Alzheimers Dement
· 2026 May · PMID 42092343
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INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission...INTRODUCTION: Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS: Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS: Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death (n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION: Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.
Alzheimers Dement
· 2026 May · PMID 42092335
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INTRODUCTION: Prospective studies of blood-based biomarkers reflecting pathogenic processes, other than Alzheimer-specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS: We jointly fitt...INTRODUCTION: Prospective studies of blood-based biomarkers reflecting pathogenic processes, other than Alzheimer-specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS: We jointly fitted linear mixed-effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble cluster of differentiation-14 (sCD14), neurofilament light chain (NfL), total tau (t-tau), and ubiquitin C-terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community-based Atherosclerosis Risk in Communities Study. sCD14 and YKL-40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS: Higher serum GFAP, YKL-40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log-base2 YKL-40 was associated with -0.11SD faster 25-year cognitive decline (95% confidence interval [CI]: -0.15,-0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t-tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION: Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.
Borberg E, Swank Z, Gilboa T
… +5 more, Shearer LAW, Melkonian AV, Rolando JC, Walt DR, Stern AM
Alzheimers Dement
· 2026 May · PMID 42084118
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INTRODUCTION: Dementia is commonly caused by underlying pathologies driven by misfolded protein aggregates. Although dementia subtypes have distinct mechanisms, overlapping symptoms make diagnosis without biomarkers diff...INTRODUCTION: Dementia is commonly caused by underlying pathologies driven by misfolded protein aggregates. Although dementia subtypes have distinct mechanisms, overlapping symptoms make diagnosis without biomarkers difficult. Misdiagnosis has previously hindered drug development by enrolling patients non-specifically in trials. METHODS: We developed a digital seed amplification assay (dSAA) that isolates individual aggregates in nanoliter compartments, enabling precise quantification of transactive response deoxyribonucleic acid binding protein 43 (TDP-43) seeds in cerebrospinal fluid (CSF). RESULTS: Testing 40 CSF samples from patients with genetic and sporadic frontotemporal lobar dementia with TDP (FTLD-TDP), as well as healthy controls, we found elevated seed concentrations in FTLD-TDP patients that correlated with disease severity, demonstrating the potential of dSAA as a sensitive diagnostic tool. DISCUSSION: This study demonstrates a new quantitative, high-sensitivity digital assay for TDP-43 seeds in CSF. The platform's single-aggregate resolution and low limits of detection and quantification establish a technical foundation for developing a diagnostic and monitoring tool for FTLD-TDP and other TDP-43-related diseases.
Gabel M, Goswami S, Bekena S
… +4 more, Solomon ED, Moulder KL, Morris JC, Mozersky J
Alzheimers Dement
· 2026 May · PMID 42084109
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INTRODUCTION: Recruitment and retention remains a major challenge in Alzheimer's disease research. This study examined the impact of describing potential financial compensation during recruitment on participant enrollmen...INTRODUCTION: Recruitment and retention remains a major challenge in Alzheimer's disease research. This study examined the impact of describing potential financial compensation during recruitment on participant enrollment to a longitudinal cohort. METHODS: Participant recruitment calls (N = 337) were randomized to either a compensation-mentioned group (n = 170) or a control group (n = 167). An intention-to-treat logistic regression assessed the effect of compensation on enrollment. RESULTS: Of 320 analyzed, 124 (38.75%) enrolled. The intervention group's consent rate was lower than the control group's in intention-to-treat (-9.72 points; p = 0.074), per-protocol (-12.72 points; p = 0.026), and complier average causal effect analyses (-11.36 points; p = 0.72). DISCUSSION: Disclosing compensation during recruitment may reduce enrollment, potentially due to perceptions that compensation conflicts with altruistic motives. However, this was observed in a highly educated sample; compensation may affect those with lower levels of education and socioeconomic status differently by helping offset participation burden, warranting further investigation.
