Amouyel P, Andrieu S, Bradshaw A
… +24 more, Carmona RC, Dumont M, Grinberg LT, Iwatsubo T, Hansson O, Jack CR, Jicha GA, Mahinrad S, McDade E, Mummery CJ, Petersen RC, Robinson S, Schneider JA, Shellcross L, Smith AG, Snyder HM, Tapply B, Teunissen C, van der Flier WM, Vellas B, Wallon D, Williamson JD, Wilcock D, Carrillo MC
Alzheimers Dement
· 2026 Jun · PMID 42298289
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Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer'...Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real-world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision-making, clear and transparent communication, and the need for real-world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.
Siengsukon CF, Hand LK, Nelson E
… +10 more, Glaser A, Ludwig R, Russell JA, Phadnis MA, Dai J, Bruce J, Vidoni ED, Drerup M, Morris J, Burns JM
Alzheimers Dement
· 2026 Jun · PMID 42298279
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INTRODUCTION: Insomnia is associated with increased risk for Alzheimer's disease (AD). It is unknown how cognitive behavioral therapy for insomnia (CBT-I) impacts two hallmarks of AD progression, cognitive performance an...INTRODUCTION: Insomnia is associated with increased risk for Alzheimer's disease (AD). It is unknown how cognitive behavioral therapy for insomnia (CBT-I) impacts two hallmarks of AD progression, cognitive performance and beta-amyloid (Aβ) burden. METHODS: Cognitively normal older adults with symptoms of insomnia were randomized into CBT-I treatment (n = 100) or control (n = 100) groups. Cognitive performance was assessed at baseline, 6-weeks, and 1-year (1 year). Aβ burden was assessed in a subsample (n = 50). RESULTS: No differences were observed between groups in change in cognitive performance, including speed of information processing (mean difference, 0.017; 95% confidence interval [CI], -0.1036 to 0.1376; p = 0.78), executive function (-0.0881; 95% CI, -0.2945 to 0.1182; p = 0.40), and memory (0.4068; 95% CI, -2.3965 to 3.2101; p = 0.77). No group differences were observed in Aβ deposition. DISCUSSION: CBT-I did not improve cognitive performance or Aβ deposition by one year. Longer follow up is needed to understand the potential impact of CBT-I on AD risk. CLINICAL TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NCT03954210) on 5/17/2019.
Hu M, Przybelski SA, Therneau TM
… +11 more, Lundt ES, Wiste HJ, Mester CT, Kamykowski M, Reid RI, Machulda MM, Knopman DS, Petersen RC, Jack CR, Graff-Radford J, Vemuri P
Alzheimers Dement
· 2026 Jun · PMID 42283327
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INTRODUCTION: White matter lesions on fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR-MRI) reflect small vessel disease (SVD) and aid in identifying vascular contributions to impairment and dementia...INTRODUCTION: White matter lesions on fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR-MRI) reflect small vessel disease (SVD) and aid in identifying vascular contributions to impairment and dementia (VCID). Emerging diffusion MRI (dMRI) biomarkers are sensitive to early SVD but the lack of validated approaches for defining dMRI abnormality has limited their clinical utility. METHODS: In 3934 participants (8749 observations) from a population-based sample, we classified 9% as vascular cognitive impairment versus not (VCI+/VCI-) using abnormal FLAIR-MRI and cognitive testing. We evaluated four distinct dMRI positivity criteria and assessed performance in an independent clinical sample. RESULTS: The young referent criterion performed best and yielded an estimated prevalence of dMRI positivity aligned with pathology literature. About 40% of the population were dMRI positive, and these individuals had lower baseline cognition and faster longitudinal decline. Cutpoints were validated in an independent clinical sample. DISCUSSION: The proposed dMRI abnormality framework can detect VCID and aid in identification of individuals at risk of VCI.
