OBJECTIVE:Hearing impairment is considered an important modifiable risk factor for dementia, but whether its association with incident dementia is consistent across inherited susceptibility profiles remains unclear. METHODS:This prospective cohort study included 80,287 UK Biobank participants aged 40 to 69 years at baseline with valid Digit Triplet Test measurements, genetic data, linked follow-up data, and complete prespecified covariates. Hearing function was quantified using the better-ear speech reception threshold (SRT). Incident dementia was ascertained from linked hospital admission and death registry records. Cox proportional hazards models were used to estimate associations between baseline hearing status and incident dementia. The fully adjusted model included demographic, socioeconomic, lifestyle, cardiometabolic, visual, psychosocial, hearing-aid-use, and genetic ancestry covariates. Effect modification by inherited susceptibility, including dementia polygenic risk score (PRS), APOE ε4 carrier status, and parental history of dementia, was assessed using stratified analyses and multiplicative interaction tests. RESULTS:During ∼988,462 person-years of follow-up, 1086 incident dementia cases were identified. Compared with normal hearing, mild and severe hearing impairment were associated with higher dementia risk in the fully adjusted model, with HRs of 1.33 (95% CI: 1.13-1.56) and 1.53 (95% CI: 1.15-2.02), respectively. Restricted cubic spline analyses supported a nonlinear dose-response association between higher SRT and dementia risk. The hearing impairment-dementia association was observed across PRS, APOE ε4 carrier status, and parental family-history strata, with no statistically significant multiplicative interaction by APOE ε4 status or parental family history and only suggestive evidence by PRS category. CONCLUSIONS:Speech-in-noise hearing impairment was associated with a higher risk of incident dementia in the UK Biobank, and this association was broadly observed across inherited-risk strata. These findings support hearing impairment as a potentially modifiable marker relevant to dementia-risk assessment across polygenic, APOE ε4, and familial risk backgrounds.
Objective: Hearing impairment is considered an important modifiable risk factor for dementia, but whether its association with incident dementia is consistent across inherited susceptibility profiles remains unclear. Methods: This prospective cohort study included 80,287 UK Biobank participants aged 40 to 69 years at baseline with valid Digit Triplet Test measurements, genetic data, linked follow-up data, and complete prespecified covariates. Hearing function was quantified using the better-ear speech reception threshold (SRT). Incident dementia was ascertained from linked hospital admission and death registry records. Cox proportional hazards models were used to estimate associations between baseline hearing status and incident dementia. The fully adjusted model included demographic, socioeconomic, lifestyle, cardiometabolic, visual, psychosocial, hearing-aid-use, and genetic ancestry covariates. Effect modification by inherited susceptibility, including dementia polygenic risk score (PRS), APOE ε4 carrier status, and parental history of dementia, was assessed using stratified analyses and multiplicative interaction tests. Results: During ∼988,462 person-years of follow-up, 1086 incident dementia cases were identified. Compared with normal hearing, mild and severe hearing impairment were associated with higher dementia risk in the fully adjusted model, with HRs of 1.33 (95% CI: 1.13-1.56) and 1.53 (95% CI: 1.15-2.02), respectively. Restricted cubic spline analyses supported a nonlinear dose-response association between higher SRT and dementia risk. The hearing impairment-dementia association was observed across PRS, APOE ε4 carrier status, and parental family-history strata, with no statistically significant multiplicative interaction by APOE ε4 status or parental family history and only suggestive evidence by PRS category. Conclusions: Speech-in-noise hearing impairment was associated with a higher risk of incident dementia in the UK Biobank, and this association was broadly observed across inherited-risk strata. These findings support hearing impairment as a potentially modifiable marker relevant to dementia-risk assessment across polygenic, APOE ε4, and familial risk backgrounds.
