J. Alzheimers Dis. [JOURNAL]
Sun
200 papers
Validation of the care partner stress scale in the CAN-PROTECT study.
Vellone D, Guan DX, Crockford JFE … +8 more , Warring I, Ballard C, Creese B, Corbett A, Pickering E, Roach P, Smith EE, Ismail Z
J Alzheimers Dis · 2026 Jun · PMID 42312378 · Publisher ↗
BackgroundFamily and friend care partners play a vital role in supporting individuals with neurocognitive disorders, such as Alzheimer's disease dementia. Care partners are often uncompensated and face multifaceted chall...
BackgroundFamily and friend care partners play a vital role in supporting individuals with neurocognitive disorders, such as Alzheimer's disease dementia. Care partners are often uncompensated and face multifaceted challenges that contribute to stress. The Care Partner Stress Scale (CPSS) was developed to assess caregiver stress across seven domains: cognition, behavior, function; unmet needs and emotional impact; work and financial strain; family and interpersonal conflict; and situational perception.ObjectiveTo evaluate psychometric properties of the CPSS in care partners of individuals with neurocognitive or neurodegenerative diseases of aging.MethodsThe CPSS was completed by 168 (83.93% female, age = 61.98 years) care partners in the CAN-PROTECT online cohort. Participants completed measures of depression, anxiety, quality of life, function, loneliness, and life satisfaction and engagement. We assessed internal consistency, item-total correlations, convergent and discriminant validity, and floor/ceiling effects.ResultsThe CPSS demonstrated excellent internal consistency (α = 0.95, 95% CI: 0.94-0.96), with item-total correlations >0.23. Higher CPSS scores were associated with greater depression ( = 2.38, 95%CI [0.72, 4.03], = 0.005), anxiety ( = 4.47, 95%CI [2.44, 6.50], < 0.001), and anxious distress ( = 6.37, 95%CI [3.54, 9.21], < 0.001), as well as lower life satisfaction ( = -3.42, 95%CI [-5.61, -1.23], = 0.002), poorer social relationships ( = -2.31, 95%CI [-4.54, -0.09] = 0.042), greater loneliness ( = 5.26, 95%CI [1.33, 9.19], = 0.009), and poorer life engagement ( = 2.89, 95%CI [1.23, 4.65], = 0.001). CPSS scores were not associated with self-care ( = -1.06, 95%CI [-5.03, 2.92], = 0.600). Floor effects were minimal (0.60%), with no ceiling effects.ConclusionsFindings provide initial support for multidimensional assessment of care partner stress in neurocognitive disorders.
Metabolic context modulates neuroinflammation: Type 2 diabetes mellitus moderates the association of interleukin-8 with amyloid pathology and cognitive decline in mild cognitive impairment.
Kim EW, Alzheimer's Disease Neuroimaging Initiative
J Alzheimers Dis · 2026 Jun · PMID 42312374 · Publisher ↗
BackgroundInterleukin-8 (IL-8) exhibits dual roles in Alzheimer's disease (AD), yet how the metabolic milieu of type 2 diabetes mellitus (T2DM) influences its impact in mild cognitive impairment (MCI) remains unclear.Obj...
BackgroundInterleukin-8 (IL-8) exhibits dual roles in Alzheimer's disease (AD), yet how the metabolic milieu of type 2 diabetes mellitus (T2DM) influences its impact in mild cognitive impairment (MCI) remains unclear.ObjectiveThis study aimed to investigate how T2DM status moderates the longitudinal association between baseline plasma IL-8 levels and AD-related outcomes, including cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration.MethodsData from 373 MCI participants (Alzheimer's Disease Neuroimaging Initiative cohort) were analyzed. Moderation analyses examined the IL-8 × T2DM interaction on cognitive trajectories, amyloid-β (Aβ) accumulation, and regional atrophy, adjusting for key covariates.ResultsIn the T2DM group, higher baseline IL-8 was significantly associated with a slower longitudinal increase in Clinical Dementia Rating-Sum of Boxes (p = 0.005), indicating preserved clinical function. Furthermore, elevated IL-8 in the T2DM cohort correlated with lower hippocampal Aβ burden (p = 0.041) and attenuated atrophy rates in the parahippocampal cortex (p = 0.044). In contrast, no significant associations between IL-8 and any AD biomarkers or cognitive trajectories were observed in the non-T2DM group.ConclusionsThis research demonstrates that the role of IL-8 in MCI is "context-dependent," contingent upon the patient's metabolic state. The author suggests that under chronic metabolic stress, IL-8 may reflect an adaptive immune response that mitigates amyloid pathology and slows neurodegeneration. These results emphasize the necessity of integrating metabolic profiles into the interpretation of neuroinflammatory biomarkers to facilitate personalized therapeutic strategies for AD.
Association between renin angiotensin system and cognitive outcomes over 15 years: The Look AHEAD study.