Alzheimers Dement
· 2026 Jun · PMID 42274018
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INTRODUCTION: The exposome encompasses all environmental exposures across the life course, yet educational environments, a critical socioenvironmental exposure, remain underexplored despite their role in cognitive aging...INTRODUCTION: The exposome encompasses all environmental exposures across the life course, yet educational environments, a critical socioenvironmental exposure, remain underexplored despite their role in cognitive aging and Alzheimer's disease and related dementias (AD/ADRD). Traditional measures, such as years of schooling, underestimate exposure heterogeneity and mechanisms influencing cognitive reserve. METHODS: The Educational Exposome Framework integrates psychosocial, resource-based, environmental, and structural domains of education: academic self-efficacy, home and community learning resources, and institutional learning contexts drawing on life-course, exposomic, and cognitive health research. RESULTS: The framework conceptualizes education as a multidimensional, interacting system shaping cognitive development, stress biology, and neurodegeneration. Legacy and emerging datasets, including High School & Beyond, Health and Retirement Study, and Add Health, enable life-course reconstruction of educational exposures linked to midlife and later-life cognition. DISCUSSION: By capturing mechanistic pathways and leveraging linked data, the framework supports equity-focused dementia prevention and clarifies education's role in AD/ADRD risk.
Cottez RJ, Peyrot C, Denis HL
… +12 more, Tremblay C, Loiselle A, Dallaire-Théroux C, Filali-Mouhim A, Hébert SS, Leclerc N, Blennow K, Zetterberg H, Consortium for the Early Identification of Alzheimer's Disease – Quebec (CIMA‐Q), Kergoat MJ, Calon F, Pichet Binette A
Alzheimers Dement
· 2026 Jun · PMID 42273887
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INTRODUCTION: We evaluated associations between phosphorylated au 217 (p-tau217), p-tau181, p-tau231, and vascular risk factors with cognitive outcomes across the Alzheimer's disease (AD) continuum. METHODS: Baseline pla...INTRODUCTION: We evaluated associations between phosphorylated au 217 (p-tau217), p-tau181, p-tau231, and vascular risk factors with cognitive outcomes across the Alzheimer's disease (AD) continuum. METHODS: Baseline plasma p-tau concentrations and vascular risk factors were assessed in 277 Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q) participants. Associations between these markers, cognition, and clinical progression over on average 3.10 years were examined. RESULTS: Higher plasma p-tau levels were associated with worse cognition at baseline and over time, with the strongest effect observed with p-tau217 in cognitively impaired individuals (β = -0.49, p < 0.001). Hypertension was further linked to steeper memory and executive function decline (β = -0.10, both p = 0.04) in this group, and it amplified the effect of p-tau217 on cognitive decline across the whole group. Higher p-tau217 levels were associated with cognitive decline in cognitively unimpaired individuals, and it also predicted progression from mild cognitive impairment (MCI) to AD dementia (hazard ratio [HR] = 1.22, p = 0.016). DISCUSSION: Plasma p-tau217 was the most sensitive marker of cognitive decline, with hypertension contributing to longitudinal cognitive changes.
David MCB, Mallas EJ, Kolanko MA
… +10 more, Del Giovane M, Kurtin DL, Nilforooshan R, Zimmerman KA, Bonet Olivares C, Lally PJ, CR&T Group of UKDRI, Sharp DJ, Malhotra PA, Scott G
Alzheimers Dement
· 2026 Jun · PMID 42273876
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INTRODUCTION: The brain is a complex dynamical system, influenced by arousal state. Cortical synchrony supports information processing and is disrupted in Alzheimer's disease (AD). Locus coeruleus (LC) integrity and pupi...INTRODUCTION: The brain is a complex dynamical system, influenced by arousal state. Cortical synchrony supports information processing and is disrupted in Alzheimer's disease (AD). Locus coeruleus (LC) integrity and pupillometry index arousal system structure and function. METHODS: Sixty-four AD and 26 controls underwent resting-state pupillometry-fMRI. Neuromelanin MRI and Addenbrooke's Cognitive Examination were conducted. Mean and standard deviation of blood oxygen level dependent (BOLD) phase coherence yielded synchrony and metastability, respectively. Leading Eigenvector Dynamics Analysis (LEiDA) produced coherence-based states. RESULTS: AD had reduced global synchrony [b = -0.90, p < 0.001], metastability [b = -0.61, p < 0.01], LEiDA "global coherence state" occupancy [b = -0.06, p < 0.01], and LC integrity [b = -0.37, p = 0.01]. Synchrony [b = 0.19, p = 0.01] and LC integrity [b = 0.17, p < 0.01] related to cognition and one another [b = 0.27, p = 0.01]. Pupil-linked arousal correlated with synchrony and global coherence state maintenance. DISCUSSION: In health, cortical activity shows widespread but dynamic synchrony across regions to meet changing demands. In AD, arousal dysfunction appears to disrupt these dynamics, impacting cognition.