Ally M, Aslan DH, Sayre MK
… +8 more, Bharadwaj PK, Maltagliati S, Grilli MD, Lai MHC, Wilcox RR, Klimentidis YC, Raichlen DA, Alexander GE
Alzheimers Dement
· 2026 May · PMID 42084104
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INTRODUCTION: Poor sleep has been associated with elevated dementia risk, potentially related to its cerebrovascular consequences, measured by cerebral white matter hyperintensity (WMH) volume. METHODS: We examined self-...INTRODUCTION: Poor sleep has been associated with elevated dementia risk, potentially related to its cerebrovascular consequences, measured by cerebral white matter hyperintensity (WMH) volume. METHODS: We examined self-reported sleep behaviors and prospective magnetic resonance imaging (MRI) WMH volume, measured 8.8 ± 1.7 (mean ± SD) years later, in 23,377 healthy UK Biobank participants. Each sleep behavior was adjusted for demographic, imaging, and clinical covariates (Model 1), as well as vascular health and lifestyle factors (Model 2), and significant sleep behaviors were then mutually adjusted. RESULTS: In Model 1, all poor sleep behaviors were associated with greater WMH volume. In Model 2, only sleep duration outside 7-9 h (β = 0.015, false discovery rate [FDR]p = 0.014), increased daytime napping (β = 0.018, FDRp = 0.008), and greater sleeplessness (β = 0.015, FDRp = 0.014) were associated with greater WMH volume, with each behavior demonstrating distinct contributions (0.004 ≤ FDRp's ≤ 0.025). DISCUSSION: Self-reported sleep behaviors were prospectively associated with greater WMH volume, suggesting a potential sleep-related pathway influencing vascular brain health and dementia risk.
Boutajangout A, Masurkar AV, Osorio R
… +15 more, Debure L, Ghuman M, Ahmed W, Vedvyas A, Pirraglia E, Links J, Bokacheva L, Vega B, Bernard MA, Marsh K, Bubu OM, Shao Y, Chodosh J, Rusinek H, Wisniewski T
Alzheimers Dement
· 2026 May · PMID 42084083
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INTRODUCTION: Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS: Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = ...INTRODUCTION: Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS: Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively. RESULTS: Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001). DISCUSSION: Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.
Hwang J, Pyun JM, Lee JY
… +8 more, Park JS, Bice PJ, Saykin AJ, Sung J, Kim S, Park YH, Nho K, Alzheimer's Disease Neuroimaging Initiative
Alzheimers Dement
· 2026 May · PMID 42080296
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INTRODUCTION: Early detection of Alzheimer's disease (AD) is essential, yet existing biomarkers are invasive or costly. Polygenic risk scores (PRS) and transcriptional risk scores (TRS) may offer accessible alternatives,...INTRODUCTION: Early detection of Alzheimer's disease (AD) is essential, yet existing biomarkers are invasive or costly. Polygenic risk scores (PRS) and transcriptional risk scores (TRS) may offer accessible alternatives, but their combined predictive performance remains understudied. METHODS: We calculated PRS and TRS using genome-wide genotype and blood transcriptome data from two ancestrally distinct cohorts: Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 313) and Seoul National University Bundang Hospital (SNUBH, N = 173). Logistic regression and machine learning models assessed associations of PRS and TRS with AD and AD classification performance. RESULTS: Individuals with high PRS and TRS values showed larger odds ratios for AD, 2.5-fold in ADNI and 3.4-fold in SNUBH, compared to those with low PRS and TRS values. The integrated PRS-TRS model achieved better classification performance (area under the curve [AUC] 0.705) than the PRS model (AUC 0.635). DISCUSSION: Integrating static genetic and dynamic transcriptomic information from blood improves early detection of AD across diverse populations.
Hofmann A, Saef B, Powell WJB
… +18 more, Paczynski M, Ponisio MR, Vila-Castelar C, Posey Z, Oh IY, Hofford MR, Aldinger M, Bateman RJ, Raji CA, Benzinger TLS, Cruchaga C, Dow A, Buckley R, Xiong C, Morris JC, Snider BJ, Gupta A, Schindler SE
Alzheimers Dement
· 2026 May · PMID 42080249
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INTRODUCTION: Usage of biomarker tests for Alzheimer's disease pathology and rates of positivity were assessed at the Washington University Memory Diagnostic Center. METHODS: Patients who underwent at least one biomarker...INTRODUCTION: Usage of biomarker tests for Alzheimer's disease pathology and rates of positivity were assessed at the Washington University Memory Diagnostic Center. METHODS: Patients who underwent at least one biomarker test for clinical purposes between June 2021 and March 2025 were included (n = 1136). Data were retrospectively extracted from electronic health records. RESULTS: The median age was 73.2 years (52% female; 93% White). In total, 455 amyloid positron emission tomography (PET) scans, 505 cerebrospinal fluid tests, and 242 blood tests were performed. The number of biomarker tests increased seven-fold over the past 4 years. The rate of positivity was ≈70% across modalities. Higher rates of biomarker positivity were associated with older age, female sex, and White race; lower rates were associated with hypertension and diabetes. DISCUSSION: Biomarker testing greatly increased following the approval of amyloid-targeting treatments. The overall rate of biomarker positivity was high and varied by demographic factors and medical comorbidities.
