Caminiti SP, Fernandes M, Zaccone C
… +9 more, Malito R, Chiaravalloti A, Manfredi N, Camedda R, Giuliano FD, D'Amelio M, Mercuri NB, Perani D, Liguori C
Alzheimers Dement
· 2026 Feb · PMID 42363277
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INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for neurodegenerative disorders. However, a causal link between OSAS and brain damage has yet to be established. METHODS: Thirty cognitive...INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a recognized risk factor for neurodegenerative disorders. However, a causal link between OSAS and brain damage has yet to be established. METHODS: Thirty cognitively normal patients with moderate-to-severe OSAS, free from systemic or neurological comorbidities, were enrolled and underwent F-fluorodeoxyglucose positron emission tomography imaging. Their scans were compared to those of cognitively normal, OSAS-free controls from the Alzheimer's Disease Neuroimaging Initiative database. Additional analyses included commonality mapping, correlations with polysomnographic parameters, and seed-based metabolic connectivity of major resting-state networks. RESULTS: Group-level analyses showed fronto-parietal glucose hypometabolism and cerebellar glucose hypermetabolism in patients with OSAS compared to controls. Cerebellar glucose hypermetabolism was associated with reduced rapid eye movement sleep latency and duration. Seed-based connectivity analysis revealed alterations in attentional and limbic networks. DISCUSSION: Moderate-to-severe OSAS may represent a cause of brain dysfunction, highlighting the importance of its early diagnosis and appropriate treatment to prevent worsening brain damage and possible future neurodegenerative processes. HIGHLIGHTS: Moderate-to-severe obstructive sleep apnea syndrome (OSAS) is associated with altered brain glucose metabolism. Cerebellar glucose hypermetabolism is associated with rapid eye movement sleep impairment. Attentional and limbic networks connectivity is disrupted in moderate-to-severe OSAS. Early recognition of patients with moderate-to-severe OSAS has the potential to overcome the risk of worsening brain damage that may lead to neurodegeneration.
Javonillo DI, Furman S, Le L
… +8 more, Fernandez K, Mulford J, Singla V, Jha R, Tsourmas KI, Kwang NE, Green KN, Lane TE
Alzheimers Dement
· 2026 Jul · PMID 42363004
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INTRODUCTION: Recent epidemiological datasets have associated viral encephalitis exposure (i.e., viral-induced neuroinflammation) with increased risk of Alzheimer's disease (AD) and dementia, highlighting the need to unc...INTRODUCTION: Recent epidemiological datasets have associated viral encephalitis exposure (i.e., viral-induced neuroinflammation) with increased risk of Alzheimer's disease (AD) and dementia, highlighting the need to uncover how it may impact AD neuropathology. METHODS: Aged 5xFAD and wild-type (WT) mice were infected with the John Howard Mueller strain of murine hepatitis virus (JHMV), a neurotropic strain of murine coronavirus to comprehensively determine how coronavirus-induced encephalitis may induce molecular and cellular changes that impact beta-amyloid (Aβ) neuropathology. RESULTS: JHMV-induced encephalitis at 12 days post-infection resulted in minimal changes to overall Aβ protein, despite increased CD4 and CD8 T-cell infiltration and Lgals3/MAC2-expressing macrophages surrounding more compact Aβ plaques in the brain. Spatial transcriptomic imaging and pathway analysis of differentially expressed genes (DEGs) within myeloid cells demonstrate down-regulated disease-associated (DAM) pathways involving Aβ clearance, response to lipids, and macrophage activation within infected 5xFAD brains. CONCLUSIONS: JHMV encephalitis induces dysregulated gene expression and myeloid cell responses to Aβ plaque burden in 5xFAD mouse brains.