Wang Z, Hossain D, Wang JJ
… +4 more, Subramaniam VR, Zhang B, Wang M, Huang KL
Alzheimers Dement
· 2026 Jun · PMID 42273872
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INTRODUCTION: Allele-specific expression (ASE), preferential expression of one allele at a heterozygous locus, is implicated in various brain diseases but remains largely uncharacterized in Alzheimer's disease (AD). METH...INTRODUCTION: Allele-specific expression (ASE), preferential expression of one allele at a heterozygous locus, is implicated in various brain diseases but remains largely uncharacterized in Alzheimer's disease (AD). METHODS: We performed a genome-wide characterization of ASE variants across seven brain regions of 2,231 AD and Control patients from Mount Sinai Brain Bank (MSBB) and Religious Orders Study/Memory and Aging Project (ROSMAP) cohorts and investigated cell-type-specific activity via single-cell analysis. RESULTS: We identified 56,136 unique ASE variants that were enriched in imprinted chromosomal regions, e.g., chr6, chr14q32, and chr15q11. ASE variants were also found in exons of known AD-associated genes, including apolipoprotein E (APOE), CLU, CTSB, and HLA-DRB1. Forty variants exhibited AD-associated ASE, and the affected genes, including SLC12A5, SYT13, and TOMM7, were predominantly downregulated in multiple cell types, including astrocytes, excitatory neurons, and oligodendrocytes. DISCUSSION: We provided a detailed landscape of ASE in AD, uncovering novel functional variants and highlighting their potential cell-type-specific contributions to disease pathogenesis.
Xiao C, Ard T, Blazhenets G
… +5 more, La Joie R, Pappas I, Toga AW, Alzheimer's Disease Neuroimaging Initiative, Health and Aging Brain Study (HABS‐HD) Study Team
Alzheimers Dement
· 2026 Jun · PMID 42273871
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INTRODUCTION: Weak associations of apolipoprotein E (APOE) ε4 with cognitive impairment have been reported in Hispanic cohorts. To determine if APOE ε4 associates with brain amyloid load differently in Hispanic and non-H...INTRODUCTION: Weak associations of apolipoprotein E (APOE) ε4 with cognitive impairment have been reported in Hispanic cohorts. To determine if APOE ε4 associates with brain amyloid load differently in Hispanic and non-Hispanic White (NHW) cohorts, we analyzed reported Centiloid values from studies that conducted amyloid positron emission tomography. METHODS: This meta-analysis included 17,017 participants (8.4% Hispanic) from five source studies. Analysis of covariance and logistic regression models adjusting for age, sex, education, and cognitive score were applied. RESULTS: Although cognitive impairment and APOE ε4 were associated with higher Centiloids in both Hispanic and NHW cohorts, cognitively impaired and APOE ε4 positive Hispanic participants had lower Centiloids than NHW participants with the same conditions. DISCUSSION: APOE ε4 may have a weaker influence on brain amyloid load in Hispanic cohorts. Further comparative analyses are necessary for Alzheimer's disease anti-amyloid treatments to be widely applicable to Hispanic populations.
