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MAGNETIC RESONANCE IMAGING-NEGATIVE CEREBRAL AMYLOID ANGIOPATHY: CEREBROSPINAL FLUID AMYLOID-Β42 OVER AMYLOID POSITRON EMISSION TOMOGRAPHY

J.-M. Pyun, M.J. Kang, S.J. Baek, K. Lee, Y.H. Park, S.Y. Kim, for the Alzheimer’s Disease Neuroimaging Initiative

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BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer’s disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer’s Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

CITATION:
J.-M. Pyun ; M.J. Kang ; S.J. Baek ; K. Lee ; Y.H. Park ; S.Y. Kim ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.49

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“BACK TO BRAAK”: ROLE OF NUCLEUS REUNIENS AND SUBCORTICAL PATHWAYS IN ALZHEIMER’S DISEASE PROGRESSION

S. Censi, C. Sestieri, M. Punzi, A. Delli Pizzi, A. Ferretti, F. Gambi, V. Tomassini, S. Delli Pizzi, S.L. Sensi, for the Alzheimer’s Disease Neuroimaging Initiative

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BACKGROUND: Patients with Alzheimer’s Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD. OBJECTIVES: To characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI). DESIGN: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum. SETTING: Prodromal and clinical stages of AD. PARTICIPANTS: We analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis. MEASUREMENTS: A multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach. RESULTS: AD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69. CONCLUSIONS: In line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.

CITATION:
S. Censi ; C. Sestieri ; M. Punzi ; A. Delli Pizzi ; A. Ferretti ; F. Gambi ; V. Tomassini ; S. Delli Pizzi ; S.L. Sensi ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): “Back to Braak”: Role of Nucleus Reuniens and Subcortical Pathways in Alzheimer’s Disease Progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.42

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ESTIMATED INVESTMENT NEED TO INCREASE ENGLAND’S CAPACITY TO DIAGNOSE ELIGIBILITY FOR AN ALZHEIMER’S TREATMENT TO G7 AVERAGE CAPACITY LEVELS

S. Mattke, Z. Shi, M. Hanson, S. Mitchell, C. Lynch, K. MacLean Kalonji, L. Lanman

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BACKGROUND: As disease-modifying Alzheimer’s (AD) treatments are becoming available, concerns have been raised that even high-income countries lack the diagnostic capacity to accurately identify eligible patients in a timely manner. OBJECTIVES: We analyze how much NHS England would have to invest in capacity for AD specialists, biomarker testing with PET scans or CSF testing and MRI scans to reach G7 average levels and estimate the effect on wait times in the diagnostic process. DESIGN: Desk research and expert interviews for cost and capacity data. Markov model to estimate wait times. SETTING: NHS England. MEASUREMENTS: AD specialists, and PET and MRI scanners per capita in G7 countries and wait times in England under different investment scenarios. RESULTS: England has the lowest number of PET and MRI scanners and the second-lowest of AD specialists per capita among the G7 countries. An investment of GBP 14 billion over ten years would be needed to reach G7 average levels, of which 31%, 22%, 10%, 37% would be devoted to capacity for memory assessment services, PET scanning, CSF analysis, and MRI scanning, respectively. This investment would reduce estimated average wait times by around 87% between 2023 and 2032. CONCLUSIONS: The NHS England has large gaps in diagnostic capacity for AD. Without substantial investments, AD patients in England would experience substantial wait times and avoidable disease progression.

CITATION:
S. Mattke ; Z. Shi ; M. Hanson ; S. Mitchell ; C. Lynch ; K. MacLean Kalonji ; L. Lanman ; (2024): Estimated Investment Need to Increase England’s Capacity to Diagnose Eligibility for an Alzheimer’s Treatment to G7 Average Capacity Levels. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.24

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JPAD Volume 11, N°03 - 2024

 

“TIME SAVED” CALCULATIONS TO IMPROVE DECISION-MAKING IN PROGRESSIVE DISEASE STUDIES

S.P. Dickson, B. Haaland, C.H. Mallinckrodt, B. Dubois, P. O’Keefe, M. Morgan, O. Peters, A. Fernández Santana III, J. Harrison, A. Schneeberger, S. Hendrix

J Prev Alz Dis 2024;3(11):529-536

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BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer’s disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study’s prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

CITATION:
S.P. Dickson ; B. Haaland ; C.H. Mallinckrodt ; B. Dubois ; P. O’Keefe ; M. Morgan ; O. Peters ; A. Fernández Santana III ; J. Harrison ; A. Schneeberger ; S. Hendrix (2024): “Time Saved” Calculations to Improve Decision-Making in Progressive Disease Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.64

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AT-HOME ADMINISTRATION OF GANTENERUMAB BY CARE PARTNERS TO PEOPLE WITH EARLY ALZHEIMER’S DISEASE: FEASIBILITY, SAFETY AND PHARMACODYNAMIC IMPACT

F.G. Boess, M.A. Scelsi, T. Grimmer, R.J. Perry, M. Tonietto, G. Klein, C. Hofmann, M. Salami, J. Wojtowicz, C.J. Lansdall, C. Lane, G.A. Kerchner, J. Smith, R.S. Doody, for the GRADUATION Investigators and the gantenerumab study group

J Prev Alz Dis 2024;3(11):537-548

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BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer’s disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes), development of gantenerumab in sporadic Alzheimer’s disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer’s disease (mild cognitive impairment/mild dementia due to Alzheimer’s disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6–15.8; n=149) and -35.48 centiloids (range: -63.2–-7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer’s disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer’s disease. Although gantenerumab’s development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer’s disease and their families.

CITATION:
F.G. Boess ; M.A. Scelsi ; T. Grimmer ; R.J. Perry ; M. Tonietto ; G. Klein ; C. Hofmann ; M. Salami ; J. Wojtowicz ; C.J. Lansdall ; C. Lane ; G.A. Kerchner ; J. Smith ; R.S. Doody ; for the GRADUATION Investigators and the gantenerumab study group ; (2024): At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer’s Disease: Feasibility, Safety and Pharmacodynamic Impact. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.60

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PHASE 2A LEARNINGS INCORPORATED INTO REWIND-LB, A PHASE 2B CLINICAL TRIAL OF NEFLAMAPIMOD IN DEMENTIA WITH LEWY BODIES

N.D. Prins, W. de Haan, A. Gardner, K. Blackburn, H.-M. Chu, J.E. Galvin, J.J. Alam

J Prev Alz Dis 2024;3(11):549-557

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BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer’s disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen’s d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

CITATION:
N.D. Prins ; W. de Haan ; A. Gardner ; K. Blackburn ; H.-M. Chu ; J.E. Galvin ; J.J. Alam (2024): Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.36

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DOMINANTLY INHERITED ALZHEIMER NETWORK TRIALS UNIT (DIAN-TU): TRIAL SATISFACTION AND ATTITUDES TOWARDS FUTURE CLINICAL TRIALS

H. Liu, J. Li, E. Ziegemeier, S. Adams, E. McDade, D.B. Clifford, Y. Cao, G. Wang, Y. Li, S.L. Mills, A.M. Santacruz, S. Belyew, J.D. Grill, B.J. Snider, C.J. Mummery, G. Surti, D. Hannequin, D. Wallon, S.B. Berman, I.Z. Jimenez-Velazquez, E.D. Roberson, C.H. van Dyck, L.S. Honig, R. Sanchez-Valle, W.S. Brooks, S. Gauthier, D. Galasko, C.L. Masters, J. Brosch, G.-Y.R. Hsiung, S. Jayadev, M. Formaglio, M. Masellis, R. Clarnette, J. Pariente, B. Dubois, F. Pasquier, R.J. Bateman, J.J. Llibre-Guerra, for the DIAN-TU Study Team

J Prev Alz Dis 2024;3(11):558-566

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BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants’ clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial’s demographic distribution. Participants’ decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

