Harvey V, Jaunmuktane Z, Collinge J, Werring DJ
Alzheimers Dement
· 2026 Jul · PMID 42381352
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INTRODUCTION: Iatrogenic transmission of amyloid beta can cause cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), but the relationship between these phenotypes is unclear. METHODS: We retrospectively analyz...INTRODUCTION: Iatrogenic transmission of amyloid beta can cause cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), but the relationship between these phenotypes is unclear. METHODS: We retrospectively analyzed standardized neuropsychological and neuroimaging data from 11 patients with iatrogenic CAA (iCAA). Brain MRI was assessed for medial temporal lobe atrophy (MTA), the posterior atrophy score for parietal atrophy, and global cortical atrophy (GCA). RESULTS: All patients (mean age 42 ± 8.3 years) had childhood neurosurgery; 91% had confirmed cadaveric dura exposure. Six patients (55%) presented with intracerebral hemorrhage, and none showed MTA, parietal atrophy, or GCA at presentation. Over a median 5-year follow-up, 8/11 (73%) developed atrophy on at least one score, moderate to severe in three patients. Cognitive impairment was present in 9/11 (82%) at a median 3-year follow-up. AD was confirmed histopathologically in 2/4 (50%) examined cases. DISCUSSION: Progressive brain atrophy and cognitive impairment are common in iCAA, suggesting frequent co-existing neurodegeneration and possible AD pathology. Vigilance for cognitive decline may enable earlier identification and management.
Li Y, Wang D, Zhou R
… +14 more, Yan S, Wang D, Wei Y, Yao H, Zhou B, Lu J, Wang P, Liao Z, Han Y, Zhang X, Zhang Y, Liu Y, Zhao K, Alzheimer's Disease Neuroimaging Initiative
Alzheimers Dement
· 2026 Jul · PMID 42381349
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INTRODUCTION: Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), shows pronounced clinical heterogeneity poorly explained by pathology burden, representing a gap complicating prognosis. As th...INTRODUCTION: Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), shows pronounced clinical heterogeneity poorly explained by pathology burden, representing a gap complicating prognosis. As the brain operates as a complex network for information integration, we hypothesized that connectome architecture mediates the link between AD pathology and clinical expression. METHODS: We developed a framework integrating structural and functional connectomes from multi-center cohorts, performing connectome-based subtyping in MCI, with analyses of upstream pathology, downstream phenotypes, and transcriptomic associations. RESULTS: This approach identified an "MCI-compromised" (MCI-C) subgroup characterized by extensive structural-functional connectomic disruption and an "MCI-preserved" (MCI-P) subgroup with relatively preserved connectome integrity. Despite comparable pathology, MCI-C demonstrated more severe neurodegeneration, accelerated cognitive decline, and elevated progression risk. Multiscale analyses linked these patterns to transcriptomic profiles of mitochondrial, synaptic, and neuroimmune processes. DISCUSSION: These findings demonstrate that the connectome acts as a critical mediator, rather than a passive endophenotype, shaping AD clinical expression.
Cary GA, Young JE, Rose SE
… +13 more, Frankowski H, Wilkins H, Amirtha Ganesh SS, Draper J, Darvas M, Bothwell M, Jayadev S, Reid AN, Greenwood A, Levey AI, Leal K, Carter GW, Wiley JC
Alzheimers Dement
· 2026 Jul · PMID 42381348
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INTRODUCTION: Alzheimer's disease (AD) can be caused by autosomal-dominant familial Alzheimer's disease (FAD) mutations in amyloid precursor protein (APP) or presenilin-1 and 2, which form an enzyme substrate complex. KA...INTRODUCTION: Alzheimer's disease (AD) can be caused by autosomal-dominant familial Alzheimer's disease (FAD) mutations in amyloid precursor protein (APP) or presenilin-1 and 2, which form an enzyme substrate complex. KAT5 binds to the APP intracellular domain. Recent reports of decreased γ-secretase activity in FAD mutants support KAT5 membrane sequestration. METHODS: We compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout (KO) mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human wild-type and AD neurons. RESULTS: The Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle, and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons. DISCUSSION: This analysis supports the hypothesis that KAT5 nuclear signaling downstream of APP cleavage plays a pivotal role in neuronal homeostasis.