Cooper ZC, Garcia-Cordero I, Tartaglia MC
… +5 more, Staffaroni AM, Duff K, Gunzler D, Boxer AL, Wills AM
Alzheimers Dement
· 2026 Jul · PMID 42362968
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INTRODUCTION: Progressive supranuclear palsy (PSP) causes executive dysfunction, fluency deficits, and behavioral changes. We examined longitudinal changes in PSP cognition using the Repeatable Battery for the Assessment...INTRODUCTION: Progressive supranuclear palsy (PSP) causes executive dysfunction, fluency deficits, and behavioral changes. We examined longitudinal changes in PSP cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). METHODS: Using the RBANS and executive function and fluency tests from 486 and 377 participants in the PASSPORT (NCT03068468) and tilavonemab (NCT02985879) clinical trials, we assessed linear mixed models of cognitive subtest score change, controlling for disease duration, age, sex, and treatment group. RESULTS: The greatest declines occurred in subtests assessing visuospatial (figure copy, figure recall), executive function (Color Trails, coding), and fluency (primarily semantic fluency), although controlling for motor and ocular motor disability reduced the magnitude of score decline. Subtests assessing immediate and delayed memory (story recall, story memory, list recall, list recognition) declined slowly or not at all. DISCUSSION: Cognition in PSP is characterized by declines in executive, visuospatial function, and fluency, with relative preservation of memory.
van Dort R, van Stek-Smits VCJ, Schriemer SE
… +14 more, van der Zwet RGJ, Schipper MR, Voigt S, Hart EP, Easwaran V, Sohrabi HR, Taddei K, Gardener SL, Martins RN, Greenberg SM, van Osch MJP, van Walderveen MAA, Wermer MJH, van Etten ES
Alzheimers Dement
· 2026 Jul · PMID 42360287
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INTRODUCTION: Cerebral amyloid angiopathy (CAA) is associated with cognitive impairment, but its longitudinal course of cognitive decline remains unclear. We investigated domain-specific cognitive trajectories in Dutch-t...INTRODUCTION: Cerebral amyloid angiopathy (CAA) is associated with cognitive impairment, but its longitudinal course of cognitive decline remains unclear. We investigated domain-specific cognitive trajectories in Dutch-type hereditary (D-CAA) and sporadic CAA (sCAA) to compare patterns and rates of decline. METHODS: We included 181 participants - 93 D-CAA mutation carriers (59 without, 34 with prior intracerebral hemorrhage [ICH]) and 88 with sCAA (57 without, 31 with ICH) - who underwent annual neuropsychological assessment. Longitudinal change in global cognition, memory, processing speed, and executive function was analyzed using linear mixed models. RESULTS: Over 5 years, cognitive decline was subtle but measurable. Memory and processing speed declined in D-CAA with prior ICH, whereas D-CAA without ICH and sCAA remained relatively stable. Global cognition showed a modest but significant decline, while executive function remained stable. DISCUSSION: CAA-related cognitive decline appears domain- and stage-dependent, suggesting progressive small-vessel injury rather than acute hemorrhage may drive deterioration.
Gross AL, Nichols E, Arce Rentería M
… +43 more, Khobragade PY, Meijer E, Petrosyan S, Varghese M, Weerman A, Hu P, Banerjee J, Chien S, Angrisani M, Dhankhar A, Vishwakarrma H, Ali I, Zhou Z, Aravindakshan R, Chakrabarti SS, Das MP, De K, Dhar M, Dewangan GC, Gupta M, Khan UH, Jain V, John JP, Kirti R, Kokane A, Lehl SS, Mohanty RR, Pandit V, Rajguru C, Sahoo DP, Sankhe L, Sukumar M, Talukdar A, Gunasekaran V, Sekher TV, Bloom DE, Langa KM, Sivakumar PT, Ganguli M, Crimmins EM, Dey S, Dey AB, Lee J
Alzheimers Dement
· 2026 Jul · PMID 42360165
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INTRODUCTION: We characterized modifiable risk and protective factors for cognitive decline in India. METHODS: Using the first nationally representative population-based longitudinal sample of N = 6168 older adults in In...INTRODUCTION: We characterized modifiable risk and protective factors for cognitive decline in India. METHODS: Using the first nationally representative population-based longitudinal sample of N = 6168 older adults in India, we evaluated associations of risk factors (demographic characteristics, self-reported and objective health characteristics, health behaviors, and sensory function) for late-life cognitive decline with up to 6.4 years of follow-up (range: 2.8 to 6.4 years). RESULTS: The mean rate of general cognitive decline was -0.029 SD per year and was progressively steeper with age. Most risk factors, particularly demographic and cardiovascular characteristics, were associated with steeper cognitive decline in expected directions: Associations of history of high cholesterol or heart attack on rate of cognitive decline, for example, were comparable to being 8 to 10 years older. DISCUSSION: Most risk factors were associated with change in expected directions, highlighting the potential generalizability to India of previously identified risk factors for dementia.