CITATION:
H. Liu ; J. Li ; E. Ziegemeier ; S. Adams ; E. McDade ; D.B. Clifford ; Y. Cao ; G. Wang ; Y. Li ; S.L. Mills ; A.M. Santacruz ; S. Belyew ; J.D. Grill ; B.J. Snider ; C.J. Mummery ; G. Surti ; D. Hannequin ; D. Wallon ; S.B. Berman ; I.Z. Jimenez-Velazquez ; E.D. Roberson ; C.H. van Dyck ; L.S. Honig ; R. Sanchez-Valle ; W.S. Brooks ; S. Gauthier ; D. Galasko ; C.L. Masters ; J. Brosch ; G.-Y.R. Hsiung ; S. Jayadev ; M. Formaglio ; M. Masellis ; R. Clarnette ; J. Pariente ; B. Dubois ; F. Pasquier ; R.J. Bateman ; J.J. Llibre-Guerra ; for the DIAN-TU Study Team (2024): Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.61

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MULTIOMICS BLOOD-BASED BIOMARKERS PREDICT ALZHEIMER’S PREDEMENTIA WITH HIGH SPECIFICITY IN A MULTICENTRIC COHORT STUDY

B. Souchet, A. Michaïl, M. Heuillet, A. Dupuy-Gayral, E. Haudebourg, C. Pech, A. Berthemy, F. Autelitano, B. Billoir, K. Domoto-Reilly, C. Fowler, T. Grabowski, S. Jayadev, C.L. Masters, J. Braudeau

J Prev Alz Dis 2024;3(11):567-581

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BACKGROUND: The primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically, those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently, there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription. OBJECTIVES: The objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity. DESIGN: Peripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study. SETTING: Participants from 7 retrospective cohorts (US, EU and Australia). PARTICIPANTS: This study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies. MEASUREMENTS: We developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats. METHODS: We analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy. RESULTS: Integrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model’s reliability on independent datasets. CONCLUSIONS: The B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.

CITATION:
B. Souchet ; A. Michaïl ; M. Heuillet ; A. Dupuy-Gayral ; E. Haudebourg ; C. Pech ; A. Berthemy ; F. Autelitano ; B. Billoir ; K. Domoto-Reilly ; C. Fowler ; T. Grabowski ; S. Jayadev ; C.L. Masters ; J. Braudeau (2024): Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.34

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CRITICAL VALUES OF DAILY SEDENTARY TIME AND ITS LONGITUDINAL ASSOCIATION WITH MILD COGNITIVE IMPAIRMENT CONSIDERING APOE Ε4: A PROSPECTIVE COHORT STUDY

H. Duan, X. He, T. Yang, N. Xu, Z. Wan, Z. Li, Y. Chen, Y. Du, M. Zhang, J. Yan, C. Sun, G. Wang, F. Ma, W. Li, X. Li, G. Huang

J Prev Alz Dis 2024;3(11):582-588

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BACKGROUND: Long sedentary time and physical inactivity are negatively related to cognition, but the cut-off value remains unclear, and apolipoprotein E polymorphism ε4 (APOE ε4) is a known genetic risk factor of mild cognitive impairment (MCI). OBJECTIVES: To explore longitudinal association of sedentary time and MCI, and to identify a cutoff value that increases the risk of developing MCI, taking into account APOE ε4 stratification and its interactions. DESIGN: A prospective cohort study. SETTING: Population-based study. PARTICIPANTS: We included 4932 older adults from Tianjin Elderly Nutrition and Cognition (TENC) cohort study recruited from March 2018 to June 2021 with 3.11 years of median follow-up time. MEASUREMENTS: The primary outcome was newly diagnosed MCI, which was diagnosed by a modified version of the Petersen’s criteria. The information of sedentary time (hours/day) and physical activity (MET-h/week) were obtained by questionnaire. Cox proportional hazard regression models and restricted spline curve were conducted. RESULTS: A total of 4932 participants were included (mean [SD] age, 67.85 [4.96] years; 2627 female [53.3%] and 2305 male [46.7%]), 740 newly onset MCI patients were identified. Longer sedentary time was associated with higher risk of MCI for all participants (HR:1.069, 95%CI: 1.034, 1.105), especially in APOE ε4 non-carriers (HR:1.083, 95%CI: 1.045, 1.123) whether adjusted potential confounders. Sedentary time had synergistic interactions with APOE ε4 (β:1.503, 95%CI: 1.163, 1.942) and physical activities (β: 1.495, 95%CI: 1.210, 1.846). Restricted spline curve showed a cut-off value of 3.03 hours/day. CONCLUSIONS: Long sedentary time (≥3.03 hours/day) could increase MCI risk, especially in APOE ε4 non-carriers, people with higher PA, aged 65 and above.

CITATION:
H. Duan ; X. He ; T. Yang ; N. Xu ; Z. Wang ; Z. Li ; Y. Chen ; Y. Du ; M. Zhang ; J. Yan ; C. Sun ; G. Wang ; F. Ma ; W. Li ; X. Li ; G. Huang (2024): Critical Values of Daily Sedentary Time and Its Longitudinal Association with Mild Cognitive Impairment Considering APOE ε4: A Prospective Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.44

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CHINA INITIATIVE FOR MULTI-DOMAIN INTERVENTION (CHINA-IN-MUDI) TO PREVENT COGNITIVE DECLINE: STUDY DESIGN AND PROGRESS

S.-Y. Li, X.-Y. Xie, D. Liu, G.-R. Cheng, F.-F. Hu, D.-Y. Zeng, X.-C. Chen, L.-F. Jia, Y.-J. Wang, X.-L. Bu, C. Qiu, F. Gao, J.-G. Gu, M.-F. Liu, Y. Li, Y.-L. Zhou, H.-J. Chang, Y.-M. Ou, L. Xu, Z.-X. Wu, J.-J. Zhang, J.-Y. Wang, L.-Y. Huang, Y.-Y. Cui, J. Zhou, X.-C. Liu, J. Liu, Q.-Q. Nie, D. Song, C. Cai, G.-B. Han, X. Yang, W. Tan, J.-T. Yu, Y. Zeng

J Prev Alz Dis 2024;3(11):589-600

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BACKGROUND: Alzheimer’s disease (AD), the most common type of irreversible dementia, is predicted to affect 152 million people by 2050. Evidence from large-scale preventive randomized controlled trials (RCTs) on modifiable risk variables in Europe has shown that multi-domain lifestyle treatments for older persons at high risk of dementia may be practical and effective. Given the substantial differences between the Chinese and European populations in terms of demographics and living conditions, direct adoption of the European program in China remains unfeasible. Although a RCT has been conducted in China previously, its participants were mainly from rural areas in northern China and, thus, are not representative of the entire nation.There is an urgent need to establish cohorts that represent different economic, cultural, and geographical situations in order to explore implementation strategies and evaluate the effects of early multi-domain interventions more comprehensively and accurately. MEDTODS: We developed an integrated intervention procedure implemented in urban neighborhood settings, namely China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI). CHINA-IN-MUDI is a 2-year multicenter open-label cluster-randomised controlled trial centered around a Chinese-style multi-domain intervention to prevent cognitive decline. Participants aged 60–80 years were recruited from a nationally representative study, i.e. China Healthy Aging and Dementia Study cohort. An external harmonization process was carried out to preserve the original FINGER design. Subsequently, we standardized a series of Chinese-style intervention programs to align with cultural and socioeconomic status. Additionally, we expanded the secondary outcome list to include genomic and proteomic analyses. To enhance adherence and facilitate implementation, we leveraged an e-health application. RESULTS: Screening commenced in July 2022. Currently, 1,965 participants have been randomized into lifestyle intervention (n = 772) and control groups (n = 1,193). Both the intervention and control groups exhibited similar baseline characteristics. Several lifestyle and vascular risk factors were present, indicating a potential window of opportunity for intervention. The intervention will be completed by 2025. CONCLUSIONS: This project will contribute to the evaluation of the effectiveness and safety of intervention strategies in controlling AD risk and reducing clinical events, providing a basis for public health decision-making in China.