Yasar S, Anderson A, Hayden KM … +7 more , Carmichael OT, Clark JM, Carlson MC, Asby DJ, Kehoe PG, Miners S, Espeland MA
J Alzheimers Dis · 2026 Jun · PMID 42312371 · Publisher ↗
BackgroundEvidence suggests that dysregulation of the renin angiotensin system (RAS) is associated with the pathophysiologic process of Alzheimer's disease (AD). Few studies have evaluated the relationship between circul...
BackgroundEvidence suggests that dysregulation of the renin angiotensin system (RAS) is associated with the pathophysiologic process of Alzheimer's disease (AD). Few studies have evaluated the relationship between circulating RAS components and incident cognitive decline or impairment.ObjectiveOur study aims to evaluate the relationship between circulating RAS biomarkers (angiotensin II [ANGII], angiotensin 1-7 [ANG1-7], angiotensin converting enzyme-1 [ACE-1], and 2 [ACE-2]), in initially cognitively healthy adults, and incident cognitive decline and cognitive impairment.MethodsIn this secondary analysis, 310 community-dwelling participants from the randomized controlled Action for Health in Diabetes (Look AHEAD) study without dementia, who were not on RAS-altering medication, were included.ResultsParticipants, compared to those excluded, were more likely to be female (65%), white (76%), overweight (34%), have lower baseline HbA1c (6.7%), lower SBP (119.7 mmHg), lower serum creatinine (0.79 mg/dL), higher total cholesterol (190.1 mg/dL) and LDL (112.5 mg/dL), and higher history of dyslipidemia (65%) at baseline. 1 SD increase of ANG1-7 measured in year 1 was associated with lower odds of cognitive impairment (OR = 0.35, 95% CI 0.16-0.77; p = 0.001), while higher ANG1-7 levels predicted better global cognitive function [β x 10 = 1.03 (0.50); p = 0.039], 15 years later.ConclusionsThese results provide preliminary evidence that circulating RAS components are predictive of protection against cognitive impairment and decline and may serve as a marker of the early stages of dementia. Further research is warranted to fully understand the relationship between the brain and the circulatory RAS.
Deep white matter injury and cognitive decline in cerebral small vessel disease: Mediation by a unified atrophy network.
Wang C, Zhang C, Li H … +10 more , Wang L, Chen X, Wang C, Zhang Y, Zhang Z, A M, Wang J, Wu J, Sun Y, Du A
J Alzheimers Dis · 2026 Jun · PMID 42312368 · Publisher ↗
BackgroundIn cerebral small vessel disease (CSVD), the burden of white matter hyperintensities (WMH) does not fully account for cognitive impairment, suggesting the involvement of intermediary mechanisms.ObjectiveWe inve...
BackgroundIn cerebral small vessel disease (CSVD), the burden of white matter hyperintensities (WMH) does not fully account for cognitive impairment, suggesting the involvement of intermediary mechanisms.ObjectiveWe investigated whether a gray matter atrophy network acts as the key mediator linking topologically specific (deep) WMH to multidomain cognitive dysfunction.MethodsIn this retrospective study, 260 patients with CSVD (62 cognitively normal, 125 with mild impairment, 73 with dementia) were included. Cognitive status was assessed neuropsychologically. 3.0 T MRI identified an atrophy network. We then conducted pre-specified mediation analyses and a primary confirmatory analysis using structural equation modeling (SEM) to test whether this atrophy network mediated the effect of deep WMH on cognitive performance.ResultsA 41-region atrophy network was identified primarily involving the medial temporal lobe and thalamus, that was significantly associated with cognitive status. The final SEM demonstrated excellent fit, showing that higher deep WMH burden was associated with greater network atrophy ( = 0.145, p < 0.05), which in turn was strongly associated with poorer executive function ( = -0.64, p < 0.001) and memory ( = -0.572, p < 0.001). The direct effect of WMH on cognition was not statistically significant in the model.ConclusionsOur findings suggest that in CSVD, a unified network of gray matter atrophy acts as a powerful statistical mediator in the effect of deep white matter injury on cognitive decline. This atrophy pattern may represent a more direct biomarker of the neurodegenerative process underlying cognitive impairment than WMH burden alone.
Narratives about the reasons for wandering in people with Alzheimer's disease: The perspective of Polish family members. Preliminary report.
Drzazga J, Segiet-Hojda NM, Początek G … +4 more , Gorzkowska A, Klimkowicz-Mrowiec A, Cunha I, Griffiths AW
J Alzheimers Dis · 2026 Jun · PMID 42307397 · Publisher ↗
BackgroundPeople living with Alzheimer's disease often require support from their relatives, who may face emotional and physical challenges in their role. Up to 90% of people living with cognitive impairment experience u...