Russell JK, Rafii MS, Kremers WK
… +6 more, Przybelski SA, Vemuri P, Petersen RC, Graff-Radford J, Jack CR, Schwarz CG
Alzheimers Dement
· 2026 Jul · PMID 42360128
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INTRODUCTION: Face identification algorithms have increased the risk of study participants being identified through different neuroimaging modalities. De-facing algorithms can de-identify neuroimages; however, none are v...INTRODUCTION: Face identification algorithms have increased the risk of study participants being identified through different neuroimaging modalities. De-facing algorithms can de-identify neuroimages; however, none are validated in individuals with Down syndrome (DS) - a population at high risk of Alzheimer's disease and the focus of numerous Alzheimer's disease cohort studies. METHODS: Overall, 37 adults with DS were parcellated using FreeSurfer before and after de-facing with mri_reface. A group of neurotypically developed individuals balanced on age, sex, and magnetic resonance imaging scanner manufacturer served as controls. RESULTS: De-facing produced no effect on cortical thickness or volumetrics in adults with DS compared to controls or regional discrimination based on an area under the receiver operating characteristic curve analysis after correcting for multiple comparisons. DISCUSSION: FreeSurfer-derived volumetric and cortical thickness measures changed minimally following de-facing with mri_reface in adults with DS and are unlikely to influence study outcomes. De-facing should be considered prior to data sharing in studies of adults with DS.
Alzheimers Dement
· 2026 Jul · PMID 42340807
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INTRODUCTION: Poor sleep is a symptom and candidate risk factor for Alzheimer's disease (AD). We investigated whether objective and subjective longitudinal sleep measures correlated with AD pathology at brain autopsy. ME...INTRODUCTION: Poor sleep is a symptom and candidate risk factor for Alzheimer's disease (AD). We investigated whether objective and subjective longitudinal sleep measures correlated with AD pathology at brain autopsy. METHODS: Rush Memory and Aging Project (MAP) participants (n = 798; Mean = 81.72) underwent annual evaluation with actigraphy along with sleep questionnaires and cognitive assessment. Brain autopsy provided quantitative neuropathologic data. RESULTS: Objective sleep fragmentation was associated with higher amyloid density. This association was only observed among individuals with low AD neuropathologic change or no/mild cognitive impairment. Last-measured sleep fragmentation had a stronger association with amyloid density than did mean sleep fragmentation across the study. Poorer subjective sleep quality was paradoxically linked to lower AD-related neuropathologic burden. DISCUSSION: These findings provide histopathologic evidence linking objectively measured sleep fragmentation to cerebral amyloid deposition and suggest that sleep disruption may be most relevant during earlier stages of AD pathogenesis.