CITATION:
S.-Y. Li ; X.-Y. Xie ; D. Liu ; G.-R. Cheng ; F.-F. Hu ; D.-Y. Zeng ; X.-C. Chen ; L.-F. Jia ; Y.-J. Wang ; X.-L. Bu ; C. Qiu ; F. Gao ; J.-G. Gu ; M.-F. Liu ; Y. Li ; Y.-L. Zhou ; H.-J. Chang ; Y.-M. Ou ; L. Xu ; Z.-X. Wu ; J.-J. Zhang ; J.-Y. Wang ; L.-Y. Huang ; Y.-Y. Cui ; J. Zhou ; X.-C. Liu ; J. Liu ; Q.-Q. Nie ; D. Song ; C. Cai ; G.-B. Han ; X. Yang ; W. Tan ; J.-T. Yu ; Y. Zeng ; (2024): China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI) to Prevent Cognitive Decline: Study Design and Progress. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.63

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THE MULTI-DOMAIN LIFESTYLE INTERVENTION FOR COGNITIVE IMPAIRMENT IN COMMUNITY-DWELLING OLDER ADULTS IN HANGZHOU (THE HERITAGE STUDY): STUDY DESIGN AND PROTOCOL

X. Xu, T. Pang, Y. Zhou, H. Zhang, A. Ma, C. Yuan, H. Chen, X. Wen, Q. Yang, X. Xu

J Prev Alz Dis 2024;3(11):601-611

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BACKGROUND: The globe has been working to promote a multi-domain lifestyle intervention for dementia prevention in older adults, referring to the Worldwide-FINGERS (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) initiative. In China, the multi-domain lifestyle intervention has been implemented in rural communities (MIND-China), yet the adaptability of such intervention based on the urban communities in China has not been verified. OBJECTIVE: To examine the effectiveness and feasibility of the multi-domain lifestyle intervention on dementia prevention in at-risk community-dwelling older adults in China. DESIGN, SETTING, PARTICIPANTS: The multi-domain lifestyle intervention study is a community-based 2-year cluster randomized controlled trial (RCT). A total of 1200 participants aged 60-80 years old will be recruited from twelve communities in Hangzhou, Zhejiang. Inclusion criteria were the Montreal Cognitive Assessment 5 minutes protocol (5 min MoCA) score of 6-9 or the Ascertain Dementia 8 (AD 8) score of ≥2, and having modifiable lifestyle factors. INTERVENTION, MEASUREMENTS, RESULTS: Participating communities will be randomized into either the structured multi-domain intervention (SMI) arm or the self-guided intervention (SGI, general health education) arm. The SMI consists of cognitive training, physical exercise, and nutritional and dietary instruction for the first 12 months; and vascular risks monitoring and control for 24 months. The primary outcome is the global cognitive performance, measured by the comprehensive Neuropsychological Test Battery (NTB). The secondary outcomes include domain-specific cognitive performances, physical function, mental health, physiological and biochemical indices, adherence to healthy lifestyles, and neuroimaging metrics. The feasibility of intervention will be evaluated around the five dimensions of the RE-AIM framework and in conjunction with quantitative data, operational data and results of focus group discussions. CONCLUSIONS: Following the Worldwide-FINGERS, this cluster RCT will verify the adaptability of the multi-domain lifestyle intervention in the urban community settings in China. This study will add evidence for global dementia prevention and management among older adults.

CITATION:
X. Xu ; T. Pang ; Y. Zhou ; H. Zhang ; A. Ma ; C. Yuan ; H. Chen ; X. Wen ; Q. Yang ; X. Xu (2024): The Multi-domain Lifestyle Intervention for Cognitive Impairment in Community-Dwelling Older Adults in Hangzhou (The Heritage Study): Study Design and Protocol. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.59

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SUSTAINABLE PARTICIPATION IN COMMUNITY HEALTH PROGRAMS TO PROMOTE A HEALTHY LIFESTYLE AND PREVENT AND PROTECT AGAINST DEMENTIA AMONG RURAL TAIWANESE MIDDLE-AGED AND OLDER ADULTS

L. Chang, S.-C. Chen, P.-Y. Lin, M.-C. Chen, L.-L. Liao, H.-P. Lin, Y.-Y. Tsao, M.-C. Chen

J Prev Alz Dis 2024;3(11):612-619

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BACKGROUND: Resource and economic constraints limit access to health care in rural populations, and consequently, rates of chronic illnesses are higher in this population. Further, little is known about how rural populations adopt active and healthy lifestyle behavior for dementia prevention. OBJECTIVES: This study aimed to explore the impact of modification in lifestyle behaviors on changes in cognitive function among middle-aged and older adults living in a rural area of Taiwan. DESIGN: In this prospective longitudinal study, changes in lifestyle and cognitive function were compared between the experimental and control groups. SETTING: Six rural community care stations were randomly cluster sampled in southern Taiwan. PARTICIPANTS: A total of 155 participants were enrolled and classified into two groups according to their community activity participation rate (CAPR). The control group (n=68) had a CAPR < 1x/month, and the experimental group (n=87) had a CAPR > 1x/month. MEASUREMENTS: Cognitive function of the participants was measured using the MMSE scale. Lifestyle behaviors were measured using a self-designed questionnaire based on the Transtheoretical Model. RESULTS: From 2018-2020, the experimental group successfully maintained a healthy lifestyle. The MMSE score in the experimental group was significantly higher in the 3rd year than that in the control group (25.37 vs 22.56, p < 0.001). CONCLUSIONS: Sustainable community participation and adopting a healthy lifestyle could effectively maintain the cognitive function of the study participants. However, more needs to be done to support rural older adults to maintain a healthy diet and control their weight.

CITATION:
L. Chang ; S.-C. Chen ; P.-Y. Lin ; M.-C. Chen ; L.-L. Liao ; H.-P. Lin ; Y.-Y. Tsao ; M.-C. Chen (2024): Sustainable Participation in Community Health Programs to Promote a Healthy Lifestyle and Prevent and Protect against Dementia among Rural Taiwanese Middle-Aged and Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.45

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THE EFFECTS OF DIFFERENT EXERCISE INTERVENTIONS ON PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

R. Chen, B. Zhao, J. Huang, M. Zhang, Y. Wang, J. Fu, H. Liang, H. Zhan

J Prev Alz Dis 2024;3(11):620-631

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BACKGROUND AND OBJECTIVE: Exercise is a promising non-pharmacological therapy for subjective cognitive decline, but it is unclear which type of exercise is most effective. The objective was to assess the comparative effects and ranks of all exercise-based interventions on cognitive function in patients with subjective cognitive decline (SCD). METHOD: In this network meta-analysis, Online databases for Web of Science, PubMed, Embase, Medline, Cochrane Library and PsycINFO were searched from inception to April 30, 2023. The included studies are randomized controlled trials assessing the efficacy of exercise interventions for individuals with SCD. The primary outcome measure is memory, while secondary outcome measures encompass executive function, attention, verbal fluency, and global cognitive function. Represented using Standardized Mean Differences (SMDs) along with their 95% Confidence Intervals (CIs). Bias assessment was conducted in accordance with the ‘Cochrane Risk of Bias Assessment Tool, 2nd Edition’ (RoB 2). Pairwise meta-analysis was carried out using the ‘meta-analysis’ module within STATA 14.0, and network meta-analysis was performed using the ‘mvmeta’ and ‘network’ packages available in STATA 14.0. Registration number CRD42023289687. RESULT: This study included a total of 11 randomized controlled trials, encompassing 1,166 patients. Mind-body exercise was found to be efficacious in enhancing or sustaining memory (SMD: 0.58, 95%CI: 0.06 ~ 1.10) and executive function (SMD: 0.41, 95%CI: 0.09 ~ 0.73) in individuals with subjective cognitive decline. Furthermore, mind-body exercise exhibited the highest probability of being the most effective measures for improving or preventing the decline in memory (surface under cumulative ranking curve (SUCRA) value: 90.4) and executive function (SUCRA value: 91.8). The second-ranked moderate-intensity aerobic exercise has also shown a positive effect on the improvement of executive function in patients with subjective cognitive decline (SMD: 0.23, 95%CI: 0.03 ~ 0.43, SUCRA value: 68.2). However, we did not observe a significant effectiveness of exercise interventions on verbal fluency, attention, and overall cognitive function in subjective cognitive decline. CONCLUSION: Mind-body exercise may potentially be the optimal strategies for enhancing memory and executive function in individuals with subjective cognitive decline. Additionally, moderate-intensity aerobic exercise has shown a modest positive effect on executive function in subjective cognitive decline. When resources permit, practical application of these findings may be considered. Nevertheless, further support for the conclusions of this study is warranted through larger sample sizes and well-designed multicenter trials.