BackgroundPeople living with Alzheimer's disease often require support from their relatives, who may face emotional and physical challenges in their role. Up to 90% of people living with cognitive impairment experience unmet needs such as wandering.ObjectiveThe aim of the study was to analyze the narrative of relatives of people living with Alzheimer's disease experiencing unsatisfied behavioral needs and whether this has a relationship with levels of burden.MethodsRelatives who cared for a family member with Alzheimer's disease at home participated in a structured interview with a psychologist and completed the Zarit Burden Interview to assess caregiver burden. An analysis was conducted of the frequency of words used in the relatives' responses to the question "What is your experience of your loved one's wandering?".ResultsA total of 15 relatives participated in the study. Relatives with higher levels of burden related to their role as caregivers were more likely to use words such as "disorder" (on average once per interview), "problem" (on average three times per interview), and "difficulty" (on average twice per interview), than people with low levels of burden. For people with low levels of burden, the word "need" appeared as a significant expression (on average four times per interview).ConclusionsRelatives who experience less burden are more likely to understand the reasons behind their loved ones' need or desire to wander. They are less likely to perceive this behavior as a problem and restrict the person's freedom of movement for their own safety.
Adverse events of Alzheimer's disease patients treated with memantine-based therapies: A disproportionality analysis of the FAERS database based on the MY FAERS platform.
Wang X, Zhang W, He J … +3 more , Zhang X, Wang R, Li Z
J Alzheimers Dis · 2026 Jun · PMID 42300750 · Publisher ↗
BackgroundAlzheimer's disease (AD) is commonly treated with memantine alone or in combination with cholinesterase inhibitors (ChEIs) or second-generation antipsychotics (SGAs), but the safety of these combinations remain...
BackgroundAlzheimer's disease (AD) is commonly treated with memantine alone or in combination with cholinesterase inhibitors (ChEIs) or second-generation antipsychotics (SGAs), but the safety of these combinations remains unclear.ObjectiveTo characterize FDA Adverse Event Reporting System (FAERS)-based signals of disproportionate reporting associated with memantine-based combination therapies in patients with AD.MethodsA disproportionality analysis was conducted using data from FAERS from 2014Q1 to 2025Q2 via the MY FAERS platform. Reporting odds ratios (RORs) with 95% confidence intervals (CI) were calculated to identify safety signals. Sensitivity analyses were conducted using ChEIs or SGAs monotherapy as reference groups to assess the robustness.Results2531 patients prescribed memantine were identified, comprising memantine monotherapy (n = 1965), memantine-ChEIs combination (n = 482), and memantine-SGAs combination (n = 84). Compared to memantine monotherapy, the memantine- ChEIs combination showed disproportionate reporting signals for skin (ROR, 3.46; 95% CI, 2.05-5.85), gastrointestinal (ROR, 2.53; 95% CI, 1.92-3.33), musculoskeletal (ROR, 2.13; 95% CI, 1.29-3.50), psychiatric (ROR, 1.60; 95% CI, 1.27-2.00), general (ROR, 1.53; 95% CI, 1.18-1.97), and nervous system disorders (ROR, 1.48; 95% CI, 1.19-1.84). The memantine-SGAs combination was strongly associated with the signals of general (ROR, 3.97; 95% CI, 1.74-9.05), psychiatric (ROR, 2.14; 95% CI, 1.32-3.49), nervous system disorders (ROR, 2.03; 95% CI, 1.20-3.43), and hip fracture (ROR, 15.84; 95% CI, 3.72-67.41). Sensitivity analyses confirmed robustness across subgroups.ConclusionsMemantine-based combination therapies were associated with distinct safety signals of disproportionate reporting compared with monotherapies. These findings should be interpreted as pharmacovigilance signals that warrant cautious interpretation and further validation in well-designed observational or prospective studies.
Language and communication disorders in dementia with Lewy bodies versus Alzheimer's disease: Objective screening and subjective perspectives of patients, their caregivers and clinicians.
Balohé M, Thivet J, Blanc F … +8 more , Krein L, Jeon YH, Botzung A, Sanna L, Ravier A, Demuynck C, Muller C, Chabran É
J Alzheimers Dis · 2026 Jun · PMID 42300742 · Publisher ↗
BackgroundLanguage and communication disorders in dementia with Lewy bodies (DLB) remain understudied and have rarely been explored from the caregiver's perspective. Comparative studies with Alzheimer's disease (AD) are...