Alzheimer Disease and Related Dementias (ADRD) affect more than 125,000 individuals in South Carolina, yet equitable representation in population genomics initiatives remains a concern. We conducted a cross-sectional descriptive analysis of 247 In Our DNA SC participants aged 50 to 89 years with at least 1 ADRD-related diagnosis, identified using ICD-10 codes, to characterize demographic and clinical features and to compare the cohort with statewide ADRD estimates. Most participants were aged 65 years or older (82.2%), female (52.2%), and White (93.1%), while only 5.3% identified as Black. Nearly half had a Charlson Comorbidity Index score of 4 or greater (48.6%), and 49.5% had at least 10 years of longitudinal electronic health record data. Compared with statewide ADRD estimates, Black individuals were substantially underrepresented despite comprising ∼one-third of ADRD cases in South Carolina. These findings highlight the need for continued efforts to improve representation and support equitable, generalizable precision health research.
BACKGROUND/AIM:To promote staff and resident well-being in Assisted Living (AL), it is essential to enhance daily care interactions between staff and older adults with Alzheimer disease and related dementias (ADRD). There is currently no comprehensive instrument that can both guide the process of improving care interactions and appraise the impact of such improvements in AL. We developed a comprehensive instrument, the Quality of Interactions Inventory (QUALII), that accomplishes both tasks. Here, we evaluate its content validity. METHODS:An eDelphi study with a convenience sample of N=10 clinical/academic experts in ADRD care and communication. Item-Content Validity Index (I-CVI) and Scale-Content Validity Index (S-CVI) were computed using quantitative ratings; item revisions were based on content analysis of qualitative comments. RESULTS:Following 3 rounds of eDelphi survey, QUALII was reduced to a 19-item tool with I-CVI=0.90 to 1.00 for item relevance, I-CVI=0.80 to 1.00 for item clarity, and S-CVI=0.93 for the overall scale. CONCLUSION AND IMPLICATIONS:QUALII demonstrated excellent content validity and will be used for pilot testing in AL communities. Upon pilot testing, QUALII could emerge as a valid, reliable, and comprehensive tool for promoting positive care interactions in ADRD care.
Endolysosomal dysfunction has been increasingly implicated in the pathogenesis of neurodegenerative diseases. The charged multivesicular body protein 2B (CHMP2B) gene encodes a component of the endosomal sorting complexes required for transport (ESCRT-III), which regulates endosomal trafficking, multivesicular body formation, and autophagosome-lysosome fusion. Mutations in CHMP2B are classically associated with autosomal dominant frontotemporal dementia. Here, we report a 59-year-old woman with biomarker-confirmed Alzheimer disease (AD) (A+T+N+) carrying a heterozygous CHMP2B c.90C>T (p.Ala30Ser) variant identified by targeted exome sequencing after negative testing for APP, APOE, PSEN1, and PSEN2. The patient presented with progressive episodic memory impairment and spatial disorientation over 3 years. Brain MRI showed prominent posterior cortical atrophy, and cerebrospinal fluid biomarkers demonstrated decreased Aβ42 and elevated phosphorylated and total tau levels consistent with AD pathology. Dysfunction of CHMP2B-mediated endolysosomal pathways may impair intracellular protein degradation and influence tau clearance mechanisms. This observation suggests that rare variants in endolysosomal pathway genes may contribute to AD pathophysiology.
Introduction:Alterations in the gut-brain axis have been increasingly linked to neurodegenerative diseases, including Alzheimer disease (AD). It remains unclear whether these microbiome changes are already present during early cognitive decline. We examined whether gut microbiome alterations characteristic of AD are detectable in mild cognitive impairment (MCI) and whether these changes follow a similar pattern across the cognitive continuum.Methods:This case-control study included 78 participants: 37 cognitively healthy controls, 20 individuals with MCI, and 21 individuals with prodromal or mild AD. Cognitive performance was assessed using the CERAD neuropsychological battery, and disease severity was assessed using the Clinical Dementia Rating. Dietary data were collected, and fecal samples were analyzed using 16S rRNA gene amplicon sequencing.Results:We identified 16 bacterial genera associated with cognitive status. Genera such as Lacticaseibacillus, Raoultella, and Buttiauxella were reduced in AD, with similar decreases already evident in MCI. In contrast, Anaerovorax and an unclassified Comamonadaceae genus were increased in AD. Several alterations showed a consistent trend from normal cognition through MCI to AD.Discussion:Gut microbiome alterations characteristic of AD appear already present in early cognitive decline and follow a similar pattern in MCI. These findings support the potential of microbiome profiles as early, noninvasive biomarkers of AD.