CITATION:
R. Chen ; B. Zhao ; J. Huang ; M. Zhang ; Y. Wang ; J. Fu ; H. Liang ; H. Zhan (2024): The Effects of Different Exercise Interventions on Patients with Subjective Cognitive Decline: A Systematic Review and Network Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.65

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FISH AND SHELLFISH CONSUMPTION, COGNITIVE HEALTH AND MORTALITY FROM ALZHEIMER’S DISEASE AMONG US ADULTS AGED 60 AND OLDER

H. Sun

J Prev Alz Dis 2024;3(11):632-638

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BACKGROUND: Relationships of fish-shellfish consumption, cognitive health and mortality from Alzheimer’s disease (AD) among US adults aged 60 years and older have not been adequately studied. OBJECTIVES: To determine the relationship of fish-shellfish consumption, cognitive health and mortality from AD in US adults aged 60 years and older. DESIGN, SETTING AND PARTICIPANTS: The data of this cross-sectional study of US adults aged 60 years and older were from the National Nutrition and Health Examination Survey (NHANES) datasets. Frequency of fish-shellfish consumption, its association with subjective cognitive decline (SCD) and AD mortality of these participants between 1999 and 2018 and cognitive assessment scores between 2011 and 2014 were analyzed. MEASUREMENTS AND RESULTS: US adults aged 60 years and older consumed fish-shellfish 1.2 times/week and had a blood Hg of 1.63 ug/L on average between 1999 and 2018. Participants aged 60 years and older in the highest quartile of fish-shellfish consumption (~3 times/week) had significantly higher cognitive assessment scores than those in the lowest quartile (rare or no fish-shellfish consumption). Adults in the highest quartile of fish-shellfish consumption had a 30% lower risk (odds ratio 0.7, 95%CI 0.57-0.87) of SCD, and 44% lower risk (hazard ratio 0.56, 95%CI 0.35-0.9) of AD mortality than those in the lowest quartile. CONCLUSION: Increased fish-shellfish consumption was associated with improved scores of cognitive assessment and reduced risks of SCD and AD mortality.

CITATION:
H. Sun (2024): Fish and Shellfish Consumption, Cognitive Health and Mortality from Alzheimer’s Disease among US Adults Aged 60 and Older. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.57

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WHO BENEFITED MOST FROM THE INTERNET-BASED CONVERSATIONAL ENGAGEMENT RCT (I-CONECT)? APPLICATION OF THE PERSONALIZED MEDICINE APPROACH TO A BEHAVIORAL INTERVENTION STUDY

C.-Y. Wu, K. Yu, S.E. Arnold, S. Das, H.H. Dodge

J Prev Alz Dis 2024;3(11):639-648

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BACKGROUND: Many Alzheimer’s Disease (AD) clinical trials have failed to demonstrate treatment efficacy on cognition. It is conceivable that a complex disease like AD may not have the same treatment effect due to many heterogeneities of disease processes and individual traits. OBJECTIVES: We employed an individual-level treatment response (ITR) approach to determine the characteristics of treatment responders and estimated time saved in cognitive decline using the Internet-based Conversational Engagement Clinical Trial (I-CONECT) behavioral intervention study as a model. DESIGN AND SETTING: I-CONECT is a multi-site, single-blind, randomized controlled trial aimed to improve cognitive functions through frequent conversational interactions via internet/webcam. The experimental group engaged in video chats with study staff 4 times/week for 6 months; the control group received weekly 10-minute check-in phone calls. PARTICIPANTS: Out of 186 randomized participants, current study used 139 participants with complete information on both baseline and 6-month follow-up (73 with mild cognitive impairment (MCI), 66 with normal cognition; 64 in the experimental group, and 75 in the control group). MEASUREMENTS: ITR scores were generated for the Montreal Cognitive Assessment (MoCA) (global cognition, primary outcome) and Category Fluency Animals (CFA) (semantic fluency, secondary outcome) that showed significant efficacy in the trial. ITR scores were generated through 300 iterations of 3-fold cross-validated random forest models. The average treatment difference (ATD) curve and the area between the curves (ABC) were estimated to measure the heterogeneity of treatment responses. Responder traits were identified using SHapley Additive exPlanations (SHAP) and decision tree models. The time saved in cognitive decline was explored to gauge clinical meaningfulness. RESULTS: ABC statistics showed substantial heterogeneity in treatment response with MoCA but modest heterogeneity in treatment response with CFA. Age, cognitive status, time spent with family and friends, education, and personality were important characteristics that influenced treatment responses. Intervention group participants in the upper 30% of ITR scores demonstrated potential delays of 3 months in semantic fluency (CFA) and 6 months in global cognition (MoCA), assuming a 5-fold faster natural cognitive decline compared to the control group during the post-treatment period. CONCLUSIONS: ITR-based analyses are valuable in profiling treatment responders for features that can inform future trial design and clinical practice. Reliably measuring time saved in cognitive decline is an area of ongoing research to gain insight into the clinical meaningfulness of treatment.

CITATION:
C.-Y. Wu ; K. Yu ; S.E. Arnold ; S. Das ; H.H. Dodge (2024): Who Benefited Most from the Internet-Based Conversational Engagement RCT (I-CONECT)? Application of the Personalized Medicine Approach to a Behavioral Intervention Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.41

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ASSOCIATIONS AND POTENTIAL MULTIPLE MECHANISMS BETWEEN SUBJECTIVE HEARING LOSS AND COGNITIVE IMPAIRMENT

L. Cui, Y.-Y. Tu, Z. Zhang, Y.-H. Guo, Y.-H. Guan, F. Xie, Q.-H. Guo

J Prev Alz Dis 2024;3(11):649-660

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BACKGROUND: Subjective hearing loss (SHL) refers to an individual’s self-assessment of their hearing loss. The association and underlying mechanisms between SHL and cognitive impairment still necessitate elucidation. OBJECTIVES: To validate potential mechanisms between SHL and cognitive impairment. DESIGN: Cross-section. SETTING: Shanghai, China. PARTICIPANTS: A total of 2369 individuals from communities and the cognitive disorder clinic. MEASUREMENTS: All participants were subjected to a comprehensive neuropsychological assessment, encompassing the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S). The participants’ brain β-amyloid (Aβ) deposition status, plasma biomarkers associated with Alzheimer’s disease (AD), and cardiovascular risk factors were also collected. RESULTS: In individuals with a heightened SHL, elevated HHIE-S score was linked to diminished cognitive and daily functioning as well as heightened levels of depressed mood. This correlation was observed in auditory memory performance but not in visual memory. The influence of SHL on cognitive function was mediated by depressed mood. SHL was associated with diabetes and smoking, whereas cognitive function was associated with hyperlipidemia and alcohol consumption. In individuals with positive brain Aβ deposition, SHL demonstrated associations with cognitive function independent of plasma Aβ42/40 ratio, P-tau181, neurofilament light chain, and APOE allele status. CONCLUSION: SHL has an independent effect on cognitive impairment. The findings do no provide evidence for the common cause mechanism. Instead, the findings support the presence of a cognitive resource mechanism and an impoverished environment mechanism, along with the potential for a pathological interaction mechanism.