BackgroundLanguage and communication disorders in dementia with Lewy bodies (DLB) remain understudied and have rarely been explored from the caregiver's perspective. Comparative studies with Alzheimer's disease (AD) are also limited.ObjectiveTo provide an initial overview of language and communication profiles in DLB, compared to AD and healthy elderly controls (HC); to assess subjective complaints reported by patients, caregivers and healthcare professionals; and to explore their relationships with rapid language screening. A further aim was to aid non-specialist professionals in identifying patients needing speech therapy referral.MethodsSeventeen DLB patients, 15 AD patients, and 11 HC completed the Diagnostic Tool for Language Assessment and the alpha version of the Communication Support Needs Assessment Tool for Dementia (CoSNAT-D), alongside a semi-directed interview (SDI). Proxy-ratings were also collected from caregivers and healthcare professionals (HP) for the CoSNAT-D and SDI.ResultsCompared to HC, DLB patients showed significantly poorer performance in repetition, verbal working memory, sentence comprehension and dictation, and reported more communication difficulties. Compared to AD patients, DLB patients had greater impairments in phonemic fluency, and more frequent reports of discomfort, vocal changes, and difficulties with writing and handwriting execution. Perceptions of communicative difficulties and their functional impact varied across patients, caregivers, and HP.ConclusionsThis study has identified distinct language and communication deficits in DLB versus AD and HC. Discrepancies between patient and caregiver perceptions were frequent in both groups and may contribute to increased caregiver burden. Findings highlight the potential value of rapid screening tools to better support patients and their caregivers.
Association between Gompertz law-based biological age and dementia: A longitudinal study of middle-aged and older Chinese adults.
Liu H, Cheng Y, Fan C
J Alzheimers Dis · 2026 Jun · PMID 42300733 · Publisher ↗
BackgroundWhile chronological age is a major but non-specific risk factor for dementia, measures of biological age based on physiological biomarkers may more accurately reflect systemic aging.ObjectiveWe aimed to assess...
BackgroundWhile chronological age is a major but non-specific risk factor for dementia, measures of biological age based on physiological biomarkers may more accurately reflect systemic aging.ObjectiveWe aimed to assess the association between a Gompertz law-based biological age (Light BioAge) and incident dementia in a national cohort of middle-aged and older adults in China, and to evaluate the potential modifying role of lifestyle.MethodsWe conducted a longitudinal analysis of 5641 participants (≥45 years) from China Health and Retirement Longitudinal Study. Light BioAge was computed at baseline (2011) using a validated algorithm incorporating chronological age, serum creatinine, fasting glucose, and high-sensitivity C-reactive protein. Dementia in 2018 was determined via cognitive tests, informant reports, and functional assessment. Logistic regression models were used to estimate odds ratios (ORs).ResultsDuring the follow-up, 788 (13.97%) participants were identified as having dementia. Each 1-year increment in Light BioAge was associated with 4% higher risk of dementia (OR 1.04, 95% CI 1.03-1.05). Compared to low BioAge, participants with high BioAge had a more than two-fold higher risk of dementia (OR 2.38, 95% CI 1.85-3.04). This association persisted across strata of favorable and unfavorable lifestyles. Joint exposure analysis revealed that individuals with both high BioAge and an unfavorable lifestyle faced the highest risk (OR 2.96, 95% CI 2.05-4.27).ConclusionsAccelerated biological aging, quantified by Light BioAge, is a robust independent risk factor for dementia. Favorable lifestyle interventions offer potential strategies. However, findings require caution given the observational design and non-clinical dementia measure.
Angiogenesis markers and cognitive response in a randomized trial of cognitive remediation plus transcranial direct current stimulation in older adults at risk of dementia.
Song BX, Schecter J, Vieira E … +13 more , Gallagher D, Diniz BS, Fischer CE, Flint AJ, Herrmann N, Kennedy JL, Mah L, Mulsant B, Pollock BG, Rajji TK, Ma C, Lanctôt KL, PACt-MD Study Group
J Alzheimers Dis · 2026 Jun · PMID 42300721 · Publisher ↗
BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive...
BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment ((SE) = 0.17(0.08) 0.04, = 0.11, = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up ((3) = 24.9, < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.
Primary and secondary prevention strategies for reducing population-level dementia burden: A microsimulation modeling study.
Van Rosmalen L, Brück CC, Wolters FJ … +2 more , Handels R, De Kok IMCM
J Alzheimers Dis · 2026 Jun · PMID 42300704 · Publisher ↗
BackgroundThe growing burden of dementia and Alzheimer's disease may be mitigated by a combination of primary and secondary preventive strategies, including lifestyle interventions and targeted disease-modifying therapy...
BackgroundThe growing burden of dementia and Alzheimer's disease may be mitigated by a combination of primary and secondary preventive strategies, including lifestyle interventions and targeted disease-modifying therapy at the individual-level.ObjectiveOur aim is to estimate the effects of primary and secondary prevention on a population level in terms of life years lived with and without dementia.MethodsWe used the previously developed and validated microsimulation model MISCAN-Dementia, modified to evaluate the impact of individual-level primary and secondary preventative interventions in the Dutch population aged 55 years and older, between 2025 and 2050. We expanded this model with prevention-specific effectiveness and eligibility, based on observed trial effects (primary analysis) and assuming a range of combinations of eligibility and effects (secondary analyses).ResultsExtrapolating results from available randomized controlled trials, combined primary and secondary preventative interventions result in a 6.1% decrease of life years lived with moderate to severe dementia until 2050, compared to no additional prevention. Dementia-free life years increased by 3.1%. The magnitude of risk reduction was the primary driver of impact, with the most optimistic assumptions resulting in a stabilization of dementia prevalence by 2050.ConclusionsA combination of primary and secondary preventative strategies likely is needed to achieve optimal effects on the future burden of dementia. These approaches differ in the time needed to achieve maximal population-level impact, with the overall magnitude of effect primarily determined by the size of the intervention's impact.
