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ALZHEIMER’S DISEASE CLINICAL TRIAL RESEARCH ADAPTATION FOLLOWING COVID-19 PANDEMIC ONSET: NATIONAL SAMPLE OF ALZHEIMER’S CLINICAL TRIAL CONSORTIUM SITES

E.K. Rhodus, P. Aisen, J.D. Grill, D.M. Rentz, R.C. Petersen, R.A. Sperling, S.P. Salloway, D. Pierce, R. Raman

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Background: The COVID-19 pandemic created challenges in clinical research operations that required immediate and lasting changes. OJBECTIVES: The purpose of this study was to explore adaptations to clinical trial research due to COVID-19 and develop a theoretical framework of emergent strategies related to pandemic mitigation in a national network of Alzheimer’s disease clinical trial sites. DESIGN: This qualitative study used a grounded theory approach including semi-structured interviews, constant comparative methods, and multi-level, iterative coding. PARTICIPANTS: Twenty-six member sites of the Alzheimer’s Clinical Trial Consortium participated with a total of 49 participants. RESULTS: Findings demonstrate processes of adaptation following COVID-19 onset including establishing safety as priority, focus on scientific preservation, accommodations (creating policies, leadership mindset, maintaining operations, and determining research procedures), and evaluation of changes throughout the course of the pandemic. Communication and maintaining integrity were vital throughout these processes. CONCLUSION: Processes of accommodation among clinical research sites during the pandemic provide critical insights and direction for future clinical trials development and emergent methods in Alzheimer’s disease and other therapeutic areas.

CITATION:
E.K. Rhodus ; P. Aisen ; J.D. Grill ; D.M. Rentz ; R.C. Petersen ; R.A. Sperling ; S.P. Salloway ; D. Pierce ; R. Raman ; (2022): Alzheimer’s Disease Clinical Trial Research Adaptation Following COVID-19 Pandemic Onset: National Sample of Alzheimer’s Clinical Trial Consortium Sites. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.79

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LETTER TO THE EDITOR: BEYOND FRAILTY IN ALZHEIMER’S DISEASE: SHOULD WE MOVE TO THE CONCEPT OF INTRINSIC CAPACITY?

A. Garnier-Crussard, V. Dauphinot, A. Zamudio-Rodriguez, P. Krolak-Salmon

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CITATION:
A. Garnier-Crussard ; V. Dauphinot ; A. Zamudio-Rodriguez ; P. Krolak-Salmon ; (2022): Beyond Frailty in Alzheimer’s Disease: Should We Move to the Concept of Intrinsic Capacity?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.75

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LETTER TO THE EDITOR: GENETICALLY DETERMINED ALZHEIMER’S DISEASE IS ASSOCIATED WITH INCREASED RISK OF VARICOSE VEIN: A MENDELIAN RANDOMIZATION STUDY

C. Zheng, R. Zeng

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CITATION:
C. Zheng ; R. Zeng ; (2022): Genetically Determined Alzheimer’s Disease Is Associated with Increased Risk of Varicose Vein: A Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.76

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DELAYED DECLINE OF COGNITIVE FUNCTION BY ANTIHYPERTENSIVE AGENTS: A COHORT STUDY LINKED WITH GENOTYPE DATA