CITATION:
L. Cui ; Y.-Y. Tu ; Z. Zhang ; Y.-H. Guo ; Y.-H. Guan ; F. Xie ; Q.-H. Guo (2024): Associations and Potential Multiple Mechanisms between Subjective Hearing Loss and Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.62

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USABILITY OF A WEB-BASED REGISTRY FOR PRECLINICAL ALZHEIMER’S DISEASE: IMPLICATIONS FROM A CROSSSECTIONAL ONLINE SURVEY

K. Sato, Y. Niimi, R. Ihara, K. Suzuki, A. Iwata, T. Iwatsubo

J Prev Alz Dis 2024;3(11):661-671

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BACKGROUND: We have been conducting a Japanese trial-ready cohort web study since 2019 as a web-based online registry to enroll individuals with preclinical Alzheimer’s disease to facilitate trials on Alzheimer’s disease prevention. The usability of a website might be an important factor in determining user participation and retention. OBJECTIVES: We conducted a user questionnaire survey to analyze the usability of the Japanese trial-ready cohort website and user characteristics for future website improvement. DESIGN: This was a cross-sectional prospective observational study. SETTING: Online survey using Google Forms. PARTICIPANTS: Among the Japanese trial-ready cohort web study participants, we enrolled those who provided consent to participate in the study and had completed one or more Cognitive Function Instrument tests before May 2, 2023. We sent an invitation e-mail, including the questionnaire web address, to eligible participants on July 21 and 22, 2023. MEASUREMENTS: We analyzed the questionnaire answers, including the system usability scale score and time of response (in 24 h). We also compared the respondents’ characteristics with that of all the Japanese trial-ready cohort web study participants to identify features associated with an increased/decreased response rate to the questionnaire. RESULTS: Among the 10,112 Japanese trial-ready cohort web study participants that we sent invitation e-mails, we received 1,574 eligible responses (15.6%) within three weeks of the response acceptance period. The mean system usability scale score was 67.6, and no difference in system usability scale scores was observed in terms of age or sex. Approximately half of the respondents of the Japanese trial-ready cohort web study heard about it online, whereas one-fourth heard about it via newspapers. Contribution to drug development for dementia treatment was the most frequent motivation for participating in the Japanese trial-ready cohort web study (51.5%), followed by participation in the latest research (48.1%), concerns about self-memory (43.4%), and a family history of dementia (34.6%). Female respondents responded approximately 1.5 h later than male respondents. Lastly, those who had participated in the Japanese trial-ready cohort onsite study, were in their 70’s, or had a larger number of Cognitive Function Instrument or Cogstate tests completion history were more likely to respond to the current online survey (relative risk of response > 1). CONCLUSIONS: We conducted an online survey using Google Forms for participants in the Japanese trial-ready cohort web study to determine the usability. The results of this study might help to improve the user experience of the Japanese trial-ready cohort website itself, increase the web study registrants, maintain user retention, facilitate future online surveys, and serve as a reference for other web-based registries of presymptomatic disease status.

CITATION:
K. Sato ; Y. Niimi ; R. Ihara ; K. Suzuki ; A. Iwata ; T. Iwatsubo ; (2024): Usability of a Web-Based Registry for Preclinical Alzheimer’s Disease: Implications from a Cross-Sectional Online Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.48

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ANTI-HYPERTENSIVE DRUGS MODERATE THE RELATIONSHIP OF BLOOD PRESSURE WITH ALZHEIMER’S PATHOLOGIES AND NEURODEGENERATIVE MARKERS IN NON-DEMENTED HYPERTENSIVE OLDER ADULTS

Y. Guo, C.-C. Tan, M.-S. Tan, L. Tan, W. Xu, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2024;3(11):672-683

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BACKGROUND: We aimed to explore whether the relationships of blood pressures (BPs) with Alzheimer’s disease (AD) endophenotypes varied by usage of antihypertensive drugs (AHDs). METHODS: A total of 765 non-demented older adults (mean age: 74.4 years; female: 43.1%) with a self-reported history of hypertension were followed for 6 years. Multiple linear regression and linear-mixed effect models were used to investigate the interaction effects of five categories of AHDs (angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARBs], β-blocker, calcium channel blockers [CCB], diuretic) with BPs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) on AD core pathology and neurodegenerative markers. RESULTS: After Bonferroni correction, significant interaction effects of BPs with AHDs were observed. Elevated SBP or PP in late-life was associated with higher levels of cerebral Aβ burden (diuretic alone/β-blocker × SBP), higher levels of CSF tau proteins (diuretic × SBP/PP, ARBs/CCB × SBP), and lower volume of entorhinal region (β-blocker × SBP, diuretic × PP) only among hypertensive patients who received no anti-hypertensive treatments, while these associations became compromised or null for users of specific AHDs except for ACEI. Compared to taking other classes of AHDs, elevated SBP in late-life was associated with lower cerebral Aβ burden in diuretic users (padjusted = 0.08) and was associated with higher CSF tau proteins in ACEI alone users (padjusted = 0.03). Longitudinal data validated the above-mentioned interaction effects on changes of cerebral Aβ burden (padjusted < 0.05), CSF tau proteins (padjusted < 0.10), and brain atrophy (padjusted < 0.05). CONCLUSIONS: The relationships of late-life BP with AD pathology and neurodegeneration could be modified by anti-hypertensive treatments and varied by AHD classification. These findings provide preliminary evidence for tailored BP management strategy for preventing AD among late-life hypertensive adults.

CITATION:
Y. Guo ; C.-C. Tan ; M.-S. Tan ; L. Tan ; W. Xu ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): Anti-Hypertensive Drugs Moderate the Relationship of Blood Pressure with Alzheimer’s Pathologies and Neurodegenerative Markers in Non-Demented Hypertensive Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.40

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24-HOUR BLOOD PRESSURE VARIABILITY VIA AMBULATORY MONITORING AND RISK FOR PROBABLE DEMENTIA IN THE SPRINT TRIAL

I.J. Sible, D.A. Nation

J Prev Alz Dis 2024;3(11):684-692

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Background: Blood pressure variability is an emerging risk factor for dementia, independent and oftentimes beyond mean blood pressure levels. Recent evidence from interventional cohorts with rigorously controlled mean blood pressure levels suggest blood pressure variability over months to years remains a risk for dementia, but no prior studies have investigated relationships with blood pressure variability over shorter time periods. OBJECTIVES: To investigate the potential effect of ambulatory blood pressure variability on the rate of cognitive outcomes under intensive vs standard blood pressure lowering. DESIGN: Post hoc analysis of the randomized, controlled, open-label Systolic Blood Pressure Intervention Trial clinical trial. SETTING: Multisite Systolic Blood Pressure Intervention Trial. PARTICIPANTS: 793 participants at increased risk for cardiovascular disease and without history of dementia at study randomization. INTERVENTION: Standard (<140 mmHg systolic blood pressure target) vs intensive (<120 mmHg systolic blood pressure target) lowering of mean blood pressure. MEASUREMENTS: 24-hour ambulatory blood pressure monitoring 27 months after treatment randomization (standard vs intensive) and follow-up cognitive testing. Intraindividual blood pressure variability was calculated as the average real variability over 24-hour, daytime, and nighttime periods. Participants were categorized into 3 adjudicated clinical outcomes: no cognitive impairment, mild cognitive impairment, probable dementia. Cox proportional hazards models examined the potential effect of ambulatory blood pressure variability on the rate of cognitive outcomes under intensive vs standard blood pressure lowering. Associations with mean blood pressure were also explored. RESULTS: Higher systolic 24-hour blood pressure variability was associated with increased risk for probable dementia in the standard group (adjusted hazard ratio [HR]: 2.56 [95% CI 1.16, 5.62], p = 0.019) but not in the intensive group (HR: 0.54 [95% CI 0.24, 1.23], p = 0.141). Similar findings were observed with daytime systolic blood pressure variability but not nighttime blood pressure variability. Mean blood pressure was not associated with cognitive outcomes. CONCLUSIONS: Higher systolic 24-hour and daytime blood pressure variability via ambulatory monitoring is associated with risk for dementia under standard blood pressure treatment. Findings support prior evidence that blood pressure variability remains a risk for dementia despite strict control of mean blood pressure levels.