Lee J, Olafson E, Toth B
… +18 more, Casavant E, Schauer S, Bittner T, Meyer MR, Verghese PB, Venkatesh V, West T, Braunstein JB, Biever A, Calderon E, Mandl M, Bayfield A, Hoogenraad CC, Teng E, Monteiro C, Anania VG, Bohórquez SMS, Yeh FL
Alzheimers Dement
· 2026 Jul · PMID 42373580
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INTRODUCTION: Positron emission tomography (PET) is a valuable tool for assessing tau pathology in Alzheimer's disease (AD), but it is not widely accessible. Clarifying the relationship between fluid tau species and tau...INTRODUCTION: Positron emission tomography (PET) is a valuable tool for assessing tau pathology in Alzheimer's disease (AD), but it is not widely accessible. Clarifying the relationship between fluid tau species and tau PET in AD may allow for the identification of fluid biomarkers that could serve as more accessible surrogates for tau PET. METHODS: Cerebrospinal fluid (CSF) and plasma tau species levels were assessed across prodromal to moderate AD subjects (CSF: n = 53, plasma: n = 181) via immunoassays and liquid chromatography-mass spectrometry. Fluid measures were correlated with [F]GTP1 tau PET at baseline for head-to-head comparisons across analytes. RESULTS: CSF C2N-eMTBR-tau243, tau phosphorylated at threonine 205 (p-tau205), p-tau217, and a peptide from the tau-441 microtubule-binding region (MTBR) (MTBR/243-254) exhibited the highest correlations with [F]GTP1 standardized uptake value ratio. Plasma p-tau181 and p-tau217 demonstrated correlation rankings with tau PET similar to those observed with corresponding CSF analytes. DISCUSSION: CSF C2N-eMTBR-tau243, MTBR/243-254, p-tau205, and p-tau217 demonstrated comparable strong correlations with tau PET. These findings may guide future development of plasma biomarker surrogates for tau PET.
Abdelmessih GT, Bransby L, Cummins H
… +2 more, Jackson ML, Lim YY
Alzheimers Dement
· 2026 Jul · PMID 42370433
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INTRODUCTION: Obstructive sleep apnea (OSA) is a potential risk factor for cognitive impairment and dementia; however, its contribution in midlife and interactions with APOE ε4 remain unclear. METHODS: Participants were...INTRODUCTION: Obstructive sleep apnea (OSA) is a potential risk factor for cognitive impairment and dementia; however, its contribution in midlife and interactions with APOE ε4 remain unclear. METHODS: Participants were 2795 cognitively unimpaired, middle-aged adults enrolled in the Healthy Brain Project. OSA status was determined by self-report. Cognition was assessed using the Cogstate Brief Battery, and dementia risk using the Cardiovascular Risk Factors, Ageing, and Incidence of Dementia (CAIDE) score. RESULTS: Participants with OSA demonstrated poorer memory than those without OSA, although this association was attenuated after adjusting for vascular risk. Individuals with OSA (with or without APOE ε4) had significantly higher CAIDE scores than those with neither risk factor. APOE ε4 did not moderate OSA-cognition associations. DISCUSSION: OSA may be associated with poorer memory and greater dementia risk, irrespective of APOE ε4 carriage. These findings highlight the need for early OSA screening to identify individuals at elevated dementia risk.
Alzheimers Dement
· 2026 Jul · PMID 42363728
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INTRODUCTION: Immune signaling alterations have been implicated in Alzheimer's disease (AD) pathophysiology, but their heterogeneity across the disease continuum in real-world cohorts is poorly characterized, limiting th...INTRODUCTION: Immune signaling alterations have been implicated in Alzheimer's disease (AD) pathophysiology, but their heterogeneity across the disease continuum in real-world cohorts is poorly characterized, limiting the development of stratified immunomodulatory approaches. METHODS: In a diverse multicenter cohort (BioHermes) of 176 amyloid-positive individuals with AD/mild cognitive impairment (MCI) and 173 age and sex-matched controls, principal component analysis was performed on Luminex-measured plasma cytokines to derive inflammatory signatures, and their direct/indirect associations with cognition and neurodegeneration. RESULTS: Two components were identified. Proinflammatory Component 2 was elevated in AD/MCI and in Black/African American participants, and strongly associated with poorer cognition (independently of neurofilament light [NfL], phosphorylated tau 217 [p-tau217], and glial fibrillary acidic protein [GFAP]). Inflammatory Component 1 showed an indirect association with cognition, mediated by neurodegeneration (plasma NfL). DISCUSSION: Plasma inflammation profiles were associated with poorer cognition via direct and neurodegeneration-mediated pathways, supporting their potential use as stratification markers in AD therapeutics.
Wang Z, Pei J, Sun T
… +6 more, Ge S, Wu T, Yin Y, Wang H, Yang J, Zheng K
Alzheimers Dement
· 2026 Jul · PMID 42363726
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INTRODUCTION: Whether cardiovascular-kidney-metabolic (CKM) syndrome stage modifies cognitive benefits of intensive blood pressure (BP) control remains unclear. METHODS: This post hoc analysis of Systolic Blood Pressure...INTRODUCTION: Whether cardiovascular-kidney-metabolic (CKM) syndrome stage modifies cognitive benefits of intensive blood pressure (BP) control remains unclear. METHODS: This post hoc analysis of Systolic Blood Pressure Intervention Trial - Memory and Cognition in Decreased Hypertension (SPRINT MIND) classified participants into non-advanced CKM (Stage 2, n = 5,632) and advanced CKM (Stages 3-4, n = 2,931). The primary outcome was probable dementia; secondary outcomes included mild cognitive impairment (MCI) and probable dementia or MCI composite. Treatment effects were evaluated using Cox models and generalized linear models. RESULTS: In non-advanced CKM, intensive BP control reduced risks of probable dementia (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.46-0.85) and composite outcome (HR 0.74, 95% CI 0.62-0.89). No benefit was observed in advanced CKM (probable dementia: HR 1.15; composite: HR 0.97). Significant interactions between treatment and CKM stage were observed for probable dementia (p = 0.009). CONCLUSION: Among patients with hypertension and non-advanced CKM syndrome, intensive BP control was associated with lower risk of probable dementia, whereas no such benefit was observed in advanced CKM (see Graphical Abstract).