Structural and load-dependent arterial stiffness are differentially associated with cognition or biomarkers of Alzheimer's disease and related dementias: The healthy brain study.
Deconne TM, Suerken CK, Lipford ME … +13 more , Lockhart SN, Bateman JR, Espeland M, Rudolph MD, Rundle MM, Sutphen C, Register TC, Mielke MM, Pewowaruk R, Gepner AD, Baker LD, Craft S, Hughes TM
J Alzheimers Dis · 2026 Jun · PMID 42300702 · Publisher ↗
BackgroundArterial stiffness is an emerging risk factor for Alzheimer's disease (AD) and related dementias (ADRD) and is assessed by measuring pulse wave velocity (PWV). Recent mathematical modeling has allowed for the d...
BackgroundArterial stiffness is an emerging risk factor for Alzheimer's disease (AD) and related dementias (ADRD) and is assessed by measuring pulse wave velocity (PWV). Recent mathematical modeling has allowed for the delineation of arterial stiffness caused by structural remodeling (S) and blood pressure, termed "load-dependent" stiffening (LD). While we recently demonstrated that S-PWV and LD-PWV are differentially associated with risk for cognitive decline and AD/ADRD brain imaging biomarkers, the associations between paired measures of S-PWV and LD-PWV with cognitive function, AD/ADRD brain imaging biomarkers, and plasma AD biomarkers have not been assessed.ObjectiveTo conduct a comprehensive analysis combining cross-sectional data from the Wake Forest Alzheimer's Disease Research Center. We hypothesized that higher S-PWV would be associated with worse cognitive function. We also hypothesized that S-PWV and LD-PWV would be differentially associated with brain imaging biomarkers of ADRD and plasma AD biomarkers.MethodsMultivariable linear regression models were used to relate S-PWV and LD-PWV to all outcomes.ResultsAs hypothesized, higher S-PWV, but not LD-PWV, was associated with lower global cognitive function. Higher S-PWV and LD-PWV were differentially associated with AD/ADRD brain MRI biomarkers. We did not observe any significant associations with plasma or PET AD biomarkers in this cohort.ConclusionsS-PWV was associated with lower cognition, while S-PWV and LD-PWV were differentially associated with brain MRI biomarkers. Interventions specifically targeting arterial stiffness may preserve cognition and brain health in AD/ADRD.
Traumatic brain injury and late-life Alzheimer's disease neuropathology: Quantitative investigation in the Adult Changes in Thought study.
Selmanovic E, Gibbons LE, Folkerth RD … +9 more , Keene CD, Nolan A, Crane P, Postupna N, Lee CS, Latimer CS, Ariza-Torres J, Hof PR, Dams-O'Connor K
J Alzheimers Dis · 2026 Jun · PMID 42300698 · Full text
BackgroundTraumatic brain injury (TBI) is associated with increased dementia risk, yet its relationship to Alzheimer's disease (AD) neuropathology is unclear. Prior autopsy studies show inconsistent results, constrained...
BackgroundTraumatic brain injury (TBI) is associated with increased dementia risk, yet its relationship to Alzheimer's disease (AD) neuropathology is unclear. Prior autopsy studies show inconsistent results, constrained by limited TBI ascertainment, semi-quantitative neuropathology methods, and selection bias.ObjectiveTo examine whether TBI with loss of consciousness (TBI-LOC) is associated with quantitative measures of tau and amyloid-β (Aβ) pathology in a community-based autopsy cohort.MethodsThe analytic sample included 810 Adult Changes in Thought study brain donors with baseline TBI-LOC ascertainment and quantitative neuropathology data, weighted to represent the full living cohort (n = 5763). Modified Poisson regression estimated rate ratios (RRs) and 95% confidence intervals (CIs) for associations of TBI-LOC with percent-positive AT8 tau immunoreactivity and soluble Aβ (GuHCl and RIPA fractions) across brain regions. Models were adjusted for age at death, sex, education, and enrollment cohort; sensitivity analyses included unweighted and quantile models.ResultsWeighted models showed lower frontal tau (RR = 0.50, p = 0.047) and lower soluble Aβ in temporal and occipital cortices (p = 0.019-0.037) among donors with baseline TBI-LOC. In unweighted sensitivity analyses, lower temporal RIPA Aβ remained significant (p < 0.001), and select inverse associations were observed in duration-stratified analyses, particularly in small >1 h LOC subgroups. Quantile analyses of pathology burden similarly suggest reduced parietal Aβ (p = 0.02-0.04); effects were small and driven by sparse subgroups.ConclusionsTBI-LOC was not associated with greater tau or amyloid burden, and inverse associations likely reflect data sparsity rather than biological protection. These findings suggest that links between TBI and late-life cognitive decline may involve non-AD pathological processes.
