Alina Zhunussova, Clare Loane, Elif Kurt, Grazia Daniela Femminella, Sabrina Lenzoni, Millie Duckett, Martina F Callaghan, Nikolaus Weiskopf, Raymond J Dolan, Robert Howard, Emrah Düzel, Dorothea Hämmerer
INTRODUCTION Pupil dilation (PD) can be easily measured and reflects responses to subjectively salient or cognitively demanding events. It therefore holds promise as a cognitive marker, especially for individuals with mild cognitive impairment (MCI) or other neurodegenerative conditions with restricted abilities to respond in cognitive assessments. METHODS We assessed PD during two tasks, an oddball task for investigating attentional allocation and a Simon task, which additionally allows for investigating cognitive effort in younger adults (YAs), older adults (OAs), and patients with MCI. RESULTS PD is a useful marker for investigating attention and cognitive effort in MCI, as suggested by elevated PD to salient stimuli in particular of individuals with better attentional control in MCI patients, as well as YAs and OAs. DISCUSSION Measurement of PD may serve as an easy‐to‐administer measure to assess changes in cognitive function in healthy aging and MCI.
{"title":"Pupil dilation as a marker of attention/effort in aging and mild cognitive impairment","authors":"Alina Zhunussova, Clare Loane, Elif Kurt, Grazia Daniela Femminella, Sabrina Lenzoni, Millie Duckett, Martina F Callaghan, Nikolaus Weiskopf, Raymond J Dolan, Robert Howard, Emrah Düzel, Dorothea Hämmerer","doi":"10.1002/alz.71180","DOIUrl":"https://doi.org/10.1002/alz.71180","url":null,"abstract":"INTRODUCTION Pupil dilation (PD) can be easily measured and reflects responses to subjectively salient or cognitively demanding events. It therefore holds promise as a cognitive marker, especially for individuals with mild cognitive impairment (MCI) or other neurodegenerative conditions with restricted abilities to respond in cognitive assessments. METHODS We assessed PD during two tasks, an oddball task for investigating attentional allocation and a Simon task, which additionally allows for investigating cognitive effort in younger adults (YAs), older adults (OAs), and patients with MCI. RESULTS PD is a useful marker for investigating attention and cognitive effort in MCI, as suggested by elevated PD to salient stimuli in particular of individuals with better attentional control in MCI patients, as well as YAs and OAs. DISCUSSION Measurement of PD may serve as an easy‐to‐administer measure to assess changes in cognitive function in healthy aging and MCI.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"53 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Taylor J. Pedersen, Sabrina G. Clemens, Joseph R. Winer, Ashish Sharma, Neus Falgàs, Brendan P. Lucey, Brian A. Gordon, Erik S. Musiek
Neuromodulatory subcortical systems (NSS) regulate arousal, cognition, and sleep–wake transitions through widespread influence on cortical and subcortical networks. Increasing evidence links dysfunction of these systems to the pathogenesis of Alzheimer's disease (AD). Degeneration and dysregulation of NSS occurs during the preclinical phase of AD, preceding the onset of cognitive decline. Alterations of NSS are implicated in sleep disruption and impair sleep‐dependent cerebrospinal fluid (CSF) clearance via the glymphatic system, a process involved in removing amyloid beta and other neurotoxic proteins. This review synthesizes current evidence linking wake‐promoting neuromodulators—norepinephrine, histamine, and orexin—to AD pathology, with an emphasis on their convergent effects on sleep regulation and brain fluid dynamics. We propose that NSS dysfunction may drive a self‐reinforcing cycle of disrupted sleep, impaired glymphatic clearance, and neurodegeneration, underscoring the need to better understand this relationship to inform pharmacological interventions slowing or preventing AD.