Z. Sternberg, B. Schaller, D. Hojnacki, M. Tian, J. Yu, R. Podolsky

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Background: Arterial hypertension is among factors with the potential for increasing the risk of cognitive impairment in elderly subjects. However, studies investigating the effects of antihypertensives on cognitive function have reported mixed results. Methods: We have used the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) to investigate the effect of each class of antihypertensives, both as single and combined, in reducing the rate of conversion from normal to mild cognitive impairment (MCI). Results: The use of antihypertensive drugs was associated with 21% (Hazard ratio: 0.79, p<01001) delay in the rate of conversion to MCI. This effect was modulated by age, gender, and genotypic APOE4 allele. Among different antihypertensive subclasses, calcium channel blockers (CCBs) (24%, HR: 0.76, P=0.004), diuretics (21%, HR: 0.79, P=0.006), and α1-adrenergic blockers (α1-ABs) (23%, HR: 0.77, P=0.034) significantly delayed the rate of MCI conversion. A significant effect was observed with the selective L-type voltage-gated CCBs, dihydropyridines, amlodipine (47%, HR=0.53, P<0.001) and nifedipine (49%, HR=0.51, P=0.012), whereas non-DHPs showed insignificant effect. Loop diuretics, potassium sparing diuretics, and thiazides all significantly reduced the rate of MCI conversion. Combination of α1-AB and diuretics led to synergistic effects; combination of vasodilators plus β-blockers (βBs), and α1-AB plus βBs led to additive effect in delaying the rate of MCI conversion, when compared to a single drug. Conclusion: Our results could have implications for the more effective treatment of hypertensive elderly adults who are likely to be at high risk of cognitive decline and dementia. The choice of combination of antihypertensive therapy should also consider the combination which would lead to an optimum benefit on cognitive function.

CITATION:
Z. Sternberg ; R. Podolsky ; J. Yu ; M. Tian ; D. Hojnacki ; B. Schaller ; (2022): Delayed Decline of Cognitive Function by Antihypertensive Agents: A Cohort Study Linked with Genotype Data. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.73

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ADJUDICATING MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE AS A NOVEL ENDPOINT EVENT IN THE TOMMORROW PREVENTION CLINICAL TRIAL

L.S. Schneider, D.A. Bennett, M.R. Farlow, E.R. Peskind, M.A. Raskind, M. Sano, Y. Stern, S. Haneline, K.A. Welsh-Bohmer, J. O’Neil, R. Walter, S. Maresca, M. Culp, R. Alexander, A.M. Saunders, D.K. Burns, C. Chiang

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Background: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer’s disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant’s clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages – independent review, collaborative review, and full committee review – requiring a unanimous decision and ratification by the chair. Results: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators’ clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80–90% for the remainder of the study. Conclusions: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

CITATION:
L.S. Schneider ; D.A. Bennett ; M.R. Farlow ; E.R. Peskind ; M.A. Raskind ; M. Sano ; Y. Stern ; S. Haneline ; K.A. Welsh-Bohmer ; J. O’Neil ; R. Walter ; S. Maresca ; M. Culp ; R. Alexander ; A.M. Saunders ; D.K. Burns ; C. Chiang ; (2022): Adjudicating Mild Cognitive Impairment Due to Alzheimer’s Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.72

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THE ROLE OF AΒ IN ALZHEIMER’S DISEASE AS AN EVOLUTIONARY OUTCOME OF OPTIMIZED INNATE IMMUNE DEFENSE

M. Tatar

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Alzheimer’s Disease is a progressive manifestation of aging associated with accumulated Amyloid β. It remains frustratingly unclear why this protein accumulates and how it contributes to Alzheimer’s Disease pathology. In one recent hypothesis, Amyloid β is suggested to function as an antimicrobial peptide in innate immune defense within the brain, where Amyloid β gains toxicity when it becomes abundant. This essay proposes an evolutionary explanation for why Amyloid β expression is regulated at an optimum based on its function as a defense and how this leads to disease. Among its potential physiological functions, Amyloid β confers benefits to reduce direct pathogen damage while this simultaneously entails cellular cost of defense. Optimal Amyloid β expression occurs when the gain in fitness from an incremental increase is balanced by the marginal cost of this increase. It proposes that natural selection acting upon the young favored systems to maintain Amyloid β at an optimal level through mechanisms that induce the defense and repress its expression. With age, the force of natural selection declines and permits mechanisms of negative feedback repression to degenerate. Consequently, Amyloid β is expressed beyond its optimum. Age also elevates cumulative pathogen exposure, reduces pathogen barriers and reactivates latent pathogens. The net effect is elevated, chronic induction of Amyloid β in the brain. The model recommends attention to innate immune negative regulation in the brain to discover ways to restore these functions toward a youthful state in the elderly.