Dhanam S, Sanderson-Cimino M, Taylor JC
… +16 more, Paolillo EW, Fregly R, Kwang W, Maruff P, Wise A, Heuer HW, Forsberg LK, Kramer JH, Boeve BF, Rosen HJ, Mackin RS, Weiner MW, Nosheny RL, Boxer AL, Staffaroni AM, and the Brain Health Registry
Alzheimers Dement
· 2026 Jun · PMID 42273832
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BACKGROUND: Remote, smartphone-based cognitive testing may improve access to cognitive assessments for Alzheimer's disease and related dementias. We evaluated the feasibility, reliability, and validity of unsupervised sm...BACKGROUND: Remote, smartphone-based cognitive testing may improve access to cognitive assessments for Alzheimer's disease and related dementias. We evaluated the feasibility, reliability, and validity of unsupervised smartphone-based cognitive tests in a registry-based cohort. METHODS: Adults without a record of cognitive impairment (N = 1815; ages 18-92) were recruited from the University of California, San Francisco (UCSF) Brain Health Registry to complete three unsupervised smartphone cognitive testing sessions within 2 weeks. Reliability was assessed with correlations between sessions. Linear regression models tested associations of smartphone tasks with demographics, self- and informant-rated cognitive concerns, and web-based cognitive testing (Cogstate Brief Battery). RESULTS: Adherence was high (82.2%) and usability favorable. Test-retest reliability was moderate to strong (ρ's = 0.61-0.85, all p's < 0.001). Lower smartphone scores were associated with older age, lower education, cognitive concerns, and worse Cogstate performance. DISCUSSION: Findings support the feasibility, reliability, and validity of remote digital assessments in adults without a record of cognitive impairment.
Raket LL, Lu M, Evans CD
… +11 more, Zimmer JA, Sparks J, Collins EC, Shcherbinin S, Wang H, Nery ESM, Epelbaum S, Dell'Agnello G, Brooks DA, Sims JR, Mintun MA
Alzheimers Dement
· 2026 Jun · PMID 42273802
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INTRODUCTION: Clinical trials indicate that disease-modifying therapies can slow clinical decline in Alzheimer's disease (AD), with earlier initiation associated with greater slowing. METHODS: In the TRAILBLAZER-ALZ 2 tr...INTRODUCTION: Clinical trials indicate that disease-modifying therapies can slow clinical decline in Alzheimer's disease (AD), with earlier initiation associated with greater slowing. METHODS: In the TRAILBLAZER-ALZ 2 trial, the treatment effect of donanemab on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score was assessed across disease stages defined by baseline tau PET, plasma P-tau217 levels, or predicted disease progression. RESULTS: Donanemab-mediated slowing of disease progression occurred across baseline tau PET and plasma P-tau217 levels. Participants with lower baseline tau PET and P-tau217 showed greater slowing with donanemab versus placebo. Modeling CDR-SB scores indicated that earlier treatment (at the 25 percentile of baseline Predicted disease progression) delayed disease progression by 60% over 76 weeks, compared to 33% and 17% at the 50 and 75 percentiles. DISCUSSION: Donanemab benefited participants with early symptomatic AD across clinical and pathological severities, with the greatest slowing in those treated earlier. CLINICALTRIALS: gov Identifier: NCT04437511.
Koops EA, Giudicessi A, Baena A
… +9 more, Martinez L, Bonillas-Felix N, Medrano R, Dutta J, Gonzalez I, Alvarez S, Aguillon D, Quiroz YT, Jacobs HIL
Alzheimers Dement
· 2026 Jun · PMID 42273784
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INTRODUCTION: Locus coeruleus (LC) structural integrity declines early in sporadic and autosomal dominant Alzheimer's disease (AD). We examined LC-entorhinal cortex (LC-EC) tract integrity and its association with amyloi...INTRODUCTION: Locus coeruleus (LC) structural integrity declines early in sporadic and autosomal dominant Alzheimer's disease (AD). We examined LC-entorhinal cortex (LC-EC) tract integrity and its association with amyloid and tau pathology and memory in autosomal dominant AD (ADAD). METHODS: We examined associations between diffusion-weighted imaging-derived LC-EC tract characteristics and age, sex, amyloid (Pittsburgh Compound B [PiB]), entorhinal tau ([F]-flortaucipir [F-FTP] positron emission tomography [PET]), and memory in PSEN1-E280A mutation carriers (n = 30) and non-carriers (n = 33). RESULTS: LC-EC tract integrity was lower in females and older individuals in both non-carriers and carriers. In mutation carriers, lower tract integrity was associated with higher entorhinal tau and poorer memory, with tau and amyloid mediating the tract-memory relationship in the entire sample but not in unimpaired carriers. DISCUSSION: These findings highlight the LC-EC tract as an early disease vulnerability marker in ADAD, with tract disruption associated with memory decline across disease stages, a relationship further mediated by entorhinal tau pathology as disease progresses.