{"title":"Wake‐promoting neuromodulators in Alzheimer's disease: Implications for sleep and brain clearance","authors":"Taylor J. Pedersen, Sabrina G. Clemens, Joseph R. Winer, Ashish Sharma, Neus Falgàs, Brendan P. Lucey, Brian A. Gordon, Erik S. Musiek","doi":"10.1002/alz.71298","DOIUrl":"https://doi.org/10.1002/alz.71298","url":null,"abstract":"Neuromodulatory subcortical systems (NSS) regulate arousal, cognition, and sleep–wake transitions through widespread influence on cortical and subcortical networks. Increasing evidence links dysfunction of these systems to the pathogenesis of Alzheimer's disease (AD). Degeneration and dysregulation of NSS occurs during the preclinical phase of AD, preceding the onset of cognitive decline. Alterations of NSS are implicated in sleep disruption and impair sleep‐dependent cerebrospinal fluid (CSF) clearance via the glymphatic system, a process involved in removing amyloid beta and other neurotoxic proteins. This review synthesizes current evidence linking wake‐promoting neuromodulators—norepinephrine, histamine, and orexin—to AD pathology, with an emphasis on their convergent effects on sleep regulation and brain fluid dynamics. We propose that NSS dysfunction may drive a self‐reinforcing cycle of disrupted sleep, impaired glymphatic clearance, and neurodegeneration, underscoring the need to better understand this relationship to inform pharmacological interventions slowing or preventing AD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"15 1","pages":"e71298"},"PeriodicalIF":14.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. J. Hansmann, Mark D'Alesio, Beth Fields, Corrina Holcomb, Gretchen Tran, Anthony D. McDonald
People with dementia often rely on family caregivers to assist with daily activities, manage healthcare needs, and make decisions. This scoping review aimed to characterize the involvement of caregivers in research about driving transitions for people with dementia. We identified 16 articles that included caregivers in studies investigating the driving of people with dementia. Key themes describing caregiver involvement in this research included that family caregivers (1) observed and assessed the driving of the person with dementia, (2) made decisions about driving, and (3) had a mixed experience of the impacts of dementia on driving. Family caregivers play a vital role in navigating driving transitions and experience their own logistical and emotional burdens associated with these transitions. To effectively include caregivers in research and intervention development, future work should explicitly consider caregivers’ unique perspectives and experiences during this complex life transition.
{"title":"Dementia and driving: A scoping review of family caregiver involvement in driving cessation research","authors":"K. J. Hansmann, Mark D'Alesio, Beth Fields, Corrina Holcomb, Gretchen Tran, Anthony D. McDonald","doi":"10.1002/alz.71258","DOIUrl":"https://doi.org/10.1002/alz.71258","url":null,"abstract":"People with dementia often rely on family caregivers to assist with daily activities, manage healthcare needs, and make decisions. This scoping review aimed to characterize the involvement of caregivers in research about driving transitions for people with dementia. We identified 16 articles that included caregivers in studies investigating the driving of people with dementia. Key themes describing caregiver involvement in this research included that family caregivers (1) observed and assessed the driving of the person with dementia, (2) made decisions about driving, and (3) had a mixed experience of the impacts of dementia on driving. Family caregivers play a vital role in navigating driving transitions and experience their own logistical and emotional burdens associated with these transitions. To effectively include caregivers in research and intervention development, future work should explicitly consider caregivers’ unique perspectives and experiences during this complex life transition.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"28 1","pages":"e71258"},"PeriodicalIF":14.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147448359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuyu Zhang, Yiju Li, Qianxu Wang, Jingxi Pang, Da Wang, Tian Yuan, Zhigang Liu
INTRODUCTION Aging worsens Alzheimer's disease (AD) peripheral metabolism and central pathology, yet few interventions are effective when started late. Methionine restriction (MR) induces the hepatokine FGF21 and may protect brain function, but its efficacy and mechanisms when started late are unclear. METHODS Fourteen‐month‐old male APP/PS1 mice received 17 weeks of MR (0.17% methionine); behavioral, histological, and molecular assays were performed and hippocampal FGFR1 was knocked down by adeno‐associated virus. RESULTS Late‐life MR improved peripheral glucose/lipid profiles, reduced Aβ deposition, preserved synaptic markers, and suppressed neuroinflammation. MR‐induced hepatic FGF21 and brain FGFR1‐AMPKα signaling to inhibit NFκB; hippocampal FGFR1 knockdown abolished MR's neuroprotective effects while leaving peripheral metabolic changes intact. DISCUSSION Even when initiated in late life, MR robustly reduces AD pathology via the hepatic FGF21‐brain FGFR1 axis, independent of peripheral metabolic changes. These preclinical findings position MR and FGF21‐FGFR1 axis as actionable late‐life intervention targets with potential for clinical translation.