CITATION:
M. Tatar ; (2022): The role of Aβ in Alzheimer’s Disease as an Evolutionary Outcome of Optimized Innate Immune Defense. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.68

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SAFETY, TOLERABILITY AND PHARMACOKINETICS OF ICAPAMESPIB, A SELECTIVE EPICHAPEROME INHIBITOR, IN HEALTHY ADULTS

M.H. Silverman, S. Duggan, G. Bardelli, B. Sadler, C. Key, M. Medlock, L. Reynolds, B. Wallner

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BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer’s Disease and amyotrophic lateral sclerosis. OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. SETTING: Single site in the United States. PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer’s Disease and other neurodegenerative diseases.

CITATION:
M.H. Silverman ; S. Duggan ; G. Bardelli ; B. Sadler ; C. Key ; M. Medlock ; L. Reynolds ; B. Wallner ; (2022): Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.71

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A HIERARCHICAL BAYESIAN LATENT CLASS MODEL FOR THE DIAGNOSTIC PERFORMANCE OF MINI-MENTAL STATE EXAMINATION AND MONTREAL COGNITIVE ASSESSMENT IN SCREENING MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE

X. Wang, F. Li, H. Zhu, Z. Jiang, G. Niu, Q. Gao

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Background: The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are low costing and noninvasive neuropsychological tests in screening Mild Cognitive Impairment (MCI) due to Alzheimer’s disease (AD). There is no consensus on which test performs better in detecting MCI due to AD based on the different imperfect reference standards. Therefore, we conducted a meta-analysis to assess the diagnostic performance of MMSE and MoCA for screening MCI due to AD in the absence of a gold standard. Methods: Six electronic databases were searched for relevant studies until April, 2022. A hierarchical Bayesian latent class model was used to estimate the pooled sensitivity and specificity of MoCA and MMSE in the absence of a gold standard. Results: 90 eligible studies covering 21273 individuals for MMSE, 26631 individuals for MoCA were included in this meta-analysis. The pooled sensitivity was 0.71(95%CI: 0.67-0.74) for MMSE and 0.85(95%CI: 0.83-0.88) for MoCA, while the pooled specificity was 0.71(95%CI: 0.68-0.74) for MMSE and 0.79(95%CI: 0.76-0.81) for MoCA. MoCA was useful to “rule in” and “rule out” the diagnosis of MCI due to AD with higher positive likelihood ratio (4.07; 95%CI: 3.60-4.62) and lower negative likelihood ratio (0.18; 95%CI: 0.16-0.22). Moreover, the diagnostic odds ratio of MoCA was 22.08(95%CI: 17.24-28.29), which showed significantly favorable diagnostic performance. Conclusions: It suggests that MoCA has greater diagnostic performance than MMSE for differentiating MCI due to AD when the gold standard is absent. However, these results should be taken with caution given the heterogeneity observed.

CITATION:
X. Wang ; F. Li ; H. Zhu ; Z. Jiang ; G. Niu ; Q. Gao ; (2022): A Hierarchical Bayesian Latent Class Model for the Diagnostic Performance of Mini-Mental State Examination and Montreal Cognitive Assessment in Screening Mild Cognitive Impairment Due to Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.70

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OBJECTIVE AND SUBJECTIVE MEASUREMENTS OF MOTOR FUNCTION: RESULTS FROM THE HELIAD STUDY

F. Kalligerou, G. Paraskevas, I. Zalonis, M.H. Kosmidis, M. Yannakoulia, E. Dardiotis, G. Hadjigeorgiou, P. Sakka, N. Scarmeas