Plasma p-tau217 measured by the Elecsys automated immunoassay: Prospective validation in a heterogeneous memory clinic cohort.
Franco-Macías E, Noval-Padillo JÁ, Hervás-Navidad R … +29 more , Espejo-Martínez B, Serrano-Gutiérrez C, Rodrigo-Herrero S, Méndez-Barrio C, Mendoza-Vázquez G, Carrera-Muñoz I, Marín-Romero B, Garzón-Maldonado F, Carazo-Barrios L, Rodríguez-Jiménez L, Martínez-Nogueras Á, Agüera-Morales E, Conde-Gavilán C, Jover AM, García-Navarro C, Iglesias-Espinosa M, Romera-Morales DJ, Cuartero-Rodríguez E, García-Roldán E, González-Acosta M, Almodóvar-Sierra Á, Marín-Cabañas M, Bernal Sánchez-Arjona M, García-Sánchez MI, Arriola-Infante JE, Arrabal-Gómez C, Oliver-Martos B, Serrano-Castro PJ, Fatela-Cantillo D
J Alzheimers Dis · 2026 Jun · PMID 42300696 · Publisher ↗
BackgroundPlasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a leading blood-based biomarker for the diagnosis of Alzheimer's disease (AD) and can be measured using fully automated, random-access platfo...
BackgroundPlasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a leading blood-based biomarker for the diagnosis of Alzheimer's disease (AD) and can be measured using fully automated, random-access platforms. The Elecsys plasma p-tau217 assay requires further validation, particularly in heterogenous populations seen in memory clinics.ObjectiveTo validate plasma p-tau217 in comparison with p-tau181 and to evaluate its association with other soluble core 1 AD biomarkers, as well as markers of neurodegeneration and neuroinflammation.MethodsBiobank data from two prospective blood-based biomarkers validation studies were analyzed. Cerebrospinal fluid (CSF) p-tau181/Aβ ratio served as the reference standard for AD diagnosis. The diagnostic performance of plasma p-tau217 and p-tau181 was compared. In patients with AD, p-tau217 was further evaluated for its association with CSF (Aβ/Aβ ratio, p-tau181, t-tau) and plasma [APOE ε4 protein (APOE ε4p), NfL (neurofilament light chain), GFAP (glial fibrillary acidic protein)] biomarkers.ResultsAmong 303 patients with mild cognitive impairment or mild dementia, plasma p-tau217 outperformed plasma p-tau181 (AUC 0.93 versus 0.87). By the two threshold diagnostic strategy, an upper cutoff (>0.312 pg/mL, specificity 95%) and a lower cutoff (<0.177 pg/mL, sensitivity 95%) were established, with 27% of cases falling into an indeterminate range. Plasma p-tau217 showed strong correlations with CSF Aβ/Aβ and p-tau181/Aβ ratios, as well as with plasma GFAP, and only moderate correlations with CSF t-tau and p-tau181, and plasma NfL.ConclusionsPlasma p-tau217 measured using Elecsys demonstrates good diagnostic performance and strong associations with other soluble Core 1 AD and neuroinflammation biomarkers.
Impacts of menopausal hormone therapy on Alzheimer's disease biomarkers: A systematic review.
Rodrigues AC, Valério FG, Moura CB … +7 more , Da Silva AMP, Tudella GCN, Almeida SS, Gomes AC, Oliveira CEM, Apóstolos-Pereira SL, Santos DH
J Alzheimers Dis · 2026 Jun · PMID 42300694 · Publisher ↗
BackgroundSex-specific vulnerability to Alzheimer's disease (AD) has been increasingly recognized, with menopause representing a decisive neuroendocrine transition. Estrogen and progesterone modulate synaptic plasticity,...
BackgroundSex-specific vulnerability to Alzheimer's disease (AD) has been increasingly recognized, with menopause representing a decisive neuroendocrine transition. Estrogen and progesterone modulate synaptic plasticity, glucose metabolism, and amyloid-tau homeostasis, yet the impact of their decline and replacement remains controversial. AD biomarkers provide objective means to assess menopausal hormone therapy (MHT) mechanistic effects beyond cognitive endpoints.ObjectiveTo determine how MHT influences validated AD biomarkers in peri- and postmenopausal women.MethodsA systematic review was conducted following PRISMA guidelines (PROSPERO CRD420251149404). PubMed, Embase, Web of Science, and Cochrane Library were searched through September 2025 for interventional and observational studies evaluating MHT and AD biomarkers after non-surgical menopause. Eligible biomarkers included cerebrospinal fluid (CSF) and plasma markers, and amyloid-, tau- or FDG-PET imaging. Study quality was assessed using RoB-2 and ROBINS-I tools, and evidence certainty with GRADE.ResultsFourteen studies met inclusion criteria. Early or continuous transdermal 17β-estradiol was linked with lower CSF and plasma p-tau181 and preserved glucose metabolism in AD-vulnerable cortical regions. Neuroimaging studies showed decreased amyloid deposition and sustained metabolic benefits years after discontinuation. Conversely, oral conjugated equine estrogens and estrogen-progestin regimens led to neutral or unfavorable biomarker trends, particularly when initiated more than five years after menopause.ConclusionsMHT's effects on AD biomarkers depend on timing, formulation and hormonal composition. Early transdermal estradiol appears to reinforce neuroprotective biomarker profiles, whereas delayed or combined therapies may nullify these benefits. Genotype-stratified trials with harmonized biomarker reports are needed to define optimal neuroprotective windows for women.