Alzheimers Dement
· 2026 Jun · PMID 42340145
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INTRODUCTION: Addressing dementia's substantial economic burden on individuals, families, health systems, governments, and payers, requires integrating national data and advanced analytic methods. METHODS: We described d...INTRODUCTION: Addressing dementia's substantial economic burden on individuals, families, health systems, governments, and payers, requires integrating national data and advanced analytic methods. METHODS: We described data sources, measures, and simulation methods of a dynamic microsimulation model developed for quantifying dementia costs in the United States and for assessing impact of innovation and change over time. Model internal validation was assessed. RESULTS: Using nationally representative Health and Retirement Study data on adults over age 50, Medicare and other national data, we produced estimates of individual-level health and economic outcomes over time. Estimates and simulation enabled measurement of population-level dementia prevalence, medical and long-term care costs, unpaid caregiving valuation, quality-of-life, and earnings for persons living with dementia and care partners. Counterfactual scenarios quantified dementia-related quality-of-life and earnings losses. Simulated outcomes aligned with observed data. CONCLUSIONS: Transparent methods support replication, extension, and informed use of dementia cost estimates in research and policy.
Thunell J, Tysinger B, Baumgart M
… +9 more, Carrillo M, Crimmins E, Goldman D, Heun-Johnson H, Jacobson M, Joyce G, Leaf D, Neumann LTV, Zissimopoulos J
Alzheimers Dement
· 2026 Jun · PMID 42340126
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INTRODUCTION: Comprehensive cost measurement is essential for an effective policy response to societal dementia costs. METHODS: Using dynamic microsimulation, the Health and Retirement Study, and other national data, we...INTRODUCTION: Comprehensive cost measurement is essential for an effective policy response to societal dementia costs. METHODS: Using dynamic microsimulation, the Health and Retirement Study, and other national data, we quantified the 2026 cost of dementia in the United States. RESULTS: In 2026, 5.7 million (95% confidence interval [CI] [5.6, 6.0]) US adults aged 51 and older are living with dementia, supported by 5.2 million (95% CI [4.9, 5.5]) care partners. Total costs are $818 billion (B, 95% CI [759, 866]), driven by quality-of-life losses for persons with dementia ($320B, 95% CI [269, 363]) and care partners ($15B 95% CI [6, 25]). Unpaid care ($237B, 95% CI [220, 253]), earnings losses ($23B), and out-of-pocket costs combined with quality-of-life losses account for 80% of costs and are borne by families. Governments cover 70% of healthcare costs ($222B, 95% CI [209, 237]). DISCUSSION: The costs of dementia fall on families, highlighting limited policy and work supports. Treatment innovation may increase medical costs but reduce caregiver burden and improve quality of life. HIGHLIGHTS: The costs of dementia in the United States in 2026 are $818 billion. Quality-of-life losses are the largest driver of dementia's total burden. Individuals and families bear over three times the cost versus health systems. Methods enable analysis of treatment, care, and policy innovations on future costs.
Yu K, Van Bogart K, Kang JE
… +5 more, Taylor HO, Harrington KD, Silbert LC, Hajjar I, Dodge HH
Alzheimers Dement
· 2026 Jun · PMID 42337961
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Despite empirical evidence linking loneliness and social isolation to cognitive decline (CD) in later life, the underlying physiological and psychobehavioral mechanisms remain unclear. We conducted a systematic review to...Despite empirical evidence linking loneliness and social isolation to cognitive decline (CD) in later life, the underlying physiological and psychobehavioral mechanisms remain unclear. We conducted a systematic review to synthesize relevant evidence. Studies examining psychobehavioral pathways required mediation analyses, whereas studies on physiological pathways were included when mediation was examined or when outcomes are dementia-related neuropathological changes. Thirty-eight articles were included. Evidence pointed to multiple physiological mechanisms, including Alzheimer's disease pathology, brain structural differences, inflammation, cardiovascular risks, neurotrophic factors, hypothalamic-pituitary-adrenal (HPA) -axis function, gene expression, and general health, although findings were mixed. Psychobehavioral pathways, including depressive symptoms, neuroticism, lower sense of control, sleep disturbance, and lower engagement in social or leisure activities, mediated the association. This review identified mechanistic targets that may be leveraged in non-pharmacological interventions. Future intervention programs aimed at reducing social isolation and loneliness to delay CD could investigate whether they impact physiological and psychobehavioral pathways summarized here.