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BACKGROUND: Slow gait speed has recently emerged as a potential prodromal feature of cognitive decline and dementia. Besides objective measurements, subjective motor function (SMF) difficulties might be present prior to the manifestation of gait disorders. Objectives: To examine the association of walking time and the presence of SMF with future cognitive decline in cognitively normal individuals. Design: Longitudinal study. Settings: Athens and Larissa, Greece. Participants: 931 cognitively normal individuals over the age of 64 with longitudinal follow-up from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Measurements: We used a simple chronometer for recording objective walking time (OWT) and SMF was assessed using a self-reported physical functioning questionnaire. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline OWT and SMF difficulties and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. Results: Each additional second of OWT was associated with 1.1% of a standard deviation more decline per year in the composite z-score, 1.6% in the memory z-score, 1.1% in the executive z-score and 1.8% in the attention-speed z-score. The presence of SMF difficulties was not associated with differential rates of decline in any cognitive domain. Conclusion: Gait speed can be indicative of future cognitive decline adding credence to the notion that gait speed might serve as a simple and easily accessible clinical tool to identify a larger pool of at risk individuals and improve the detection of prodromal dementia.

CITATION:
F. Kalligerou ; G. Paraskevas ; I. Zalonis ; M.H. Kosmidis ; M. Yannakoulia ; E. Dardiotis ; G. Hadjigeorgiou ; P. Sakka ; N. Scarmeas ; (2022): Objective and Subjective Measurements of Motor Function: Results from the HELIAD Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.69

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ASSOCIATION OF A MIND DIET WITH BRAIN STRUCTURE AND DEMENTIA IN A FRENCH POPULATION

A. Thomas, S. Lefèvre-Arbogast, C. Féart, A. Foubert-Samier, C. Helmer, G. Catheline, C. Samieri

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Background: Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, which combines higher consumption of vegetables, berries, nuts, whole grains, olive oil, fish, beans and poultry, with lower consumption of meat, sugars and saturated fats, is a promising strategy to prevent dementia. However, evidence in populations with non-US food culture, especially from Europe, is limited. Objectives: To evaluate the association of a French-adapted MIND diet score with gray matter volumes, white matter microstructure and incident dementia. Design and setting: This longitudinal study included participants from the population-based Three-City Bordeaux cohort (≥65 years), with a follow-up from June 2001 to February 2018. Participants: Dementia-free participants at dietary assessment, in 2001-2002, who underwent systematic detection of incident dementia (over up to 7 visits). A subset of the cohort was included in an ancillary MRI study in 2010-2011. Measurements: A French-adapted MIND diet score (range, 0-15) was computed from a 148-item Food Frequency Questionnaire and a 24-hour recall administered at home. Incident dementia and its subtypes were adjudicated by an expert committee; and gray matter volumes and white matter microstructure were assessed by 3D-T1 MRI and diffusion-MRI. Results: Among 1,412 participants (mean age, 75.8 [SD, 4.8]; 63% women), followed for a median of 9.7 years (maximum 16.3 years), 356 (25.2%) developed incident dementia. In multivariable-adjusted Cox model, a higher French MIND diet score was associated with lower risks of dementia and AD (hazard ratios for 1-point of score = 0.89 [95% confidence interval, 0.83-0.95] and 0.88 [0.81-0.96], respectively). In Tract-Based Spatial Statistics analysis of 175 participants included in the MRI sub-study, a higher MIND diet score was associated with lower diffusivity values in the splenium of the corpus callosum (P < .05 after Family-Wise Error-correction). In contrast, there was no significant association of the adapted MIND diet score with gray matter volumes in Voxel-Based Morphometry analysis. Conclusion: In this cohort of French older adults, higher adherence to the French MIND diet was associated with a lower dementia risk and with preserved white matter microstructure. These results provide further evidence for a role of the MIND diet in the prevention of dementia.