CITATION:
I.J. Sible ; D.A. Nation (2024): 24-Hour Blood Pressure Variability Via Ambulatory Monitoring and Risk for Probable Dementia in the SPRINT Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.35

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COGNITIVE TRAINING WITH OLDER ADULTS USING SMARTPHONE AND WEB-BASED APPLICATIONS: A SCOPING REVIEW

A.F. Silva, R.M. Silva, E. Murawska-Cia?owicz, G. Zurek, N. Danek, M. Cialowicz, J. Carvalho, F.M. Clemente

J Prev Alz Dis 2024;3(11):693-700

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INTRODUCTION: The present scoping review focused on: i) which apps were previously studied; ii) what is the most common frequency for implementing cognitive training; and iii) what cognitive functions the interventions most focus on. METHODS: PRISMA guidelines were followed, and the search was conducted on Web of Science, PsycInfo, Cochrane, and Pubmed. From 1733 studies found, 34 were included. RESULTS: it was highlighted the necessity for forthcoming investigations to tackle the methodical restrictions and disparities in the domain. DISCUSSION: great diversity in intervention protocols was found. Incorporating evaluations of physical fitness in conjunction with cognitive evaluations can offer a more all-encompassing comprehension of the impacts of combined interventions. Furthermore, exploring the efficacy of cognitive training applications requires additional scrutiny, considering individual variances and practical outcomes in real-life settings.

CITATION:
A.F. Silva ; R.M. Silva ; E. Murawska-Ciałowicz ; G. Zurek ; N. Danek ; M. Cialowicz ; J. Carvalho ; F.M. Clemente (2024): Cognitive Training with Older Adults Using Smartphone and Web-Based Applications: A Scoping Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.17

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POLYGENIC RISK SCORE REVEALS GENETIC HETEROGENEITY OF ALZHEIMER’S DISEASE BETWEEN THE CHINESE AND EUROPEAN POPULATIONS

F. Li, S. Xie, J. Cui, Y. Li, T. Li, Y. Wang, J. Jia

J Prev Alz Dis 2024;3(11):701-709

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BACKGROUND: The polygenic risk score (PRS) aggregates the effects of numerous genetic variants associated with a condition across the human genome and may help to predict late-onset Alzheimer’s disease (LOAD). Most of the current PRS studies on Alzheimer’s disease (AD) have been conducted in Caucasian ancestry populations, while it is less studied in Chinese. OBJECTIVE: To establish and examine the validity of Chinese PRS, and explore its racial heterogeneity. DESIGN: We constructed a PRS using both discovery (N = 2012) and independent validation samples (N = 1008) from Chinese population. The associations between PRS and age at onset of LOAD or cerebrospinal fluid (CSF) biomarkers were assessed. We also replicated the PRS in an independent replication cohort with CSF data and constructed an alternative PRS using European weights. SETTING: Multi-center genetics study. PARTICIPANTS: A total of 3020 subjects were included in the study. MEASUREMENTS: PRS was calculated using genome-wide association studies data and evaluated the performance alone (PRSnoAPOE) and with other predictors (full model: LOAD ~ PRSnoAPOE + APOE+ sex + age) by measuring the area under the receiver operating curve (AUC). RESULTS: PRS of the full model achieved the highest AUC of 84.0% (95% CI = 81.4-86.5) with pT< 0.5, compared with the model containing APOE alone (61.0%). The AUC of PRS with pT< 5e-8 was 77.8% in the PRSnoAPOE model, 81.5% in the full model, and only ranged from 67.5% to 75.1% in the PRS with the European weights model. A higher PRS was significantly associated with an earlier age at onset (P <0.001). The PRS also performed well in the replication cohort of the full model (AUC=83.1%, 95% CI = 74.3-92.0). The CSF biomarkers of Aβ42 and the ratio of Aβ42/Aβ40 were significantly inversely associated with the PRS, while p-Tau181 showed a positive association. CONCLUSIONS: This finding suggests that PRS reveal genetic heterogeneity and higher prediction accuracy of the PRS for AD can be achieved using a base dataset and validation within the same ethnicity. The effective PRS model has the clinical potential to predict individuals at risk of developing LOAD at a given age and with abnormal levels of CSF biomarkers in the Chinese population.

CITATION:
F. Li ; S. Xie ; J. Cui ; Y. Li ; T. Li ; Y. Wang ; J. Jia (2024): Polygenic Risk Score Reveals Genetic Heterogeneity of Alzheimer’s Disease between the Chinese and European Populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.29

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LONGITUDINAL IMPACTS OF PRECISION GREENNESS ON ALZHEIMER’S DISEASE

S.C. Brown, W.W. Aitken, J. Lombard, A. Parrish, J.R. Dewald, R. Ma, S. Messinger, S. Liu, M.I. Nardi, T. Rundek, J. Szapocznik

J Prev Alz Dis 2024;3(11):710-720

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BACKGROUND: The potential for greenness as a novel protective factor for Alzheimer’s disease (AD) requires further exploration. OBJECTIVES: This study assesses prospectively and longitudinally the association between precision greenness - greenness measured at the micro-environmental level, defined as the Census block - and AD incidence. DESIGN: Older adults living in consistently high greenness Census blocks across 2011 and 2016 were compared to those living in consistently low greenness blocks on AD incidence during 2012-2016. SETTING: Miami-Dade County, Florida, USA. PARTICIPANTS: 230,738 U.S. Medicare beneficiaries. MEASUREMENTS: U.S. Centers for Medicare and Medicaid Services Chronic Condition Algorithm for AD based on ICD-9 codes, Normalized Difference Vegetation Index, age, sex, race/ethnicity, neighborhood income, and walkability. RESULTS: Older adults living in the consistently high greenness tertile, compared to those in the consistently low greenness tertile, had 16% lower odds of AD incidence (OR=0.84, 95% CI: 0.76-0.94, p=0.0014), adjusting for age, sex, race/ethnicity, and neighborhood income. Age, neighborhood income and walkability moderated greenness’ relationship to odds of AD incidence, such that younger ages (65-74), lower-income, and non-car dependent neighborhoods may benefit most from high greenness. CONCLUSIONS: High greenness, compared to low greenness, is associated with lower 5-year AD incidence. Residents who are younger and/or who reside in lower-income, walkable neighborhoods may benefit the most from high greenness. These findings suggest that consistently high greenness at the Census block-level, may be associated with reduced odds of AD incidence at a population level.

CITATION:
S.C. Brown ; W.W. Aitken ; J. Lombard ; A. Parrish ; J.R. Dewald ; R. Ma ; S. Messinger ; S. Liu ; M.I. Nardi ; T. Rundek ; J. Szapocznik (2024): Longitudinal Impacts of Precision Greenness on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.38

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ASSOCIATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS WITH RISK OF ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

S.S. Zakariaee, N. Naderi, E. Azizi

J Prev Alz Dis 2024;3(11):721-729

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BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss. Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the association of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease was investigated using systematic review and meta-analysis. METHODS: A systematic literature search was carried out using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. The meta-analysis was performed using the random-effects model and only case-control publications describing VEGF concentrations in Alzheimer’s patients were considered for calculating the pooled effect size. RESULTS: In the systematic literature search, 6 and 13 studies met the inclusion criteria to evaluate CSF and serum VEGF concentrations of Alzheimer’s patients, respectively. This meta-analysis retrieved a total number of 2380 Alzheimer’s patients and 5368 healthy controls. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer’s patients were -0.13 (95%CI,-0.42–0.16) and 0.23 (95%CI,-0.27–0.73), respectively. Results of meta-regression analysis showed that the quality scores of papers and female sex ratios of participants did not affect the associations of VEGF concentrations with the risk of Alzheimer’s disease. However, the age average of patients significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer’s disease (P=0.051). There was a statistically significant subgroup effect for the disease severity of Alzheimer’s patients which modifies the associations of serum VEGF concentrations with the risk of Alzheimer’s disease (P<0.01) and subgroup analysis shows that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease (P<0.01). CONCLUSION: The results show that the serum VEGF concentrations increased for Alzheimer’s patients in accordance with the increased expression of VEGF and the VEGF levels of Alzheimer’s patients decreased by increasing their disease severities. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.