Alzheimers Dement
· 2026 Jun · PMID 42337959
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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by intersecting pathological processes. Persistent attrition in AD drug-development pipelines highlights the limited clinical impact of singl...Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by intersecting pathological processes. Persistent attrition in AD drug-development pipelines highlights the limited clinical impact of single-target therapies and has increased interest in multi-target approaches acting on shared biological hubs. Although recent strategies extend beyond amyloid-centered interventions, much of the evidence supporting multifunctional compounds remains preclinical or shows heterogeneous outcomes in advanced clinical stages. This narrative review examines drug candidates that have entered Phase III clinical trials in the last decade, with emphasis on emerging multitarget pharmacotherapies such as muscarinic M1 receptor agonists, dual M1/sigma-1 receptor (σ1R) agonists, and dual σ1R agonist/anti-amyloid agents. We also discuss complementary non-pharmacological interventions, including physical exercise and targeted nutrition, that may support cognitive and emotional outcomes. Finally, we propose the Synergistic Optimized Pharmacological and Holistic Interventions for AD (SOPHI-AD) framework as a conceptual and testable approach integrating multitarget pharmacology with lifestyle-based strategies for AD management.
Pieperhoff L, Lorenzini L, Almeida F
… +32 more, Tranfa M, Bollack A, Arunachalam P, Masserini F, Wolz R, Grootoonk S, Ritchie C, Boada M, Marquié M, Vijverberg J, Vandenberghe R, Hanseeuw BJ, Martinez-Lage P, Payoux P, Visser PJ, Schöll M, Frisoni GB, Pardini M, Roccataglia L, Stephens AW, Buckley C, Farrar G, Jessen F, Gispert JD, Salvadó G, Luckett ES, Mutsaerts HM, Wink AM, Collij LE, Barkhof F, Oliveira TG, AMYPAD consortium
Alzheimers Dement
· 2026 Jun · PMID 42337956
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INTRODUCTION: Early Alzheimer's disease (AD) involves subtle cortical changes that may precede atrophy. Magnetic resonance imaging (MRI) microstructural markers may detect earlier pathology than classical morphometry. ME...INTRODUCTION: Early Alzheimer's disease (AD) involves subtle cortical changes that may precede atrophy. Magnetic resonance imaging (MRI) microstructural markers may detect earlier pathology than classical morphometry. METHODS: We analyzed cross-sectional MRI and amyloid-β (Aβ) positron emission tomography (PET) data from 1323 non-demented AMYPAD participants. Cortical volume, thickness, gray-white matter contrast (GWC), and mean diffusivity (MD) were related to global Aβ burden and estimated time to Aβ-positivity using regression, correlation, and change-point analyses. RESULTS: Microstructural measures showed stronger age associations than macrostructural measures, whereas all measures were unaffected by apolipoprotein E (APOE) -ε4 carriership. GWC and MD showed minimal overlap with volume and thickness. Higher Aβ burden was most strongly associated with reduced GWC and cortical thinning. Change-point analyses showed GWC alterations preceded Aβ-positivity by several years. DISCUSSION: Cortical microstructural MRI, particularly GWC, changes earlier than atrophy and may serve as an early in vivo marker of AD pathology.
Chang A, Kim M, Glittenberg M
… +3 more, Qu W, Li D, Li L
Alzheimers Dement
· 2026 Jun · PMID 42337953
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INTRODUCTION: The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal mai...INTRODUCTION: The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal maintenance. The high-density lipoprotein (HDL)-mimetic peptide 4F offers a potential therapeutic strategy. METHODS: To investigate how APOE4 alters brain gene expression and lipid metabolism and to evaluate the therapeutic potential of 4F, we performed dual-omics analysis in APOE4/4 and APOE3/3 mice treated intraperitoneally with D-enantiomer of 4F (D4F) or vehicle for 12 weeks from 10 to 13 months of age. RESULTS: APOE4/4 mice showed widespread transcriptomic and lipidomic alterations, including downregulation of lipid metabolism and synaptic pathways, increased ceramides, sphingomyelins, and cholesteryl esters, with decreased diglycerides and triglycerides. D4F treatment shifted relevant gene expression and lipid profiles toward APOE3/3 levels. DISCUSSION: These findings reveal molecular mechanisms underlying APOE4-driven dysregulation and support the therapeutic potential of HDL-mimetic peptides to mitigate APOE4-associated alterations in AD.