CITATION:
A. Thomas ; S. Lefèvre-Arbogast ; C. Féart ; A. Foubert-Samier ; C. Helmer ; G. Catheline ; C. Samieri ; (2022): Association of a MIND Diet with Brain Structure and Dementia in a French Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.67

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COGNITIVE DIGITAL BIOMARKERS FROM AUTOMATED TRANSCRIPTION OF SPOKEN LANGUAGE

N. Tavabi, D. Stück, A. Signorini, C. Karjadi, T. Al Hanai, M. Sandoval, C. Lemke, J. Glass, S. Hardy, M. Lavallee, B. Wasserman, T.F.A. Ang, C.M. Nowak, R. Kainkaryam, L. Foschini, R. Au

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BACKGROUND: Although patients with Alzheimer’s disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. Objective: To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing Design: Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. Setting: Observational cohort study. Participants: 146 participants in the Framingham Heart Study. Measurements: Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. Results: Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. Conclusions: The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

CITATION:
N. Tavabi ; D. Stück ; A. Signorini ; C. Karjadi ; T. Al Hanai ; M. Sandoval ; C. Lemke ; J. Glass ; S. Hardy3 ; M. Lavallee ; B. Wasserman ; T.F.A. Ang ; C.M. Nowak ; R. Kainkaryam ; L. Foschini ; R. Au ; (2022): Cognitive Digital Biomarkers from Automated Transcription of Spoken Language. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.66

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ORAL TAU AGGREGATION INHIBITOR FOR ALZHEIMER’S DISEASE: DESIGN, PROGRESS AND BASIS FOR SELECTION OF THE 16 MG/DAY DOSE IN A PHASE 3, RANDOMIZED, PLACEBOCONTROLLED TRIAL OF HYDROMETHYLTHIONINE MESYLATE

C.M. Wischik, P. Bentham, S. Gauthier, S. Miller, K. Kook, B.O. Schelter

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BACKGROUND: Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer’s disease (AD). Objectives: The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY). Design: The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase. Setting: 76 clinical research sites in North America and Europe. Participants: 545 patients with probable AD or MCI-AD in the final version of the protocol. Intervention: Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose. Measurements: Co-primary clinical outcomes are the 11-item Alzheimer’s Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography. Results: 446 participants are expected to complete the 12-month placebo-controlled phase in March 2022. Conclusions: If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.

CITATION:
C.M. Wischik ; P. Bentham ; S. Gauthier ; S. Miller ; K. Kook ; B.O. Schelter ; (2022): Oral Tau Aggregation Inhibitor for Alzheimer’s Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.63

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ASSOCIATION OF PREECLAMPSIA WITH INCIDENT DEMENTIA AND ALZHEIMER’S DISEASE AMONG WOMEN IN THE FRAMINGHAM OFFSPRING STUDY

K. Wang, K. Guo, Z. Ji, Y. Liu, F. Chen, S. Wu, Q. Zhang, Y. Yao, Q. Zhou

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Background: This study aimed to investigate the association between preeclampsia and all-cause dementia and Alzheimer’s Disease (AD). Methods: This population-based cohort study was a secondary analysis of data from the Framingham Offspring Study (FOS). History of preeclampsia was assessed between 1986 and 1990(4th cycle). Participants were followed up until incident events or censorship from the study through 2014. Hazard ratios comparing dementia rates among women with and without a history of preeclampsia were estimated using Cox regression models. Results: A total of 1249 women with 18631 person-years of follow-up were included in the analytic sample. Of those, 142 women had a history of preeclampsia, and 98 women experienced dementia of which 62 were AD during follow-up of nearly 15 years. After multivariate adjustments, women with a history of preeclampsia had a higher risk of all-cause dementia and AD compared with women without it, with HRs of 1.56 (95%CI, 1.03-2.15) for all-cause dementia and 1.65 (95%CI 1.08-2.20) for AD. And the comparable results were shown in the subgroup for elder women over 65 years old. Conclusion: History of preeclampsia was associated with an increased risk of all-cause dementia and AD.