OBJECTIVES:Practice effects (PEs), improvements in cognitive test performance with repeated exposure, must be addressed in longitudinal studies of cognitive aging. Although many cognitive assessments are marketed as robust to PEs, evidence is limited. Randomizing testing features enables direct quantification of PEs but remains underutilized. METHODS:Among Nurses' Health Study II participants (N=14,802), we examined PEs in the Cogstate Brief Battery arising from increased testing repetition and frequency using conditionally randomized 6- or 12-month regimens (2014 to 2019). RESULTS:Taking the assessment twice previously, compared with once previously, at the 12-month assessment (defined as frequency PEs) was associated with 0.13 SD-higher global cognitive scores (95% CI: 0.10-0.16), corresponding to between-person age differences of 4.3 to 6.8 years. Taking the second assessment 6-months compared with 12-months after baseline (defined as frequency of PEs) was associated with 0.04 SD-higher global cognitive scores ( P <0.01), corresponding to between-person 1.3 to 1.6-year age differences. Repetition and frequency PEs both appeared to be greater in magnitude for participants who were older at baseline, but uncertainty was high in formal tests of effect modification. CONCLUSIONS:Over short follow-up periods, repetition PEs may obscure age-related cognitive decline using Cogstate. Randomizing testing features can be used to strengthen cognitive aging research.
BACKGROUND:Emerging evidence highlights the critical involvement of noncoding RNAs (ncRNAs) in the pathologic process of Alzheimer disease (AD). However, the precise functional contributions and regulatory landscapes of long noncoding RNAs (lncRNAs) in AD remain unclear. OBJECTIVE:This study aims to delineate the regulatory roles of functional lncRNAs in AD by systematically analyzing lncRNA-mRNA interactions within an AD-associated network, leveraging the competing endogenous RNA (ceRNA) framework. METHODS:We constructed an AD-specific lncRNA-mRNA network by integrating a probe reannotation pipeline with experimentally validated microRNA (miRNA)-lncRNA/mRNA interactions. Key lncRNAs were identified through topological analysis, while bidirectional hierarchical clustering was applied to define functional modules. Pearson correlation coefficients were computed to assess the association patterns of lncRNA-mRNA pairs. RESULTS:Using a structured analytical approach, we identified 31 differentially expressed lncRNAs and 1045 mRNAs within the AD network. Topological analysis revealed SNHG12, MIR17HG, and GAS5 as central regulatory nodes, indicating their potential roles in network stability and transcriptional regulation. A functionally coherent module of lncRNA-mRNA interactions was identified through clustering, with enrichment in multiple AD-relevant signaling pathways, including neuroinflammation and synaptic dysfunction, suggesting a mechanistic role for lncRNAs in disease-associated processes. Furthermore, leveraging the ceRNA model, we mapped dysregulated ceRNA interactions, uncovering significant alterations in ceRNA crosstalk between AD and non-AD conditions, which may reflect broader disruptions in posttranscriptional gene regulation. CONCLUSIONS:Our findings provide key insights into the functional architecture of lncRNA regulatory networks in AD, offering a refined perspective on their contributions to disease pathology and highlighting potential biomarkers and therapeutic targets.
BACKGROUND:Evidence from neuroscience, epidemiology, and electronic health records studies implicates herpes simplex viruses (HSV) as potentially etiologic for Alzheimer disease (AD). METHODS:The VALMCI study was conducted in a research outpatient clinic specializing in memory disorders. The efficacy and side effects of valacyclovir 4 g/day were compared with placebo in a 12-month pilot, randomized, double-blind trial of participants with mild cognitive impairment (MCI), seropositivity to HSV1 or HSV2, and positive 18 F-florbetapir PET scan. RESULTS:Totally, 42 of 50 participants (84%) completed the trial. In linear mixed-effects model analyses with age, sex, and apolipoprotein E e4 genotype as covariates, change in the primary outcome of 18 F-florbetapir PET mean SUVR was not significant with least-squares mean difference -0.01 (95% CI: -0.12 to 0.10; P =0.82). For secondary cognitive and functional outcomes, PACC composite z -score showed the least square mean difference 0.16 (95% CI: -0.17 to 0.49; P =0.32), and ADCS-ADL-PI score showed the least square mean difference 1.96 (95% CI: -0.43 to 4.34; P =0.11). CONCLUSION:The results do not support the use of valacyclovir in the treatment of individuals with MCI with HSV seropositivity and PET amyloid positivity.