DuBois KN, Pal S, Maher AC
… +7 more, Heidebrink J, Persad C, Giordani B, Hampstead BM, Bakulski KM, Morgan DG, Kanaan NM
Alzheimers Dement
· 2026 Jun · PMID 42337943
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INTRODUCTION: Accurate ante mortem differentiation among dementia etiologies remains challenging, particularly for atypical or mixed clinical presentations. Multiplexed plasma proteomics paired with supervised machine le...INTRODUCTION: Accurate ante mortem differentiation among dementia etiologies remains challenging, particularly for atypical or mixed clinical presentations. Multiplexed plasma proteomics paired with supervised machine learning offers a minimally invasive and accessible approach for differential diagnosis. METHODS: Plasma from 194 participants was analyzed using the Nucleic acid Linked Immuno-Sandwich Assay (NULISA) Central Nervous System 120+ plasma biomarker panel. Differentially abundant protein patterns associated with Alzheimer's disease, frontotemporal lobar degeneration, Lewy body disease, and vascular disease were identified. These features were used to train supervised XGBoost classifier models. Models were then applied to participants with mild cognitive impairment (MCI) to generate data-driven predictions of etiology. RESULTS: NULISA plasma biomarkers revealed disease-specific protein patterns. XGBoost classifiers differentiated disease etiologies with high specificity. Application of the models to participants with MCI yielded robust etiologic predictions. DISCUSSION: These results support the feasibility of using multiplexed NULISA plasma proteomics, combined with machine learning, for differential diagnosis of complex neurodegenerative dementia etiologies.
Wong J, Wang T, Datta R
… +7 more, Abdollahi RO, Li J, Rowe CC, Henley D, Kolb HC, Saad ZS, Alzheimer's Disease Neuroimaging Initiative
Alzheimers Dement
· 2026 Jun · PMID 42337927
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INTRODUCTION: Inhibition of pathological tau spread may slow cognitive decline in Alzheimer's disease. Here, we evaluate two tau positron emission tomography (PET) analysis methods designed for detecting tau spread. METH...INTRODUCTION: Inhibition of pathological tau spread may slow cognitive decline in Alzheimer's disease. Here, we evaluate two tau positron emission tomography (PET) analysis methods designed for detecting tau spread. METHODS: Spatial progression of tauopathy (SPOT) and tau-naïve anatomical region of interest (tau-naïve ROI) methods were assessed in two large observational cohorts in amyloid-positive (A+) cognitively unimpaired (CU) or mildly cognitively impaired (MCI) participants versus CU amyloid-negative (A-) participants. RESULTS: SPOT and tau-naïve ROI demonstrated measurable annualized change in CU A+ and MCI A+ participants versus CU A- participants. These spread estimates produced effect sizes comparable to standardized uptake value ratio (SUVR) change measures in anatomically defined ROIs. Effect sizes were increased when evaluating the subset of tau positive CU A+ and MCI A+ participants. DISCUSSION: SPOT and tau-naïve ROI methods are designed to measure tau spread and may be used in addition to traditional SUVR measures to evaluate tau progression in AD.