{"title":"Late‐life methionine restriction attenuates neuroinflammation in Alzheimer's disease mice via FGF21 activation in a metabolism‐independent manner","authors":"Yuyu Zhang, Yiju Li, Qianxu Wang, Jingxi Pang, Da Wang, Tian Yuan, Zhigang Liu","doi":"10.1002/alz.71287","DOIUrl":"https://doi.org/10.1002/alz.71287","url":null,"abstract":"INTRODUCTION Aging worsens Alzheimer's disease (AD) peripheral metabolism and central pathology, yet few interventions are effective when started late. Methionine restriction (MR) induces the hepatokine FGF21 and may protect brain function, but its efficacy and mechanisms when started late are unclear. METHODS Fourteen‐month‐old male APP/PS1 mice received 17 weeks of MR (0.17% methionine); behavioral, histological, and molecular assays were performed and hippocampal FGFR1 was knocked down by adeno‐associated virus. RESULTS Late‐life MR improved peripheral glucose/lipid profiles, reduced Aβ deposition, preserved synaptic markers, and suppressed neuroinflammation. MR‐induced hepatic FGF21 and brain FGFR1‐AMPKα signaling to inhibit NFκB; hippocampal FGFR1 knockdown abolished MR's neuroprotective effects while leaving peripheral metabolic changes intact. DISCUSSION Even when initiated in late life, MR robustly reduces AD pathology via the hepatic FGF21‐brain FGFR1 axis, independent of peripheral metabolic changes. These preclinical findings position MR and FGF21‐FGFR1 axis as actionable late‐life intervention targets with potential for clinical translation.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"17 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to “A comparison between tau and amyloid‐β cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease”","authors":"","doi":"10.1002/alz.70808","DOIUrl":"https://doi.org/10.1002/alz.70808","url":null,"abstract":"","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"59 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen Hall, Leticia Garcia, Marie Stahmer, Percy Griffin, Maria C. Carrillo, Rebecca M. Edelmayer
BACKGROUND Roughly 7.2 million older Americans are living with Alzheimer's disease (AD). Research participation remains one of the largest barriers facing dementia research advancements. METHODS TrialMatch is a dementia research awareness tool. TrialMatch consolidates research opportunities to serve as an open‐access, centralized, and user‐friendly resource to identify research opportunities. Between August 2020 and June 2024, we tracked the number of research opportunities available, enrollment targets, and TrialMatch engagement. RESULTS TrialMatch maintained a database of over 700 opportunities and received 18,802 calls and 122,461 web sessions, and provided 17,725 referrals to opportunities. An estimated 1,867,403 participants are needed to populate all the ongoing studies in the United States. DISCUSSION By using a broad inclusion criteria, TrialMatch highlights the burden that AD/ADRD research faces with recruitment. While TrialMatch has demonstrated its ability to serve as an awareness tool, future analyses are needed to better evaluate the impact of the tool on enrollment.
{"title":"The Alzheimer's Association TrialMatch—Increasing awareness of all dementia trials","authors":"Stephen Hall, Leticia Garcia, Marie Stahmer, Percy Griffin, Maria C. Carrillo, Rebecca M. Edelmayer","doi":"10.1002/alz.71250","DOIUrl":"https://doi.org/10.1002/alz.71250","url":null,"abstract":"BACKGROUND Roughly 7.2 million older Americans are living with Alzheimer's disease (AD). Research participation remains one of the largest barriers facing dementia research advancements. METHODS TrialMatch is a dementia research awareness tool. TrialMatch consolidates research opportunities to serve as an open‐access, centralized, and user‐friendly resource to identify research opportunities. Between August 2020 and June 2024, we tracked the number of research opportunities available, enrollment targets, and TrialMatch engagement. RESULTS TrialMatch maintained a database of over 700 opportunities and received 18,802 calls and 122,461 web sessions, and provided 17,725 referrals to opportunities. An estimated 1,867,403 participants are needed to populate all the ongoing studies in the United States. DISCUSSION By using a broad inclusion criteria, TrialMatch highlights the burden that AD/ADRD research faces with recruitment. While TrialMatch has demonstrated its ability to serve as an awareness tool, future analyses are needed to better evaluate the impact of the tool on enrollment.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"29 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alfie Wearn, Kate M. Onuska, Taylor W. Schmitz, Gary R. Turner, R. Nathan Spreng
Sporadic Alzheimer's disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factors converge on neuromodulatory subcortical systems to confer AD risk or resilience. Neuromodulatory projection neurons are uniquely fragile due to their large size, sparse myelination, and high basal metabolic demands. We propose that the increased prevalence of AD in older adult populations likely reflects a universal weakness within these projection systems, which is increasingly exposed as cellular transport and maintenance mechanisms deteriorate with age. The key insight of this “neuromodulatory fragility hypothesis” is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and amyloid beta plaque formation, the two pathological hallmarks of AD. We therefore predict that strengthening or preserving the endogenous functions of these systems in midlife represents the most effective strategy for preventing AD.