People with low educational levels or low literacy skills tend to obtain lower scores on cognitive screens, even in the absence of cognitive impairments, possibly resulting in false positive diagnoses. The Montreal Cognitive Assessment-Basic (MoCA-B) has been developed to overcome this, but studies so far are limited to low-income countries. This study examined the MoCA-B [total score and Memory Index Score (MIS)] in a European memory clinic context. Fifty-five controls, 37 patients with mild cognitive impairment and 47 dementia patients were included. Results showed that a MoCA-B total cutoff score <25 is valid for distinguishing controls from MCI or dementia patients. The MoCA-B MIS showed an acceptable diagnostic accuracy for controls versus MCI (<12) and controls versus dementia (<11). No valid cutoff score could be established for MCI versus dementia patients. Our findings show that the MoCA-B can also be validly applied in a European memory clinic setting.
Background:Alzheimer disease (AD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases causing memory decline. Previous studies have demonstrated an altered gut microbiome (GM) in both conditions. In this study, we compared the GM composition between the groups to find out how if the GM composition differed between the cognitively healthy individuals (CO) and AD groups, as well as between the AD and iNPH groups.Methods:Thirty-seven CO participants, 21 mild AD patients and 10 participants with shunted iNPH gave fecal samples, which were subjected to 16S amplicon sequencing. Then, genus-level differences were analyzed. Information about comorbidities and diet was collected, and cognitive function was evaluated.Results:Compared with the CO group, Anaerovorax and an unknown genus of the Comamonadaceae family increased, whereas Enterobacter, Absicoccus, Buttiauxella, Raoultella, and Lacticaseibacillus decreased in the AD group. Compared with the iNPH group, Paramuribaculum, an unknown genus of the Desulfovibrionaceae family, Ruficoccus and Mitsuokella increased, whereas Anaeromassilibacillus and Desulfovibrio decreased in the AD group.Conclusions:We demonstrated differences in the GM composition between the AD and CO groups, as well as between the AD and iNPH groups. To our knowledge, this is the first report to compare the 2 neurodegenerative diseases and demonstrate GM differences.
OBJECTIVE:To evaluate whether serum lipoprotein subclasses and related metabolites quantified by nuclear magnetic resonance (NMR) are associated with longitudinal tensor-based morphometry (TBM) atrophy in mild cognitive impairment (MCI). METHODS:Secondary analysis of ADNI-GO and ADNI-2 participants with a baseline diagnosis of MCI, baseline serum Nightingale NMR metabolomics, and at least 2 quality-controlled T1-weighted MRI examinations processed with the Mayo TBM-SyN pipeline. The TBM-SyN summary score was the mean annualized log-Jacobian volume change across 31 Alzheimer disease (AD)-vulnerable regions, derived from baseline-to-follow-up symmetric registration. Linear mixed-effects models adjusted for age and included subject-level random intercepts. Associations with the Clinical Dementia Rating (CDR) and the Alzheimer Disease Assessment Scale (ADAS) were tested. RESULTS:The analytic cohort included 93 participants (mean age: 65.23 y, SD: 6.47; 51 male, 54.8%). Eight biomarkers were significantly associated with TBM-SyN atrophy: medium HDL free cholesterol percentage (M_HDL_FC_PCT; β =-0.0020, P =0.0016), apolipoprotein B ( P =0.005), apolipoprotein A1 ( P =0.017), extra-large HDL particle concentration (XL_HDL_P; P =0.029), medium HDL particle concentration ( P =0.028), medium HDL cholesterol ( P =0.025), medium HDL cholesterol esters ( P =0.031), and glycerol ( P =0.038). XL_HDL_P alone was associated with the CDR score ( P =0.03). CONCLUSIONS:Specific HDL-related lipoprotein subclasses, apolipoproteins, and glycerol are associated with TBM-derived structural atrophy in MCI, supporting peripheral lipid metabolism as a candidate scalable correlate of early neurodegeneration.