Corriveau-Lecavalier N, Falgàs N, Putcha D
… +34 more, Graff-Radford J, Yong KXX, Boon BDC, Mohanty R, Westman E, Groot C, Jones DT, Grinberg LT, Rabinovici GD, Whitwell JL, Apostolova LG, Murray ME, Hammers DB, Schindler SE, Atonsdottir I, Rhodus EK, Schott JM, Illán-Gala I, Chukwuanugo O, Guerra JJL, Peters R, Abner EL, Abdelnour C, Lladó A, La Joie R, de Souza LC, Rezaii N, Shir D, Pijenburg YAL, Carrillo MC, Dickerson BC, Aisen P, Ossenkoppele R, Raman R
Alzheimers Dement
· 2026 Jun · PMID 42334062
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Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non-amnestic impairments and a more aggressive disease course. Historically, individuals with atypical present...Patients with atypical variants of Alzheimer's disease (AD) often present at a younger age with predominantly non-amnestic impairments and a more aggressive disease course. Historically, individuals with atypical presentations have not been included in large-scale clinical trials, which typically focus on late-onset, sporadic amnestic-predominant AD. Consequently, treatment options and research efforts specific to atypical AD remain limited. The emergence of amyloid-targeting therapies that slow disease progression underscores these challenges, as evidence supporting their efficacy in early-onset amnestic and non-amnestic AD variants is scarce. This perspective article argues that atypical AD represents an excellent disease model for clinical trials and proposes strategies to address critical gaps in clinical trial design for this population. Key considerations include optimizing participant selection approaches, establishing syndrome-specific or surrogate biological and clinical endpoints, and fostering advocacy to enhance early and accurate diagnosis, equitable representation, and outcomes for these populations.
Zeng Y, Cook N, Yang C
… +17 more, Sivasankaran SK, Fujita M, Gardell ZA, Le Guen Y, Shigemizu D, Ozaki K, Morizono T, Hara N, Miyashita A, Ikeuchi T, Pottier C, Cruchaga C, Napolioni V, Corces MR, Menon V, Greicius MD, Belloy ME
Alzheimers Dement
· 2026 Jun · PMID 42328930
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INTRODUCTION: Genetics studies can identify drug targets that counteract the effects of the apolipoprotein E ε4 allele (APOE*4) on Alzheimer's disease (AD) but have remained limited in power and crucially did not assess...INTRODUCTION: Genetics studies can identify drug targets that counteract the effects of the apolipoprotein E ε4 allele (APOE*4) on Alzheimer's disease (AD) but have remained limited in power and crucially did not assess genetic findings with regard to APOE*4's cell-type-specific impact on pathobiology. METHODS: We conducted a novel APOE*4-stratified genome-wide association study (GWAS) of AD (N = 447,669) and integrated results with brain cell-type-specific multi-omics data to identify APOE*4 and cell-type-specific AD genes, followed by compound and drug repurposing. RESULTS: In APOE*4 non-carriers (APOE*4-) and carriers (APOE*4+), we respectively identified 33 and 11 cell type-gene pairs with strong prioritization support. Oligodendrocytes displayed the largest proportion of APOE*4+ genes. Several genes were druggable and pinpointed APOE*4-stratified drugs or compounds. DISCUSSION: We identified a set of APOE*4-stratified genes that may be causal for AD through brain cell-type-specific mechanisms. We additionally identified compounds that may shed light on therapeutic avenues for treating AD based on an individual's APOE*4 status.
Alzheimers Dement
· 2026 Jun · PMID 42325010
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INTRODUCTION: Women make up two-thirds of people with Alzheimer's disease (AD). Research has focused on biological explanations for this sex difference, while contributions of psychosocial risk factors are less well unde...INTRODUCTION: Women make up two-thirds of people with Alzheimer's disease (AD). Research has focused on biological explanations for this sex difference, while contributions of psychosocial risk factors are less well understood. METHODS: We examined sex differences in the effects of adverse childhood experiences (ACEs) on late-life cognition in groups along a continuum of AD risk: cognitively unimpaired controls (CU; n = 128), subjective cognitive decline (SCD; n = 113), mild cognitive impairment (MCI; n = 241), and AD (n = 77), from the Canadian Consortium on Neurodegeneration in Aging Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. RESULTS: Women reported more ACEs than men. There were negative associations between ACEs and hippocampal and prefrontal cortical volumes in CU men and prefrontal volumes in men with SCD. In MCI, ACEs were linked to poorer executive function and associative memory in women. No ACE-related effects were found in AD. DISCUSSION: ACEs may have enduring effects on late-life cognition that differ between men and women and vary by cognitive status.