Alzheimer's disease and related dementias state policies and mortality in the United States: A descriptive study.
Churchill N, Le TT, Nianogo RA
J Alzheimers Dis · 2026 Jun · PMID 42299870 · Publisher ↗
BackgroundAlzheimer's disease and related dementias (ADRD) were the sixth leading cause of death among people aged 65 + in 2022 and are currently the leading cause of disability and morbidity in older adults. In 2025, an...
BackgroundAlzheimer's disease and related dementias (ADRD) were the sixth leading cause of death among people aged 65 + in 2022 and are currently the leading cause of disability and morbidity in older adults. In 2025, an estimated 7.2 million Americans aged 65 years and older were living with Alzheimer's disease (AD), with prevalence projected to rise.ObjectiveWe describe 1) the trends in the adoption of ADRD policies that were implemented in the U.S. from 2008-2020, as well as 2) the trends in ADRD mortality during 1999-2022.MethodsWe presented mortality data for the age-adjusted rate of ADRD mortality per 100,000 people in 1999-2022 from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER). We also collected policy data from state websites from 2008-2020.ResultsPolicies were implemented for all 50 states, starting in 2008 and ending in 2020. ADRD mortality steadily rose during 1999-2022. The first states to implement ADRD in 2008 were Iowa and Kentucky. The largest number of states added policies in 2013. South Dakota, Wyoming, Ohio, and Kansas were the last states to implement policies.ConclusionsOur study documented that all the states in the United States implemented a policy to reduce ADRD cases. We also observed that ADRD mortality steadily rose between 1999 and 2022. This rise may reflect increased reporting of ADRD as a cause of death, or policies needing more time to meet national reduction goals.
Identification of candidate diagnostic biomarkers and gene networks for moderate stages of Alzheimer's disease in fusiform gyrus exhibiting neurofibrillary tangles.
Beh-Pajooh A
J Alzheimers Dis · 2026 Jun · PMID 42299852 · Publisher ↗
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder whose incidence grows with age and its development is gradual. However, if detected earlier there is much hope to prevent further exacerbation. In this s...
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder whose incidence grows with age and its development is gradual. However, if detected earlier there is much hope to prevent further exacerbation. In this study, NGS transcriptomics data from cases and controls with Braak scores of III-IV were investigated that all possessed neurofibrillary tangles (NFTs) in their fusiform gyrus.ObjectiveThe aim of this study was to discover the underlying mechanisms at gene level which could explain cognitive impairment by considering the presence of NFTs in both groups.MethodsDifferentially expressed genes (DEGs) were determined and ROC AUC were evaluated by leave-one-out cross-validation method on the diagnostic DEGs to detect candidate gene biomarkers. WGCNA was employed to identify co-expression modules with their trait association. Finally, hybridization of lncRNAs from potential biomarkers with important AD-related microRNAs was carried out.ResultsHighly ranked potential diagnostic gene biomarkers revealed assessed AUC ranges of 80-90% in which demonstrated the highest value. WGCNA demonstrated upregulated genes in favor of dephosphorylation of tau, proper proteostasis and vascular health in resilient controls whereas dysfunctional proteostasis, chronic protein misfolding, heightened cellular stress and tetrahydrobiopterin deficiency were attributed to cognitive impairment in AD patients. analyses predicted some lncRNAs with a high possibility of acting as sponge for AD-related microRNAs.ConclusionsThis study discovered potential diagnostic gene biomarkers and transcriptional signatures that could explain the mechanisms of cognitive decline by considering the existence of NFTs, which could provide further insight for diagnosis and treatment of the disease.
Prediction of Alzheimer's disease risk factors from retinal images via deep learning: Development and validation of biologically relevant morphological associations in the UK Biobank.
Leem S, Yang Y, Woods AJ … +1 more , Fang R
J Alzheimers Dis · 2026 Jun · PMID 42299837 · Publisher ↗
BackgroundThe systemic, metabolic, lifestyle factors have established associations with Alzheimer's disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains...