INTRODUCTION:We investigated associations of impaired odor identification with signs of early Alzheimer disease (AD) and Lewy Body disease (LBD). METHODS:In 787 community-sampled adults aged ≥65 without dementia or Parkinson disease, we evaluated cross-sectional associations of olfaction (Brief Smell Identification Test, BSIT) with 5 cognitive domain scores, gait, tone, tremor, REM sleep behavior disorder (RBD) symptoms, and plasma biomarkers of neurodegeneration. RESULTS:In adjusted regression models, worse BSIT scores were associated with lower cognitive scores in all domains, slowed gait, resting tremor, and RBD-like symptoms. The association between BSIT and memory was stronger in APOE4 carriers. In cognitively unimpaired participants (Clinical Dementia Rating=0), most associations remained significant. BSIT scores were associated with plasma p-tau217 and NfL in exploratory analyses. CONCLUSION:Odor identification is associated with cognition in an undifferentiated pattern and with Parkinsonian signs in older adults, even among those with normal cognition. The stronger association in APOE4 carriers potentially suggests an emerging AD-like pathway, consistent with exploratory plasma biomarker analyses. In sum, evidence points to olfactory dysfunction as relevant for both AD and LBD-associated future risk.
OBJECTIVE:To investigate the association between cognitive changes and new friendship formation among older adults in a multidomain dementia prevention program. METHODS:A 1-year multidomain intervention was conducted for 34 community-dwelling older adults (18 females, 16 males, mean age 78.3 y, SD=4.3) meeting the operational criteria for mild cognitive impairment. Cognitive changes were evaluated using the Montreal Cognitive Assessment (MoCA-J). Participants reported new friendships based on social support functions (eg, emotional and instrumental support). A 2-way repeated-measures ANCOVA (time×group), adjusted for education, examined the main effects and interactions on the total MoCA-J and subscale scores. RESULTS:The total MoCA-J scores showed no significant main effects or interaction. However, subscale analysis revealed a significant main effect of time on visuospatial/executive function and a significant main effect of friend-presence group on orientation. Specifically, the friend-presence group consistently exhibited higher orientation scores than the absence group at both time points. CONCLUSION:Overall, cognitive function was maintained throughout the program. Exploratory findings suggest that visuospatial/executive functions showed potential improvement, and preserved orientation was associated with successful friendship formation. Thus, facilitating social connections alongside standard activities may enhance future dementia prevention programs.
BACKGROUND:Alzheimer disease and related dementias (ADRD) are more prevalent in Black and Hispanic older adults and are also more likely to be undetected and misdiagnosed. The purpose of this study was to engage with Black and Hispanic communities about interest in and support needed for memory screening. METHODS:Participants were recruited from established community partners of the South Texas Alzheimer's Disease Research Center to engagein a 90-minute listening session. The session was recorded with participants' permission, and a thematic analysis was conducted by 2 independent coders. RESULTS:Sixteen individuals (81% female, 88% Hispanic or Black) from various perspectives participated (eg, health care workers, persons with dementia, caregivers). Four core themes emerged: building trust, access and time barriers, community-specific literature, and representative messengers. Trust was noted to be foundational, encompassing who delivers the screening and where it takes place. Transportation, time burden, competing caregiving responsibilities, work schedules, and limited access to technology/internet were key barriers. The need to create accessible and relatable literature and videos tailored to diverse educational levels and cultural backgrounds was also emphasized. CONCLUSIONS:Trusted members of the community could be accepted to perform memory screenings and provide education. Partnering with faith-based organizations, senior centers, and other community hubs would help overcome barriers to screening.