Jaen J, Cortés-Valencia A, Rodríguez AS
… +12 more, Manrique-Espinoza B, Bello-Chavolla OY, Tapia BM, Levy TS, Mundo-Rosas V, Ortiz ALS, Castillo IA, Gomez-Flores-Ramos L, Lamar M, Bennett DA, Grodstein F, Lajous M
Alzheimers Dement
· 2026 Jun · PMID 42325003
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INTRODUCTION: Expanding research on aging and cognition in low- and middle-income countries is critical, yet logistically complex. Large, established cohorts, such as the Mexican Teachers' Cohort (MTC; >100,000 women), p...INTRODUCTION: Expanding research on aging and cognition in low- and middle-income countries is critical, yet logistically complex. Large, established cohorts, such as the Mexican Teachers' Cohort (MTC; >100,000 women), pose unique opportunities for neurocognitive research in Latin America. METHODS: We evaluated the feasibility of home-based cognitive assessments in 150 Mexico City MTC participants, equally distributed across ages 55 to 59, 60 to 64, and ≥65. Tests included immediate/delayed word list recall, forward/backward digit span, and semantic verbal fluency. RESULTS: Over 3 weeks, 274 homes were approached; 186 participants (56%) were at the known addresses, and 153 (82%) participated. Participants (median age = 61; 53% college-educated) demographically resembled non-participants. Cognitive scores spanned a broad range, demonstrating no floor/ceiling effects (immediate recall: 3 to 10; delayed recall: 1 to 10; digits forward: 3 to 8; digits backwards: 0 to 6; semantic fluency: 6 to 38 animals). DISCUSSION: Home cognitive assessments may be feasible for large established cohorts in Latin America. These studies are promising for aging research.
Yin H, Deng Y, Lu Z
… +9 more, Jiang Y, Zuo C, Li J, Guo L, Ying B, Battaglia G, Tian X, Gong Q, Alzheimer's Disease Neuroimaging Initiative (ADNI)
Alzheimers Dement
· 2026 Jun · PMID 42325001
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INTRODUCTION: Impaired cerebrospinal fluid (CSF) -mediated clearance has been implicated in Alzheimer's disease (AD), but how choroid plexus (ChP) remodeling relates to these processes in vivo remains incompletely unders...INTRODUCTION: Impaired cerebrospinal fluid (CSF) -mediated clearance has been implicated in Alzheimer's disease (AD), but how choroid plexus (ChP) remodeling relates to these processes in vivo remains incompletely understood. METHODS: In a large ADNI cohort, we integrated structural magnetic resonance imaging (MRI), amyloid/tau positron emission tomography (PET), and diffusion tensor imaging (DTI) -derived analysis along the perivascular space (ALPS) to characterize ChP changes and their associations with ventricular measures, glymphatic marker, CSF biomarkers, and cognition across diagnostic stages. Our experiments in APP/PS1 mice complemented human analyses. RESULTS: ChP volume increased with disease stage, while PET signal decreased. Larger ChP volume was associated with ventricular enlargement, a lower ALPS index, higher cortical amyloid/tau burden, and worse cognitive performance. Glymphatic impairment partially mediated ChP effects on cognition and pathology. APP/PS1 mice recapitulated the key ChP and glymphatic MRI phenotypes observed in humans, alongside altered expression and localization of key proteins. DISCUSSION: ChP remodeling linked to impaired CSF-mediated clearance, highlighting its role as an early diagnostic and therapeutic target.