Andrade V, Kleineidam L, Wagner-Thelen H
… +17 more, Ballarini T, Campos-Martin R, Martino-Adami P, Tripathi KP, Guyonnet S, Vellas B, Scherer M, Maier W, Pentzek M, Schmid M, Riedel-Heller S, Weyerer S, Bickel H, Wiese B, Egert S, Wagner M, Ramírez A
Alzheimers Dement
· 2026 Jun · PMID 42271192
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INTRODUCTION: The polyunsaturated fatty acids (PUFAs) omega-6 (ω6) and omega-3 (ω3) are linked to cognitive performance and Alzheimer's-type dementia (DAT), but ω3-PUFA supplementation offers limited benefits. We propose...INTRODUCTION: The polyunsaturated fatty acids (PUFAs) omega-6 (ω6) and omega-3 (ω3) are linked to cognitive performance and Alzheimer's-type dementia (DAT), but ω3-PUFA supplementation offers limited benefits. We propose that the ω6-PUFA/ω3-PUFA ratio better explains cognitive decline and DAT risk. METHODS: PUFA profiles were examined in the AgeCoDe cohort (n = 3327) and MAPT trial (n = 1679). Cox and linear mixed models evaluated associations of individual PUFAs and the ω6-PUFA/ω3-PUFA ratio with DAT progression and cognitive decline. Mendelian randomization (MR) assessed genetic causal effects. The effect of ω3-PUFA on ω6-PUFA levels was analyzed. RESULTS: Higher ω6-PUFA/ω3-PUFA ratio increased DAT risk beyond ω3-PUFA levels alone. A baseline high (detrimental) ratio predicted faster cognitive decline, whereas longitudinal improvements slowed decline. MR supported a genetic non-causal link. Higher ω3-PUFA levels correlated with lower ω6-PUFA species. DISCUSSION: The ω6-PUFA/ω3-PUFA ratio better predicts cognitive decline and DAT progression than individual PUFAs, suggesting that dietary adjustments may help prevent dementia.
Fan L, Sun Y, Liu D
… +7 more, Robb WH, Pechman KR, Shashikumar N, Vyas Y, Landman BA, Hohman TJ, Jefferson AL
Alzheimers Dement
· 2026 Jun · PMID 42271188
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INTRODUCTION: Prior studies showed inconsistent links between dietary fat and Alzheimer's disease (AD) risk. We examined whether dietary fat affected brain atrophy markers differentially based on risk factors like female...INTRODUCTION: Prior studies showed inconsistent links between dietary fat and Alzheimer's disease (AD) risk. We examined whether dietary fat affected brain atrophy markers differentially based on risk factors like female sex, apolipoprotein ε4 (APOE ε4) status, and cognitive status. METHODS: Participants from the Vanderbilt Memory and Aging Project, classified as cognitively unimpaired (CU) or with mild cognitive impairment (MCI), were included (n = 758). Linear mixed-effects regression models examined associations between total fat intake (Tfat, times/day) and percentage of energy from fat (Pfat, %) and longitudinal gray matter volumes, as well as interactions. RESULTS: Over 4.6 ± 3.1 years, Pfat interacted with cognitive status on longitudinal temporal lobe (p = 0.009) and inferior lateral ventricle volume (p = 0.002). Higher Pfat was associated with faster reduction in temporal lobe volume in CU participants (β = 47.2, p = 0.007) but slower enlargement of the inferior lateral ventricle among participants with MCI (β = -22.5, p = 0.006). DISCUSSION: Different mechanisms may underlie the fat-neurodegeneration relationship across cognitive statuses.