CITATION:
S.S. Zakariaee ; N. Naderi ; E. Azizi (2024): Association of Vascular Endothelial Growth Factor Levels with Risk of Alzheimer’s Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.18

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SERUM TAU-A AND TAU-C LEVELS AND THEIR ASSOCIATION WITH COGNITIVE IMPAIRMENT AND DEMENTIA PROGRESSION IN A MEMORY CLINIC DERIVED COHORT

T.M. Axelsen, P. Høgh, A.R. Bihlet, M.A. Karsdal, K. Henriksen, S.G. Hasselbalch, A.H. Simonsen

J Prev Alz Dis 2024;3(11):730-738

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BACKGROUND: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia. OBJECTIVES: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD– β-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia. DESIGN: Cross-sectional and a substudy using a retrospective cohort design. SETTING: Memory clinic derived subjects contributing to the Danish Dementia Biobank. PARTICIPANTS: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer’s dementia (n=52). MEASUREMENTS: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C. RESULTS: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 – 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 – 7.05) when compared to those in the lowest quartile. CONCLUSIONS: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation.

CITATION:
T.M. Axelsen ; P. Høgh ; A.R. Bihlet ; M.A. Karsdal ; K. Henriksen ; S.G. Hasselbalch ; A.H. Simonsen (2024): Serum Tau-A and Tau-C Levels and Their Association with Cognitive Impairment and Dementia Progression in a Memory Clinic Derived Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.43

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ASSOCIATION OF COGNITIVE RESERVE INDICATOR WITH COGNITIVE DECLINE AND STRUCTURAL BRAIN DIFFERENCES IN MIDDLE AND OLDER AGE: FINDINGS FROM THE UK BIOBANK

W. Yang, J. Wang, J. Guo, A. Dove, X. Qi, D.A. Bennett, W. Xu

J Prev Alz Dis 2024;3(11):739-748

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BACKGROUND: Cognitive reserve (CR) contributes to preserving cognition when facing brain aging and damage. CR has been linked to dementia risk in late life. However, the association between CR and cognitive changes and brain imaging measures, especially in midlife, is unclear. OBJECTIVE: We aimed to explore the association of CR with cognitive decline and structural brain differences in middle and older age. DESIGN: This longitudinal study was from the UK Biobank project where participants completed baseline surveys between 2006 to 2010 and were followed (mean follow-up: 9 years). SETTING: A population-based study. PARTICIPANTS: A total of 42,301 dementia-free participants aged 40–70 were followed-up to detect cognitive changes. A subsample (n=34,041) underwent brain magnetic resonance imaging scans. MEASUREMENTS: We used latent class analysis to generate a CR indicator (categorized as high, moderate, and low) based on education, occupation, and multiple cognitively stimulating activities. Cognitive tests for global and domain-specific cognition were administrated at baseline and follow-up. Total brain, white matter, grey matter, hippocampal, and white matter hyperintensity volumes (TBV, WMV, GMV, HV, and WMHV) were assessed at the follow-up examination. Data were analyzed using mixed-effects models and analysis of covariance. RESULTS: At baseline, 16,032 (37.9%), 10,709 (25.3%), and 15,560 (36.8%) participants had low, moderate, and high levels of CR, respectively. Compared with low CR, high CR was associated with slower declines in global cognition (β [95% confidence interval]: 0.10 [0.08, 0.11]), prospective memory (0.10 [0.06, 0.15]), fluid intelligence (0.07 [0.04, 0.10]), and reaction time (0.04 [0.02, 0.06]). Participants with high CR had lower TBV, WMV, GMV, and WMHV, but higher HV when controlling for global cognition (corrected P <0.01 for all). The significant relationships between CR and cognition and TBV were present among both middle-aged (<60 years) and older (≥60 years) participants. The CR-cognition association remained significant despite reductions in brain structural properties. CONCLUSIONS: Higher CR is associated with slower cognitive decline, higher HV, and lower microvascular burden, especially in middle age. Individuals with high CR could tolerate smaller brain volumes while maintaining cognition. The benefit of CR for cognition is independent of structural brain differences. Our findings highlight the contribution of enhancing CR to helping compensate for neuroimaging alterations and ultimately prevent cognitive decline.

CITATION:
W. Yang ; J. Wang ; J. Guo ; A. Dove ; X. Qi ; D.A. Bennett ; W. Xu ; (2024): Association of Cognitive Reserve Indicator with Cognitive Decline and Structural Brain Differences in Middle and Older Age: Findings from the UK Biobank. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.54

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MENDELIAN RANDOMIZATION ANALYSIS REVEALS CAUSAL FACTORS BEHIND ALZHEIMER’S DISEASE RISK: EVIDENCE, OPPORTUNITIES, AND CHALLENGES

X. Feng, L. Zhang, Y. Hou, W. Ma, J. Ma, X. Chang, L. Yang

J Prev Alz Dis 2024;3(11):749-758

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Alzheimer’s disease and its comorbidities pose a heavy disease burden globally, and its treatment remains a major challenge. Identifying the protective and risk factors for Alzheimer’s disease, as well as its possible underlying molecular processes, can facilitate the development of interventions that can slow its progression. Observational studies and randomized controlled trials have provided some evidence regarding potential risk factors for Alzheimer’s disease; however, the results of these studies vary. Mendelian randomization is a novel epidemiological methodology primarily used to infer causal relationships between exposures and outcomes. Many Mendelian randomization studies have identified potential causal relationships between Alzheimer’s disease and certain diseases, lifestyle habits, and biological exposures, thus providing valuable data for further mechanistic studies and the development and implementation of clinical prevention strategies. However, the results and data from Mendelian randomization studies must be interpreted based on comprehensive evidence. Moreover, the existing Mendelian randomization studies on the epidemiology of Alzheimer’s disease have some limitations that are worth exploring. Therefore, the aim of this review was to summarize the available evidence on the potential protective and risk factors for Alzheimer’s disease by assessing published Mendelian randomization studies on Alzheimer’s disease, and to provide new perspectives on the etiology of Alzheimer’s disease.

CITATION:
X. Feng ; L. Zhang ; Y. Hou ; W. Ma ; J. Ma ; X. Chang ; L. Yang ; (2024): Mendelian Randomization Analysis Reveals Causal Factors behind Alzheimer’s Disease Risk: Evidence, Opportunities, and Challenges. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.30

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EDUCATION AS RISK FACTOR OF MILD COGNITIVE IMPAIRMENT: THE LINK TO THE GUT MICROBIOME

M. Klee, V.T.E. Aho, P. May, A. Heintz-Buschart, Z. Landoulsi, S.R. Jónsdóttir, C. Pauly, L. Pavelka, L. Delacour, A. Kaysen, R. Krüger, P. Wilmes, A.K. Leist, on behalf of the NCER-PD Consortium

J Prev Alz Dis 2024;3(11):759-768

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BACKGROUND: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. OBJECTIVES: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. DESIGN: Cross-sectional study. SETTING: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). PARTICIPANTS: Control participants of the Luxembourg Parkinson’s Study. MEASUREMENTS: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0-10, 11-16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. RESULTS: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15-0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. CONCLUSIONS: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.