INTRODUCTION:While extensive research has explored cognitive processing with pupillometry in the general population, limited attention has been given to its application in neurodegenerative diseases. This study, for the first time, investigates general cognitive processing using pupillometry in both Alzheimer disease (AD) and behavioral variant frontotemporal dementia (bvFTD). METHODS:Pupil diameter was monitored in patients with AD, patients with bvFTD, and control participants under 2 conditions. The first condition involved subtraction (ie, subtracting 9 from 100 and continuing to subtract to a total of 5 subtractions). The second control condition involved counting aloud from 1. RESULTS:Analysis demonstrated increased pupil diameters during subtraction than during counting in patients with bvFTD, patients with AD, and control participants. During both counting and subtraction, smaller pupil diameters were observed in patients with bvFTD compared with patients with AD and in patients with AD compared with control participants. CONCLUSIONS:These findings indicate that pupil size can effectively reflect the cognitive load intensity in patients with bvFTD and patients with AD, suggesting the potential of pupillometry as a differential indicator of cognitive processing in neurodegenerative diseases.
Mobile phones are increasingly being proposed as tools to support daily life among older adults with cognitive impairment; however, empirical data on their actual ownership and use in clinical settings remain limited. This study aimed to clarify mobile phone ownership and usage patterns among older adults with cognitive impairment attending memory clinics. Eighty-two older adults with cognitive impairment (mean age: 80.4 y; mean Mini-Mental State Examination score: 18.1 points) were included. Data were collected using caregiver-administered questionnaires and analyzed descriptively. Among the participants, 65 (79.3%) owned a mobile phone, with an almost equal distribution of smartphones (n=33) and featured phones (n=32). Fifteen phone owners did not use their devices. Reported use was largely limited to basic communication functions. These findings indicate limited mobile phone ownership and functional use among older adults with cognitive impairment and underscore the need to consider cognitive limitations when implementing mobile technologies.
Background:As the global population ages, the prevalence of major neurocognitive disorders (MND), particularly Alzheimer disease (AD), continues to rise. Mild Cognitive Impairment (MCI) is considered a prodromal stage of AD, yet differentiating MCI from early-stage AD remains a clinical challenge, especially regarding language impairments.Objective:This study aimed to examine the diagnostic utility of the Turkish adaptation of the Batterie d'& Eacute;valuation Cognitive du Langage (BECLA-Tr) and to determine its effectiveness as one of the first multidimensional language assessments standardized for Turkish speakers.Methods:Ninety participants (30 MCI, 30 AD, and 30 healthy controls) completed the BECLA-Tr in addition to general cognitive and language screening tests. The BECLA-Tr assesses 4 domains: recognition of spoken and written words, semantic processing, spoken production, and written language.Results:AD participants showed significant impairments across nearly all BECLA-Tr domains compared with both MCI and controls. MCI participants exhibited selective deficits in semantic processing while maintaining comparable performance to controls in spoken and written production.Conclusion:The BECLA-Tr demonstrated strong diagnostic sensitivity for detecting language impairments across the neurodegeneration continuum, supporting its clinical use for early detection and intervention in MCI and AD.
INTRODUCTION:Agitation is a common behavioral symptom in dementia that increases caregiver burden and contributes to hospitalization or institutionalization. Nonpharmacological interventions are essential to manage agitation; however, their effectiveness has been inconsistent. A potential explanation is that engagement-defined as patients' attitudes and behaviors during therapy-has rarely been incorporated into the evaluation of these interventions. This study aimed to clarify the association between engagement and agitation and to identify related clinical and environmental factors. METHODS:This cross-sectional study included 66 hospitalized individuals with dementia (mean age 81.4±6.9 y). Assessments comprised demographics, cognitive function, activities of daily living, behavioral and psychological symptoms, environmental parameters, comorbidities, pain, and engagement. Correlation and multiple regression analyses were conducted to explore factors associated with engagement. RESULTS:Engagement was positively correlated with cognitive function and daily living abilities, and negatively correlated with dementia severity, pain, agitation, depression, visual impairment, and humidity. Multiple regression analysis showed engagement was independently associated with pain, dementia severity, visual impairment, and agitation. CONCLUSIONS:Engagement in dementia was influenced by pain, dementia severity, visual impairment, and agitation. Attention to these factors, particularly pain management, may optimize nonpharmacological interventions, enhance engagement, and help reduce agitation in dementia.