Wugalter KA, Thurston RC, Wu M
… +4 more, Aizenstein HJ, Kamboh MI, Karikari TK, Maki PM
Alzheimers Dement
· 2026 Jul · PMID 42363721
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INTRODUCTION: Women carrying the apolipoprotein E4 (APOE4) allele have a greater risk of Alzheimer's disease (AD) from ages 65-75 years compared to men, yet the effects of APOE4 on cognitive and neuroimaging outcomes amo...INTRODUCTION: Women carrying the apolipoprotein E4 (APOE4) allele have a greater risk of Alzheimer's disease (AD) from ages 65-75 years compared to men, yet the effects of APOE4 on cognitive and neuroimaging outcomes among midlife women remain poorly understood. We investigated APOE4-related differences in memory-based functional neuroimaging outcomes in cognitively normal, midlife postmenopausal women. METHODS: We measured blood-oxygen-level-dependent activation and hippocampal functional connectivity during a functional magnetic resonance imaging verbal encoding task. Linear regression models tested APOE4 differences (carriers vs. non-carriers) and associations of neuroimaging indices with verbal memory measures and plasma AD biomarkers, adjusting for age, race, and education. RESULTS: Among 145 women from MsBrain, APOE4 carriers and non-carriers did not differ in verbal memory performance or AD biomarker levels. During verbal encoding, APOE4 carriers had significantly decreased activation and hippocampal functional connectivity in several regions compared to non-carriers. DISCUSSION: APOE4-related functional brain differences are present by midlife in postmenopausal women.
Gebremedhin Asefa N, Romero JM, Hu YH
… +9 more, Li Z, Meirelles O, Mbangdadji D, Beydoun MA, Sigurdsson S, Gudmundsdottir V, Aspelund T, Gudnason V, Launer L
Alzheimers Dement
· 2026 Jul · PMID 42363718
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INTRODUCTION: There is well-established evidence showing an association between accelerated biological aging (BA) and brain pathology. However, it remains unclear whether dynamic change in BA during adulthood is directly...INTRODUCTION: There is well-established evidence showing an association between accelerated biological aging (BA) and brain pathology. However, it remains unclear whether dynamic change in BA during adulthood is directly associated with brain health or primarily reflects cumulative life-course environmental and lifestyle exposures. METHODS: We analyzed data from the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS; n = 2081), with assessments at midlife (≈50 [SD 6.3] years) and late-life (baseline ≈76 [4.8]; follow-up ≈81 [4.8] years). We identified individuals with substantial change in BA (measured by DunedinPACE) and examined associations with brain magnetic resonance imaging (MRI) and cognitive outcomes. Mediation analyses tested whether late-life BA mediated associations between midlife cardiovascular health and later-life brain health. RESULTS: Shifting to accelerated BA was associated with lower brain volumes and incident dementia. Associations with brain infarcts and cognitive function largely reflected cumulative life-course exposure. DISCUSSION: These findings underscore the need for further investigation into the timing, reversibility, and pathways linking BA to brain health.
Preitner N, Dehlinger V, Rodriguez P
… +17 more, Fabbri K, Varisco Y, Pigni M, Lovison A, Münzenmaier L, Piorkowska K, Fuchs A, Ait-Bouziad N, Fournier N, Jepaul S, Molette J, Gabellieri E, Darmency V, Poli S, Pfeifer A, Kosco-Vilbois M, Capotosti F
Alzheimers Dement
· 2026 Jul · PMID 42363714
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INTRODUCTION: Pathological tau aggregates are key therapeutic targets in Alzheimer's disease (AD), but current approaches face limitations including poor intracellular penetration, lack of selectivity for aggregated over...INTRODUCTION: Pathological tau aggregates are key therapeutic targets in Alzheimer's disease (AD), but current approaches face limitations including poor intracellular penetration, lack of selectivity for aggregated over physiological tau, or reliance on invasive administration. METHODS: ACI-16664, an orally available brain penetrant tau aggregation inhibitor, was identified through medicinal chemistry optimization of the Morphomer library and characterized using biochemical assays, neuronal cultures, and the Tg4510 tauopathy mouse model. RESULTS: ACI-16664 selectively bound aggregated tau with high apparent affinity, destabilized its β-sheet structures, blocked intracellular seeding by both soluble and insoluble tau, and prevented tau-induced neurotoxicity. In Tg4510 mice, ACI-16664 reduced both soluble tau aggregates and tangles, and prevented neuronal loss, synaptic degeneration, and cortical atrophy. DISCUSSION: These findings demonstrate the therapeutic value of targeting tau aggregation across its diverse pathological forms and cellular compartments, supporting the potential of this approach to benefit patients with AD and other tauopathies across disease stages.