Huang C, Cai Q, Feng Z
… +4 more, Zhang C, Luo Z, Cheng X, Wu H
Alzheimers Dement
· 2026 Jun · PMID 42271186
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INTRODUCTION: Periodontal pathogen Porphyromonas gingivalis is epidemiologically linked to Alzheimer's disease (AD), yet how oral infection disrupts the central circadian clock to drive hippocampal neurodegeneration rema...INTRODUCTION: Periodontal pathogen Porphyromonas gingivalis is epidemiologically linked to Alzheimer's disease (AD), yet how oral infection disrupts the central circadian clock to drive hippocampal neurodegeneration remains unknown. METHODS: C57BL/6 mice received oral P. gingivalis for 6 months; hippocampal clock gene oscillations, phosphorylated protein kinase B (p-AKT), glial fibrillary acidic protein (GFAP)/Ionized calcium-binding adapter molecule 1 (Iba1), and amyloid beta (Aβ) load were quantified. C8-D1A astrocytes and BV2 microglia were infected with P. gingivalis ± phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT inhibitor or agonist; Bmal1 (brain and muscle ARNT-like 1)/Clock (circadian locomotor output cycles kaput) were knocked down by lentivirus. RESULTS: P. gingivalis-induced periodontitis dampened hippocampal Bmal1 rhythms, lowered p-AKT, activated glia, and elevated Aβ and interleukin 1β (IL-1β). In glial cells, P. gingivalis flattened Bmal1 oscillation; PI3K blockade mimicked these effects, whereas AKT agonist restored rhythms and suppressed GFAP/Iba1/IL-1β. Bmal1 knockdown alone triggered glial activation and cytokine release. DISCUSSION: P. gingivalis oral infection suppresses PI3K/AKT signaling, destabilizing glial circadian clocks and unleashing neuroinflammation that fosters hippocampal AD-like pathology; rescuing PI3K/AKT or clock function may mitigate the oral-brain axis in AD.
O'Hora KP, Morehouse AB, Hernandez B
… +10 more, Burda KF, Babros MC, Lazzeroni L, Zeitzer JM, Friedman L, Posner D, Kushida C, Manber R, Yesavage JA, Goldstein-Piekarski AN
Alzheimers Dement
· 2026 Jun · PMID 42271184
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INTRODUCTION: This secondary analysis examined whether mild cognitive impairment (MCI) moderates the effectiveness of non-pharmacological insomnia therapy and whether insomnia therapy is associated with clinically meanin...INTRODUCTION: This secondary analysis examined whether mild cognitive impairment (MCI) moderates the effectiveness of non-pharmacological insomnia therapy and whether insomnia therapy is associated with clinically meaningful symptom reduction. METHODS: Cognitively intact (CI; n = 87) and MCI (n = 38) older adults with insomnia completed insomnia therapy. The primary outcome was the Insomnia Severity Index (ISI), assessed at baseline, post-treatment, and 6-month follow-up (6FU). Linear mixed effects models evaluated ISI changes across time and group. Logistic regression examined clinically meaningful reductions (ISI decrease ≥ 6). RESULTS: Both groups showed significant ISI reductions at post-treatment and 6FU (p-values < 0.0001). There were no between-group differences at post-treatment (p = 0.869). Yet, at 6FU, CI participants, compared to MCI, showed significantly greater symptom reduction (p = 0.036), and a higher proportion achieved clinically meaningful reduction in ISI (78.7% vs. 45.8%). DISCUSSION: Older adults with MCI benefit from insomnia therapy; however, their continued symptom reduction 6-months later may be dampened compared to CI older adults. CLINICAL TRIAL REGISTRATION INFORMATION: Treatments for Insomnia: Mediators, Moderators and Quality of Life ClinicalTrials.gov, NCT02117388.
Cary GA, Ganesh SSA, Heath L
… +7 more, Leal K, Kampmann M, Longo FM, Butler RR, Levey AL, Carter GW, Wiley J
Alzheimers Dement
· 2026 Jun · PMID 42271180
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INTRODUCTION: The Target Enablement to Accelerate Therapy Development for AD (TREAT-AD) bioinformatics pipeline employs a rank-and-organize strategy. Disease-associated genes drive enrichment of large AD-linked endopheno...INTRODUCTION: The Target Enablement to Accelerate Therapy Development for AD (TREAT-AD) bioinformatics pipeline employs a rank-and-organize strategy. Disease-associated genes drive enrichment of large AD-linked endophenotypes. However, these biological areas were too large to promote hypothesis development or target identification. Here we delineate subdomains that map to, and enrich, specific biological processes. METHODS: To refine the biodomains into more focused areas, we built κ networks out of the Gene Ontology terms in the biodomain and employ shared gene annotation between terms to determine edge weights. κ-value filtration enabled us to identify data-driven subdomains, which we employed in an analysis of TREAT-AD harmonized datasets. RESULTS: The subdomain enrichment highlights core areas of biological impairment within the biodomain space and facilitates a deeper interpretation of large-scale multiomic datasets. DISCUSSION: The subdomain mapping of AD-risk-associated processes may facilitate an open-source, open-science shareable resource for the comparison of large datasets for the formulation of future hypotheses and identification of therapeutic targets.