CITATION:
K. Wang ; K. Guo ; Z. Ji ; Y. Liu ; F. Chen ; S. Wu ; Q. Zhang ; Y. Yao ; Q. Zhou ; (2022): Association of Preeclampsia with Incident Dementia and Alzheimer’s Disease among Women in the Framingham Offspring Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.62

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SEX MODERATES THE ASSOCIATION BETWEEN FRAILTY AND MILD BEHAVIORAL IMPAIRMENT

D.X. Guan, K. Rockwood, E.E. Smith, Z. Ismail

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BACKGROUND: Frailty has been associated with cognitive markers of dementia but its relationship with behavioral markers of dementia are poorly understood. OBJECTIVES: To investigate the association between frailty and mild behavioral impairment (MBI), and whether this association is moderated by sex. DESIGN: Cross-sectional observational study. PARTICIPANTS/SETTING: 219 non-dementia participants (cognitively normal and mild cognitive impairment) from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. MEASUREMENTS: Frailty was measured using the frailty index (FI) with higher scores indicating more health deficits/greater frailty. MBI symptoms were derived from Neuropsychiatric Inventory Questionnaire scores using a published algorithm with a cut-off of >0 indicating MBI symptom presence and higher scores indicating greater severity. Multivariable logistic and linear regressions adjusted for age, sex, education, and cognitive diagnosis were used to test the association between FI and MBI symptom presence and severity, respectively, with MBI as the outcome variable. An FI-by-sex interaction term was included to test for sex-dependent effects. RESULTS: The FI mean and SD across the entire cohort was 0.14 ± 0.06 (median = 0.14, IQR = 0.09–0.17, range = 0.02–0.38). Higher FI scores were associated with the presence of MBI symptoms both globally and in the domains of decreased motivation, affective dysregulation, and psychosis. Higher FI scores were also associated with more severe MBI symptoms in a sex-dependent manner: both sexes reported similarly low MBI symptom severity at low (-1 SD) levels of FI but males reported 1.9x higher MBI symptom severity relative to females at high (+1 SD) levels of FI. CONCLUSIONS: The FI is associated with both the presence and severity of MBI, especially for males. This suggests that screening for early dementia risk should incorporate assessments of MBI for patients with frailty, and assessments of frailty for patients with MBI.

CITATION:
D.X. Guan ; K. Rockwood ; E.E. Smith ; Z. Ismail (2022): Sex Moderates the Association between Frailty and Mild Behavioral Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.61

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IN VIVO DETECTION OF CHANGES RELATED TO CORTICAL COLUMNAR ORGANIZATION AND NEUROINFLAMMATION ACROSS THE AD CONTINUUM

M. Torso, G.R. Ridgway, I. Hardingham, A.J. Schwarz, S.A. Chance, for the Alzheimer’s Disease Neuroimaging Initiative

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Background: Alzheimer’s disease (AD) neuropathology reveals progressive microstructural alterations of cortical architecture. Recent studies reported intriguing biphasic trajectories of cortical structural changes in the early stages of Alzheimer’s disease (AD), comprising decreased mean diffusivity (MD) and increased cortical thickness in cognitively normal amyloid-positive individuals, ahead of increases and decreases, respectively, in subsequent disease stages. Objective: To better understand the cytoarchitectural correlates of these observations, we assessed novel cortical diffusion tensor imaging (DTI) metrics that are correlated with disruption of cortical minicolumns and protein deposition. Design: Cross-sectional and longitudinal analysis of whole brain and temporal lobe cortical diffusivity measures. Investigation of associations between baseline cortical diffusivity values and 24-month longitudinal structural-MRI changes. Investigations of the relationships between cortical diffusivity measures and biomarkers of neuroinflammation. Setting: Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants: Twenty-four amyloid-negative controls (CN-), 28 amyloid-positive controls (CN+), 46 amyloid-positive subjects with mild cognitive impairment (MCI+) and 22 amyloid-positive subjects with AD were included. Measurements: 3DT1 and DTI scans at baseline and approximately 24-month follow-up were used to calculate cortical MD and three novel cortical diffusivity measures: the angle between the radial minicolumnar axis and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD+), and the principal diffusion component parallel with the minicolumns (ParlPD). Cortical macrostructural measurements (cortical volume fraction and cortical thickness), were used to test the hypothesis that baseline cortical diffusivity values can predict change in structural MRI outcomes over approximately 24 months. CSF soluble TREM2 and progranulin (PGRN) concentrations were used to investigate associations with microglial activity and potentially other aspects of neuroinflammation. Results: Cortical diffusivity metrics revealed a dependence on disease stage, with AngleR and PerpPD+ displaying biphasic relationships and ParlPD a monotonic relationship with clinical severity. The novel metrics were able to differentiate between Amyloid+ and Amyloid- controls (AngleR) and to differentiate among disease stages along the AD continuum (PerpPD+). Linear regression revealed significant associations between baseline cortical diffusivity values and subsequent 24-month longitudinal structural-MRI changes. AngleR values were significantly associated with CSF sTREM2 and PGRN concentrations. Conclusions: Cortical diffusivity parameters reflecting minicolumnar organization and neuroinflammation may provide a sensitive and biologically interpretable measurement of cortex quality and microstructure across the AD continuum.