Puri S, van der Spek SJF, Lin M
… +13 more, Wang Z, Porter J, Hu J, Hu L, Rondón-Ortiz AN, Knyshov A, Libera JL, Counts SE, Lahiri DK, Tcw J, Emili A, Zhang X, Wolozin B
Alzheimers Dement
· 2026 May · PMID 42080242
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INTRODUCTION: Circular RNAs (circRNAs) are emerging as key regulators of gene expression, synaptic plasticity, and neuronal function in Alzheimer's disease (AD). Here, we characterize the biological actions of circPDE4B,...INTRODUCTION: Circular RNAs (circRNAs) are emerging as key regulators of gene expression, synaptic plasticity, and neuronal function in Alzheimer's disease (AD). Here, we characterize the biological actions of circPDE4B, a highly expressed circRNA markedly reduced in AD. METHODS: circPDE4B knockdown in neuronal progenitor cells was combined with RNA sequencing to identify regulated pathways. circPDE4B affinity purification identified major protein and micro RNA (miRNA) interactors. Assays of translation and autophagy integrated circPDE4B actions. RESULTS: We found that circPDE4B knockdown inhibited translation through a mechanism mediated by its major interacting protein, gem-associated protein 5. circPDE4B knockdown also decreased mechanistic target of rapamycin and correspondingly enhanced autophagic flux. Consistent with these actions, circPDE4B knockdown strongly attenuated microtubule-associated protein tau pathology in a 3D human assembloid model of tauopathy. DISCUSSION: Collectively, our findings identify circPDE4B as a regulator of neuronal homeostasis that integrates translation, autophagy, and miRNA pathways, highlighting a potentially important role in the pathophysiology of AD.
Finlay JM, Rigby D, DeJohn A
… +18 more, Sun Y, Davis BA, Aldulaimy A, Alvarez-McNelis D, Bowie A, Hawkins K, Lin Z, Kan W, Ketterhagen TS, Lin X, Liwur SB, Sagehorn M, Sullivan L, Vaughan L, Zhu S, Berry A, Hicken MT, Esposito MH
Alzheimers Dement
· 2026 May · PMID 42080239
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INTRODUCTION: Neighborhood "third places" are increasingly studied as contextual determinants of cognitive health, yet the reliability of geospatial datasets is poorly understood. METHODS: We evaluated Advan Research, Da...INTRODUCTION: Neighborhood "third places" are increasingly studied as contextual determinants of cognitive health, yet the reliability of geospatial datasets is poorly understood. METHODS: We evaluated Advan Research, Data Axle, FourSquare, and the National Establishment Time Series (NETS) across five categories: cafes/coffee shops, civic/social organizations, libraries, performing arts/museums, and recreation centers/gyms. Bayesian multilevel logistic regression models estimated locational accuracy and categorical validity for 13,168 coder ratings of 4876 unique businesses. Qualitative content analysis examined reflections from 18 coders. RESULTS: Advan showed high locational accuracy (≥95%), with Data Axle and FourSquare performing well for most categories and NETS the lowest. Inaccuracies stemmed from outdated or incorrect addresses and non-fixed locations. Advan, Data Axle, and FourSquare performed moderately well for categorization (70% to 97%) and NETS the worst. Misclassification reflected ambiguous purposes, misleading names, and uncertainty around third places. DISCUSSION: Study-specific dataset selection, triangulation, cleaning, error calibration, and clearer third place conceptualization are critical to strengthen neighborhood-based dementia research.