CITATION:
M. Klee ; V.T.E. Aho ; P. May ; A. Heintz-Buschart ; Z. Landoulsi ; S.R. Jónsdóttir ; C. Pauly ; L. Pavelka ; L. Delacour ; A. Kaysen ; R. Krüger ; P. Wilmes ; A.K. Leist ; on behalf of the NCER-PD Consortium ; (2024): Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.19

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INVESTIGATING THE IMPACT OF TEA CONSUMPTION ON COGNITIVE FUNCTION AND EXPLORING TEA-GENETIC INTERACTIONS IN OLDER ADULTS AGED 65-105 YEARS: FINDINGS FROM THE 2002−2018 CLHLS DATA

L. Yu, M. Yang, K.X. Ye, C. Li, M. Zou, J. Wang, X. Yuan, D. Zheng, C. Sun, Y. Zhang, Q. Feng, A.B. Maier, L. Sun, L. Feng, Y. Wang, H. Chen, Y. Zeng

J Prev Alz Dis 2024;3(11):769-779

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BACKGROUND: As the global population ages, cognitive impairment (CI) becomes more prevalent. Tea has been one of the most popular drinks in the world. Several studies have demonstrated that tea consumption has an impact on cognitive function. OBJECTIVE: This study aims to examine the association between tea consumption and cognitive function and explore the potential effect of genetics on the relationship between tea consumption and CI risk in older adults. DESIGN: This is a prospective longitudinal study using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). SETTING: Six waves of data from CLHLS containing 76,270 subjects were analyzed. Generalized estimation equations (GEE) with a logit link function were adopted to estimate the effect of tea consumption on CI risk from a cross-sectional and longitudinal perspective. PARTICIPANTS: A population-based cohort of adults aged 65-105 years. MEASUREMENTS: The frequency and type of tea consumption were obtained by questionnaires. CI was measured based on MMSE. Polygenic risk was measured using the polygenic score approach described by the International Schizophrenia. RESULTS: The results showed that drinking green tea had a better protective effect on cognitive function than other types of tea, the incidence of CI gradually decreased with the increase of tea consumption frequency, and men were more likely to benefit from tea consumption. Additionally, we also found a significant interaction between tea consumption and genetic risk, measured by polygenic risk score (PRS). CONCLUSIONS: Based on current research evidence, tea consumption, may be a simple and important measure for CI prevention.

CITATION:
L. Yu ; M. Yang ; K.X. Ye ; C. Li ; M. Zou ; J. Wang ; X. Yuan ; D. Zheng ; C. Sun ; Y. Zhang ; Q. Feng ; A.B. Maier ; L. Sun ; L. Feng ; Y. Wang ; H. Chen ; Y. Zeng (2024): Investigating the Impact of Tea Consumption on Cognitive Function and Exploring Tea-Genetic Interactions in Older Adults Aged 65-105 Years: Findings from the 2002−2018 CLHLS Data. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.22

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GLOBAL BURDEN OF ALZHEIMER’S DISEASE AND OTHER DEMENTIAS ATTRIBUTED TO HIGH FASTING PLASMA GLUCOSE FROM 1990 TO 2019

M. Wang, K. Huang, Y. Jin, Z.-J. Zheng

J Prev Alz Dis 2024;3(11):780-786

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BACKGROUND: Burden of Alzheimer’s disease (AD) and other dementias have grown rapidly over the decades, and high fasting plasma glucose (HFPG) was one of the well-established risk factors. It is urgently needed to estimate the global burden of AD and other dementias attributable to high fasting plasma glucose between regions, countries, age groups, and sexes to inform development of effective primary disease prevention strategies and intervention policies. METHODS: The burden of AD and other dementias attributable to HFPG was estimated based on a modeling strategy using the Global Burden of Disease Study 2019 dataset. The disease burden and time trend globally and by region, country, development level, age group, and sex were evaluated. RESULTS: The number of AD and other dementias-related deaths attributable to HFPG increased from 42,998.23 (95% uncertainty interval, UI: 4459.86–163,455.78, the year of 1990) to 159,244.53 deaths (95% UI 18,385.23–583,514.15, the year of 2019). The age-standardized death rate increased from 1.69 (95% UI 0.18–6.54) in 1990 to 2.24 (95% UI 0.26-8.24) in 2019. The burden was higher in more developed regions. The burden in women was double that in men, that HFPG-attributable AD and other dementias caused 99,812.79 deaths (95% UI 9005.67–387,160.60) in women and 59,431.74 deaths (95% UI 5439.02–214,819.23) in men, with age-standardized death rate of 2.27 (95% UI 0.20–8.79) per 100,000 population in women and 2.20 (95% UI 0.20–8.00) in men. CONCLUSION: Findings from the current study emphasizes the urgent requirement for targeted interventions in high-development regions, as well as the importance of proactive measures in middle-development countries in protection of AD and other dementias. The gender disparity necessitates the integration of gender-specific considerations in targeted approaches in prevention of AD and other dementias.

CITATION:
M. Wang ; K. Huang ; Y. Jin ; Z.-J. Zheng (2024): Global Burden of Alzheimer’s Disease and Other Dementias Attributed to High Fasting Plasma Glucose from 1990 to 2019. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.47

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EXAMINING DEMOGRAPHIC FACTORS, PSYCHOSOCIAL WELLBEING AND CARDIOVASCULAR HEALTH IN SUBJECTIVE COGNITIVE DECLINE IN THE BRAIN HEALTH REGISTRY COHORT

R. Tank, A. Diaz, M.T. Ashford, M.J. Miller, J. Eichenbaum, A. Aaronson, B. Landavazo, J. Neuhaus, M.W. Weiner, R.S. Mackin, J. Barnes, R.L. Nosheny

J Prev Alz Dis 2024;3(11):787-797

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Background: Subjective cognitive decline (SCD) is defined as an individual’s perception of sustained cognitive decline compared to their normal state while still performing within boundaries for normal functioning. Demographic, psychosocial and medical factors have been linked to age-related cognitive decline, and Alzheimer’s dementia (AD). However, their relation to risk for SCD remains unclear. This study aims to identify demographic factors, psychosocial and cardiovascular health associated with SCD within the Brain Health Registry (BHR) online cohort. METHODS: Participants aged 55+ (N=27,596) in the BHR self-reported SCD measured using the Everyday Cognition Scale (ECog) and medical conditions, depressive symptoms, body mass index, quality of sleep, health, family history of AD, years of education, race, ethnicity and gender. Multivariable linear regression was used to examine whether SCD was associated with demographic, psychosocial, and medical conditions. RESULTS: We found that advanced age, depressive symptoms, poorer sleep quality and poorer quality of health were positively associated with more self-reported SCD in all models. No race or ethnicity differences were found in association with SCD. Males who reported alcohol and tobacco use or underweight BMI had higher ECog scores compared with females. CONCLUSION: In addition to well-established risk factors for cognitive decline, such as age, our study consistently and robustly identified a strong association between psychosocial factors and self-reported cognitive decline in an online cohort. These findings provide further evidence that psychosocial health plays a pivotal role in comprehending the risk of SCD and early-stage cognitive ageing. Our findings emphasise the significance of psychosocial factors within the broader context of cardiovascular and demographic risk factors.

CITATION:
R. Tank ; A. Diaz ; M.T. Ashford ; M.J. Miller ; J. Eichenbaum ; A. Aaronson ; B. Landavazo ; J. Neuhaus ; M.W. Weiner ; R.S. Mackin ; J. Barnes ; R.L. Nosheny ; (2024): Examining Demographic Factors, Psychosocial Wellbeing and Cardiovascular Health in Subjective Cognitive Decline in the Brain Health Registry Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.39

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ERRATUM TO: EDUCATION AS RISK FACTOR OF MILD COGNITIVE IMPAIRMENT: THE LINK TO THE GUT MICROBIOME

M. Klee, V.T.E. Aho, P. May, A. Heintz-Buschart, Z. Landoulsi, S.R. Jónsdóttir, C. Pauly, L. Pavelka, L. Delacour, A. Kaysen, R. Krüger, P. Wilmes, A.K. Leist, on behalf of the NCER-PD Consortium

J Prev Alz Dis 2024;3(11):798

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CITATION:
M. Klee ; V.T.E. Aho ; P. May ; A. Heintz-Buschart ; Z. Landoulsi ; S.R. Jónsdóttir ; C. Pauly ; L. Pavelka ; L. Delacour ; A. Kaysen ; R. Krüger ; P. Wilmes ; A.K. Leist ; on behalf of the NCER-PD Consortium (2024): Erratum to: Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.53

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