CITATION:
M. Torso ; G.R. Ridgway ; I. Hardingham ; A.J. Schwarz ; S.A. Chance ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2022): In Vivo Detection of Changes Related to Cortical Columnar Organization and Neuroinflammation Across the AD Continuum. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.59

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EVERYDAY FUNCTIONING AND ENTORHINAL AND INFERIOR TEMPORAL TAU BURDEN IN COGNITIVELY NORMAL OLDER ADULTS

M.A. Dubbelman, J. Sanchez, A.P. Schultz, D.M. Rentz, R.E. Amariglio, S.A.M. Sikkes, R.A. Sperling, K.A. Johnson, G.A. Marshall, on behalf of the A4 Study team, full listing of team and site personnel available at A4STUDY.org

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Background: Performance of cognitively complex “instrumental activities of daily living” (IADL) has previously been related to amyloid deposition in preclinical Alzheimer’s disease. Objectives: We aimed to investigate the relationship between IADL performance and cerebral tau accumulation in cognitively normal older adults. Design: Cross-sectional. Setting: Data was collected in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants: Participants (n = 447, age 71.9±4.9 years, 57.5% female) who underwent tau positron emission tomography were selected from the A4 and LEARN studies. Measurements: IADL performance was measured using the self- and study partner-reported versions of the Alzheimer’s Disease Cooperative Study Activities of Daily Living – Prevention Instrument (ADCS ADL-PI). We also investigated discordance between participants and their study partners. Cross-sectional associations between entorhinal and inferior temporal tau (independent variables) and ADCS ADL-PI total scores, item-level scores and discordance (dependent variables) were investigated in linear and logistic regressions. Analyses were adjusted for age, sex and education and a tau by amyloid interaction was also included. Results: Participants and their study partners reported high levels of IADL performance. Entorhinal and inferior temporal tau were related to study partner but not to self-reported total ADCS ADL-PI scores. The association was not retained after adjustment for global cerebral amyloid burden. At the item level, greater entorhinal tau was associated with study partner-reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008) and difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Greater inferior temporal tau was associated with self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018) and study partner-reported difficulties remembering the details of TV programs and movies (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Discordance between participant and study partner-report was more likely with greater entorhinal (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) and inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002). Discussion: We found a cross-sectional relationship between study partner-reported everyday functioning and tau in cognitively normal older adults. Participants were more likely to self-report difficulties differently from their study partners when tau burden was higher. This may hint at an altered early-disease awareness of functional changes and underscores the importance of self-report of IADL functioning in addition to collateral report by a study partner.