Van Meter TE, Wilson EN, Elahi F
… +19 more, Rissman RA, Lago AL, Faber K, Gauthreaux K, Osorio R, Perkins M, Gray N, Morris J, Liu A, Stockwell H, Kukull W, Wilson R, Wingo TS, Kanaan NM, Russ K, Wilcock D, Biber SA, Bekris LM, Karikari TK
Alzheimers Dement
· 2026 May · PMID 42080228
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The Biofluid Biomarkers Best Practices Workgroup of the National Alzheimer's Coordinating Center-Alzheimer's Disease Research Center (ADRC) Biomarker Core Steering Committee was convened to update pre-analytical handling...The Biofluid Biomarkers Best Practices Workgroup of the National Alzheimer's Coordinating Center-Alzheimer's Disease Research Center (ADRC) Biomarker Core Steering Committee was convened to update pre-analytical handling guidelines for biofluid biomarkers, focusing on cerebrospinal fluid (CSF) and blood. We reviewed current literature pertinent to best practices for biomarker studies and surveyed the ADRCs for biomarker analytes, platforms, and protocols used at each center. Across 37 ADRCs, 16 CSF and 28 plasma/serum analytes were reported to be studied at multiple centers. The pre-analytical handling steps and concerns related to each, as supported by empirical studies and expert opinion, were integrated to generate a revised guideline document. The guideline aimed to standardize steps in biospecimen and biomarker analyte collection, storage, and pre-analytical handling across the ADRCs. The 2025 ADRC guidelines represent the current working knowledge on biomarker best practices, providing guidance and harmonized protocols, and promoting robust analysis and reporting of composite data.
Grebe LA, Morin BT, Pillai J
… +15 more, Baquirin DPG, Ratnasiri B, Bogley R, Ezzes Z, Wauters LD, Mandelli ML, Miller ZA, Tee BL, de Leon J, Casaletto KB, Rosen HJ, Gorno Tempini ML, Galletta EE, Goral M, Vonk JMJ
Alzheimers Dement
· 2026 May · PMID 42071171
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INTRODUCTION: Cognitive reserve (CR) refers to the brain's ability to maintain cognitive performance despite neurodegeneration. Studying CR in semantic variant primary progressive aphasia (svPPA) may clarify variability...INTRODUCTION: Cognitive reserve (CR) refers to the brain's ability to maintain cognitive performance despite neurodegeneration. Studying CR in semantic variant primary progressive aphasia (svPPA) may clarify variability in disease progression and identify protective factors. METHODS: We examined whether education and occupational attainment-two common CR proxies-moderated relationships between gray matter brain volume and cognitive performance in 58 individuals with svPPA. Multiple linear regression models assessed baseline and longitudinal change across five semantic and non-semantic tasks. RESULTS: Greater brain volume related to better cognitive performance across all tasks. However, CR moderated this relationship only for semantic tasks. At baseline, higher education/occupation was linked to better semantic performance when brain volume was lower. Longitudinally, higher education/occupation was associated with faster decline in semantic performance when brain volume was lower. DISCUSSION: CR influences language performance in svPPA, suggesting its effects are domain-specific and aligned with the progression pattern of this syndrome.
Winer JR, Plastini MJ, Romero A
… +20 more, Vossler H, Sai I, Channappa D, Abdelnour C, Shahid-Besanti M, Wilson EN, Oh HS, Young CB, Trelle A, Yutsis M, Sha SJ, Ramirez V, Taylor R, Younes K, Wyss-Coray T, Greicius MD, Henderson VW, Wagner AD, Poston KL, Mormino EC
Alzheimers Dement
· 2026 May · PMID 42071168
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INTRODUCTION: α-Synuclein is the hallmark pathology of Parkinson's disease and dementia with Lewy bodies, described together as Lewy body disease (LBD). We investigated effects of α-syn biomarker positivity in clinically...INTRODUCTION: α-Synuclein is the hallmark pathology of Parkinson's disease and dementia with Lewy bodies, described together as Lewy body disease (LBD). We investigated effects of α-syn biomarker positivity in clinically unimpaired (CU) individuals. METHODS: We assessed α-syn status (α-syn ±) in 269 CU individuals using a cerebrospinal fluid (CSF) seed amplification assay (SAA). Fifty-six participants with AD and 85 LBD spectrum participants were included for comparison. We compared α-syn SAA results with demographics, fluid biomarkers, cognitive performance, and clinical measures. RESULTS: α -Syn positivity was detected in 9% of CU individuals, a lower rate than in clinically impaired participants with AD (16%) and LBD diagnoses (81%). Compared to α-syn-, α-syn+ CU individuals were older, showed lower synaptic integrity, performed worse on tests of executive function and working memory, and reported more LBD-related non-motor symptoms. DISCUSSION: Further work is needed to understand the timeline of neural and clinical changes in α-syn+ CU individuals and heterogeneity in disease progression.