BackgroundThe systemic, metabolic, lifestyle factors have established associations with Alzheimer's disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear.ObjectiveTo determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability.MethodsUsing 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD pathology or incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, body mass index, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls.ResultsPredictive performance of DL ranged from AUROC between 0.5654 and 0.9480 for categorical factors and R between -0.0291 and 0.7620 for continuous factors, outperforming most of the morphometry-based machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of AD-related risk factors and preclinical AD-associated changes.ConclusionsCFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.
Neuronal resilience as an active and programmable property.
Acquarone E
J Alzheimers Dis · 2026 Jun · PMID 42294922 · Publisher ↗
Amyloid-β oligomers are widely implicated in synaptic dysfunction in Alzheimer's disease, yet their presence alone does not determine neuronal failure. In this commentary, I discuss recent findings by Johnson et al. show...
Amyloid-β oligomers are widely implicated in synaptic dysfunction in Alzheimer's disease, yet their presence alone does not determine neuronal failure. In this commentary, I discuss recent findings by Johnson et al. showing that nano-pulsed laser therapy reprograms adult hippocampal neural stem cells to generate neurons resistant to amyloid-β toxicity, likely through hormetic modulation of reactive oxygen species signaling and mitochondrial function. These findings support a reframing of Alzheimer's disease pathophysiology in which neuronal resilience is not merely a passive property, but an active and programmable therapeutic target.
Social and environmental determinants of dementia risk: An umbrella review.
Ghiasvand S, Tegegne GT, Tabatabaei-Jafari H … +3 more , Mazumdar S, Ambikairajah A, Bagheri N
J Alzheimers Dis · 2026 Jun · PMID 42286895 · Publisher ↗
BackgroundGrowing evidence suggests that dementia risk is influenced not only by genetic factors but also by social and environmental determinants. Understanding these modifiable factors is critical for informing prevent...
BackgroundGrowing evidence suggests that dementia risk is influenced not only by genetic factors but also by social and environmental determinants. Understanding these modifiable factors is critical for informing prevention strategies.ObjectiveTo synthesize existing evidence from systematic reviews on the associations between social and environmental determinants and the risk of dementia, including Alzheimer's disease, vascular dementia, and frontotemporal dementia.MethodsAn umbrella review was conducted by systematically searching five major databases for systematic reviews published between 2004 and 2024. Eligible reviews examined the relationship between at least one social or environmental determinant and dementia outcomes.ResultsThe review found strong associations between environmental exposures and increased dementia risk. Exposure to fine particulate matter (PM) was consistently linked to elevated dementia risk, with estimates ranging from 3% to 226% per 10 μg/m increase. Occupational exposures to toxic metals, pesticides, and electromagnetic fields were also associated with higher neurodegeneration risk. Conversely, protective environmental factors included residential greenness and walkable neighborhoods. Among social determinants, higher education, socioeconomic status, and social engagement were found to promote cognitive resilience. In contrast, social disadvantage and limited access to healthcare contributed to increased dementia risk, likely through cumulative psychosocial stress.ConclusionsThis umbrella review underscores the significant role of social and environmental determinants in dementia risk. Targeted public health policies aimed at reducing environmental hazards and addressing social inequalities are essential for mitigating dementia risk and promoting cognitive health at the population level.
A mechanistic framework linking the oral microbiome to Alzheimer's disease through neuroinflammation.
Evers MJAP, Krom BP, de Jongh CA
J Alzheimers Dis · 2026 Jun · PMID 42286894 · Publisher ↗
Alzheimer's disease (AD) is a growing problem in our society and the most common form of dementia. This neurodegenerative disease is characterized by neuroinflammation and the accumulation of amyloid-β (Aβ) and tau. Prev...
Alzheimer's disease (AD) is a growing problem in our society and the most common form of dementia. This neurodegenerative disease is characterized by neuroinflammation and the accumulation of amyloid-β (Aβ) and tau. Previous studies have found associations between the oral microbiome and AD. This review aims to elucidate the role of the oral microbiome in AD, through neuroinflammation, and reviews the relationship between AD and bacteria and fungi. Studies have found bacteria (e.g., ) and fungi (e.g., ) in postmortem AD brains. Moreover, mice models have shown that oral microbes are able to cross the blood-brain barrier (BBB), and were correlated with activated microglia, neuroinflammation, and Aβ load. This review introduces a mechanistic framework that describes how oral microbes cause an inflammatory response resulting in AD pathology. Specifically, oral dysbiosis causes oral pathogens to disseminate into the bloodstream, this triggers an inflammatory response, subsequently activating microglia, ultimately resulting in AD pathology. This process can follow two pathways: First, there is a direct response of the immune system in the brain to oral pathogens that migrate through the bloodstream and cross the BBB, which causes neuroinflammation and activates microglia, leading to AD pathology. Second, an early-life systemic inflammation causes microglia to get into a "hyperactive" state, in which they respond in an exaggerated way to normal stimuli triggering immune responses throughout a person's life that result in AD pathology. This mechanistic framework provides new line of thought for future research on the question of causality of AD.
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