{"title":"The neuromodulatory fragility hypothesis of Alzheimer's disease pathogenesis","authors":"Alfie Wearn, Kate M. Onuska, Taylor W. Schmitz, Gary R. Turner, R. Nathan Spreng","doi":"10.1002/alz.71249","DOIUrl":"https://doi.org/10.1002/alz.71249","url":null,"abstract":"Sporadic Alzheimer's disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factors converge on neuromodulatory subcortical systems to confer AD risk or resilience. Neuromodulatory projection neurons are uniquely fragile due to their large size, sparse myelination, and high basal metabolic demands. We propose that the increased prevalence of AD in older adult populations likely reflects a universal weakness within these projection systems, which is increasingly exposed as cellular transport and maintenance mechanisms deteriorate with age. The key insight of this “neuromodulatory fragility hypothesis” is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and amyloid beta plaque formation, the two pathological hallmarks of AD. We therefore predict that strengthening or preserving the endogenous functions of these systems in midlife represents the most effective strategy for preventing AD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"15 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ethan C. Cicero, Jace D. Flatt, Oumaima Kaabi, Vin Tangpricha, Darios Getahun, Courtney McCracken, Timothy L. Lash, Michael J. Silverberg, Suma Vupputuri, Molly Perkins, Lisa L. Barnes, Michael Goodman
We investigated whether Alzheimer's disease and related dementias (ADRD) are more common among transfeminine (TF) adults than among demographically similar cisgender people enrolled in the same health system.
{"title":"Alzheimer's disease and related dementias among transfeminine adults: A cohort study","authors":"Ethan C. Cicero, Jace D. Flatt, Oumaima Kaabi, Vin Tangpricha, Darios Getahun, Courtney McCracken, Timothy L. Lash, Michael J. Silverberg, Suma Vupputuri, Molly Perkins, Lisa L. Barnes, Michael Goodman","doi":"10.1002/alz.71277","DOIUrl":"https://doi.org/10.1002/alz.71277","url":null,"abstract":"We investigated whether Alzheimer's disease and related dementias (ADRD) are more common among transfeminine (TF) adults than among demographically similar cisgender people enrolled in the same health system.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"45 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Teresa Liu-Ambrose, Ryan S. Falck, Elizabeth Dao, Rachel A. Crockett, Cindy K. Barha, Narlon C. Boa Sorte Silva, Walid A. Alkeridy, John R. Best, Ging-Yuek R. Hsiung, Thalia S. Field, Kenneth M. Madden, Jennifer C. Davis, Lisanne F. ten Brinke, Roger C. Tam
It is unknown whether progressive resistance training (PRT) improves cognitive function in adults with cerebral small vessel disease and mild cognitive impairment (i.e., subcortical vascular cognitive impairment [SVCI]).
{"title":"Resistance training and subcortical vascular cognitive impairment: A 12-month randomized trial","authors":"Teresa Liu-Ambrose, Ryan S. Falck, Elizabeth Dao, Rachel A. Crockett, Cindy K. Barha, Narlon C. Boa Sorte Silva, Walid A. Alkeridy, John R. Best, Ging-Yuek R. Hsiung, Thalia S. Field, Kenneth M. Madden, Jennifer C. Davis, Lisanne F. ten Brinke, Roger C. Tam","doi":"10.1002/alz.71245","DOIUrl":"https://doi.org/10.1002/alz.71245","url":null,"abstract":"It is unknown whether progressive resistance training (PRT) improves cognitive function in adults with cerebral small vessel disease and mild cognitive impairment (i.e., subcortical vascular cognitive impairment [SVCI]).","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"36 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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