Li K, Shacham E, Zhu Y
… +2 more, Trani JF, Babulal GM
Alzheimers Dement
· 2026 May · PMID 42071101
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INTRODUCTION: Naturalistic driving provides real-world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in-vehicle sensors with p...INTRODUCTION: Naturalistic driving provides real-world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in-vehicle sensors with points of interest (POIs) to quantify daily environmental engagement among older adults who were cognitively normal at enrollment. METHODS: Data from 438 participants enrolled in the Driving Real-world in-Vehicle Evaluation System Project were used to generate daily POI share vectors and model latent engagement patterns using a logistic-normal hidden Markov model (HMM). Thirteen latent states described distinct modes of environmental interaction. From each participant's inferred state sequence, we derived mobility features - state occupancy, dwell time, transition entropy, and self-transition probability - and examined their differences across clinical status groups and associations with Preclinical Alzheimer's Cognitive Composite (PACC) performance. RESULTS: Transition entropy and several state-specific occupancy and dwelling metrics differed across clinical groups, but none of the mobility features were significantly associated with PACC scores. DISCUSSION: Mobility-derived behavioral features differentiate clinical status groups and may reflect early functional changes preceding cognitive decline.
Cockell S, Bakulski KM, Tsai AL
… +7 more, Liu Y, Goodrich AJ, Okorie CN, Alexeeff S, Whitmer RA, Gilsanz P, Conlon KC
Alzheimers Dement
· 2026 May · PMID 42063316
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BACKGROUND: The associations between adult lead exposure and late-life cognition are largely unknown. METHODS: In two cohorts, Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE, n = 1638) and Study of Healthy Ag...BACKGROUND: The associations between adult lead exposure and late-life cognition are largely unknown. METHODS: In two cohorts, Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE, n = 1638) and Study of Healthy Aging in African Americans (STAR, n = 741), we assessed residential proximity to lead-releasing facilities for association with domain-specific cognition 2 years later. Linear regression models adjusted for age, sex, race/ethnicity, income, education, marital status, smoking status, and alcohol consumption. We meta-analyzed across cohorts. RESULTS: Average age was 76.1 (KHANDLE), 68.8 years (STAR); average residential distance to a lead facility was 8.2 km (KHANDLE), 3.6 km (STAR). In meta-analysis, for every 5 km closer a residence was located to a lead-releasing facility, episodic memory scores 2 years later were -0.05 (95% confidence interval: -0.08, -0.02) standard deviation lower. DISCUSSION: Residential proximity to a lead-releasing facility was associated with poorer cognition 2 years later among adults in two cohorts.
Skolariki K, Rosenberg PB, Oh ES
… +3 more, Leoutsakos J, Lyketsos CG, Adams R
Alzheimers Dement
· 2026 May · PMID 42063315
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INTRODUCTION: Understanding factors associated with cognitive resilience is critical for developing interventions to preserve cognitive health in the old-old. Our aim is identifying clinical predictors of cognitive resil...INTRODUCTION: Understanding factors associated with cognitive resilience is critical for developing interventions to preserve cognitive health in the old-old. Our aim is identifying clinical predictors of cognitive resilience in a large real-world cohort of adults aged 75+. METHODS: Longitudinal analysis of electronic health records from Johns Hopkins primary care clinics between January 1, 2014, and August 31, 2025. A minimum of two follow-up visits at least a year apart were required. To estimate the associations between predictors and cognitive resilience, we employed a Cox model with cognitive disorder diagnosis as the outcome. RESULTS: Of 43,178 patients, 6563 developed cognitive disorder during follow-up. Psychiatric conditions were strongly associated with decreased resilience. Antihypertensive use was associated with increased resilience. Black race and Medicaid enrollment were associated with decreased resilience. DISCUSSION: Most adults reaching 90 remained cognitively healthy. Resilience reflected physiological reserve and care engagement, while vascular, psychiatric, and social factors reduced resilience.