Ramezan M, Demetriou A, Burke SN
… +2 more, Nalvarte I, Shin AC
Alzheimers Dement
· 2026 Jun · PMID 42271173
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Sex differences are increasingly recognized as central to the biology of Alzheimer's disease (AD), yet the mechanisms through which they shape brain metabolism and disease vulnerability remain incompletely understood. Br...Sex differences are increasingly recognized as central to the biology of Alzheimer's disease (AD), yet the mechanisms through which they shape brain metabolism and disease vulnerability remain incompletely understood. Brain glucose hypometabolism is a core hallmark of AD and emerges decades before clinical decline, but accumulating evidence indicates that its causes, timing, and functional consequences differ between women and men. In this review, we synthesize findings from neuroimaging, molecular, and cellular studies to examine how sex-dependent regulation of glucose transport, glycolysis, and mitochondrial function interacts with aging and AD pathology. We highlight reinforcing evidence for a steeper and more pathology-linked decline in mitochondrial glucose metabolism in females, particularly in the context of menopause and apolipoprotein E (APOE) ε4 genotype. We identify major knowledge gaps at the level of cell type, brain region, and disease stage, and outline priorities for sex-informed, mechanistically anchored research to enable metabolic-precision interventions for AD risk and progression.
Alzheimers Dement
· 2026 Jun · PMID 42267641
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The cholinergic neurons of the basal forebrain are among the most vulnerable cell types to age- and Alzheimer's disease-related dysfunction and neurodegeneration. However, the biological bases of basal forebrain choliner...The cholinergic neurons of the basal forebrain are among the most vulnerable cell types to age- and Alzheimer's disease-related dysfunction and neurodegeneration. However, the biological bases of basal forebrain cholinergic vulnerability (the why) and the temporal sequence (the how) have yet to be fully resolved. In this review, we summarize multi-disciplinary evidence to present a lifespan staging model of basal forebrain cholinergic vulnerability, which outlines how converging biological stressors position these neurons to fail. We trace the origins of basal forebrain cholinergic vulnerability from evolutionary and neurodevelopmental pressures, which ultimately interact with midlife stressors to culminate in two divergent trajectories of cholinergic aging: resilient and vulnerable. Lastly, we highlight that the branch point in cholinergic aging trajectories may serve as a critical window for intervention if sensitive, specific, and clinically scalable in vivo cholinergic biomarkers can be developed.
Wu J, Oishi K, Soldan A
… +12 more, Pettigrew C, Lin Z, Zhu Y, Jiang D, Li X, Gou Y, Moghekar A, Liu P, Bakker A, Oishi K, Albert M, Lu H
Alzheimers Dement
· 2026 Jun · PMID 42265841
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INTRODUCTION: It is desirable to measure brain metabolism without needing ionizing radiation and elucidate its time trajectory. This study employed a positron emission tomography -validated, non-invasive magnetic resonan...INTRODUCTION: It is desirable to measure brain metabolism without needing ionizing radiation and elucidate its time trajectory. This study employed a positron emission tomography -validated, non-invasive magnetic resonance imaging (MRI) technique to characterize longitudinal changes in cerebral metabolic rate of oxygen (CMRO) in both cognitively normal and impaired older adults. METHODS: Participants received serial MRI-based CMRO scans between 2015 and 2025. Levels of AD pathology were measured in cerebrospinal fluid and plasma at the initial MRI. RESULTS: At the initial visit, participants with MCI/dementia had lower CMRO than normal participants. In the longitudinal analyses, CMRO decreased over time in those who were cognitively impaired but remained unchanged in normals. Among normal participants, higher initial levels of total tau and phosphorylated tau at threonine 181 were associated with an increase in CMRO during follow-up, especially in amyloid-positive individuals. DISCUSSION: Aside from the well-known metabolic slowdown in the later phases of AD, the brain exhibits tau-dependent hypermetabolism during the preclinical stage.