Zhang SQ, Lee J, Pan JP
… +5 more, Enger R, Hrubos-Strøm H, Musiek ES, Fang EF, Le W
Alzheimers Dement
· 2026 May · PMID 42063312
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The circadian rhythm system and sleep coordinate whole-body functions across the 24-h cycle, yet these rhythms progressively deteriorate with neurodegenerative diseases, including dementia. Growing evidence indicates tha...The circadian rhythm system and sleep coordinate whole-body functions across the 24-h cycle, yet these rhythms progressively deteriorate with neurodegenerative diseases, including dementia. Growing evidence indicates that nicotinamide adenine dinucleotide (NAD) interacts with the circadian system through multiple molecular pathways and that NAD levels decline with dementia. In this review, we synthesize current evidence on the bidirectional relationship between NAD metabolism and circadian regulation in several dementia disorders, emphasizing the key circadian pathways, the nicotinamide phosphoribosyltransferase-mediated salvage synthesis, the NAD/sirtuins-dependent signaling, and the consumption of NAD by PARP1 and CD38. Finally, we also examine pharmacological and lifestyle strategies that target NAD, including NAD precursors, modulators of NAD biosynthetic and depleting enzymes, timed light and activity exposure, structured exercise programs, and dietary interventions. Overall, we focus on the bidirectional interplay between NAD metabolism and circadian rhythm regulation in dementia, with particular emphasis on how this interaction influences sleep and cognitive phenotypes across different dementia subtypes. Trial Registration: ClinicalTrials.gov identifier: NCT05040321, NCT04430517, NCT06971224, NCT05500170, NCT04070378.
O'Shea DM, Wang L, Lukacsovich D
… +7 more, Dhanekula D, Zhang W, Galvin C, Joshi M, Besser L, Rundek T, Galvin JE
Alzheimers Dement
· 2026 May · PMID 42062774
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INTRODUCTION: Heterogeneity in cognitive ability increases with age and predicts mild cognitive impairment (MCI) and dementia, but scalable blood-based biomarkers are lacking. We developed and validated MethylCog, a pars...INTRODUCTION: Heterogeneity in cognitive ability increases with age and predicts mild cognitive impairment (MCI) and dementia, but scalable blood-based biomarkers are lacking. We developed and validated MethylCog, a parsimonious DNA methylation (DNAm) marker of general cognitive ability (g). METHODS: MethylCog was developed using elastic net regression on principal components analysis (PCA) -derived g in a population-based cohort (n = 2,069; training/test split) externally validated (n = 112). Criterion validity, MCI discrimination, and specificity relative to GrimAge and Alzheimer's disease (AD) biomarkers were assessed. RESULTS: MethylCog (29 CpGs) predicted g in the test set (R = 0.17) and external cohort (R = 0.13), explaining ∼11% of variance beyond age and sex. MethylCog improved MCI discrimination beyond demographics (ΔAUC = 0.03-0.07) and outperformed GrimAge but did not add value beyond cognitive screeners. Exploratory analyses showed no significant associations with AD plasma biomarkers or MRI measures. DISCUSSION: MethylCog provides initial evidence that parsimonious DNAm scores can index individual differences in cognitive ability, with potential utility where direct assessment is unavailable.
Song Z, Huang X, Jannu AJ
… +3 more, Johnson TS, Zhang J, Huang K
Alzheimers Dement
· 2026 May · PMID 42056682
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INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous disease with diverse disease progression trajectories and brain pathology. Identifying AD subtypes is essential for understanding AD etiology, heterogeneity, and...INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous disease with diverse disease progression trajectories and brain pathology. Identifying AD subtypes is essential for understanding AD etiology, heterogeneity, and developing precise treatment. METHODS: We applied a subspace-merging algorithm to integrate multi-omics data from brain tissues of three large AD cohorts and identify data-driven AD subtypes. Within each cohort, we performed multiple analyses to characterize subtype-specific biology. A Phenome-wide Association Study (PheWAS) of expression quantitative trait loci (eQTLs) targeting differentially expressed genes (DEGs) was conducted to link molecular differences to disease phenotypes. RESULTS: We identified AD subtypes that differed in cognitive and pathological phenotypes in three cohorts. Further analyses highlighted synaptic and neurotransmission pathways, and the PheWAS revealed significant associations with disease phenotypes. DISCUSSION: Our developed integration algorithm successfully merged different data modalities into a common subspace for patient clustering and identified data-driven subtypes. The identified transcriptomic signatures provide valuable insights into the molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.