CITATION:
M.A. Dubbelman ; J. Sanchez ; A.P. Schultz ; D.M. Rentz ; R.E. Amariglio ; S.A.M. Sikkes ; R.A. Sperling ; K.A. Johnson ; G.A. Marshall ; on behalf of the A4 Study team, full listing of team and site personnel available at A4STUDY.org ; (2022): Everyday Functioning and Entorhinal and Inferior Temporal Tau Burden in Cognitively Normal Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.58

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OBESITY AND BRAIN HEALTH: THE IMPACT OF METABOLIC SYNDROME AND CARDIORESPIRATORY FITNESS ON COGNITIVE PERFORMANCES IN MIDDLE-AGED OBESE WOMEN

W. Wichayanrat, S. Boripuntakul, P. Keawtep, P. Worakul, S. Sungkarat

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BACKGROUND: Mid-life obesity has been reported to be a significant risk factor for later-life dementia and Alzheimer’s disease. Metabolic syndrome (MetS) has been suggested to have an adverse effect while cardiorespiratory fitness (CRF) has been suggested to have a protective effect on cognitive function of older adults. However, studies investigating such effects in middle-aged obese women are limited. OBJECTIVES: To compare cognitive performances between obese and normal weight middle-aged women and examine the effects of MetS and CRF on cognitive performances when combined with obesity. DESIGN AND PARTICIPANTS: Cross-sectional study with the data of 87 middle-aged women (58 obese and 29 normal weight, with age and education matched). MEASUREMENTS: The non-invasive screening method for metabolic syndrome (NIM-MetS) was used to detect MetS. CRF was determined by using maximal oxygen consumption (VO2 max) and was classified as high or low (VO2 max higher or lower than 50th percentile) based on the American College of Sports Medicine’s guidelines. Neurocognitive tests including Montreal Cognitive Assessment (MoCA), digit span (DS), trail making test (TMT), hand reaction time (HRT), logical memory (LM), and semantic verbal fluency test (SVFT) were administered to all participants. RESULTS: The obese group demonstrated significantly lower score in MoCA, DS, TMT, HRT, and LM than the normal weight group (p < 0.05). The obese with MetS subgroup (n = 28) showed significantly lower score in LM than the obese non-MetS subgroup (n = 30) (p = 0.002). Normal weight with high CRF participants (NW-high CRF; n = 28) demonstrated significantly higher score in MoCA and HRT than obese with high CRF participants (OB-high CRF; n = 24) (p < 0.05), and demonstrated better score in MoCA, DS, TMT, HRT, and LM than obese with low CRF participants (OB-low CRF; n = 24) (p < 0.05). OB-high CRF showed significantly greater score in DS, TMT and LM than OB-low CRF (p < 0.05). CONCLUSION: Obesity shows negative impact on several cognitive functions, which memory appears to be further affected when combined with MetS in middle-aged women, whereas CRF is suggested to have benefit on certain aspects of cognitive domains. Maintaining a healthy body weight and improving CRF are beneficial for cognitive function of middle-aged women.

CITATION:
W. Wichayanrat ; S. Boripuntakul ; P. Keawtep ; P. Worakul ; S. Sungkarat ; (2022): Obesity and Brain Health: The Impact of Metabolic Syndrome and Cardiorespiratory Fitness on Cognitive Performances in Middle-Aged Obese Women. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.54

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VALIDATION OF THE SAINT LOUIS UNIVERSITY QUALITY OF LIFE QUESTIONNAIRE IN OLDER ADULTS WITH ALZHEIMER’S DISEASE

K.Y. Yamashita, E.S. Deol, S.J. Elliott, J.E. Morley, T.K. Malmstrom

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Background/Objectives: Alzheimer’s disease (AD) is the most common cause of dementia and negatively impacts individuals’ quality of life (QOL). One essential component of disease management in older adults with AD is the maintenance and improvement of QOL. The QOL-AD is a tool that can be administered to evaluate QOL in AD patients, but it can take too long to administer in a patient visit. The purpose of this study was to investigate the validity of a more brief, 6-item QOL questionnaire, LIFEAD, comparing it to the QOL-AD in older adults with mild to moderate cognitive dysfunction. Design: Prospective validation study. Setting: Participants were patients presenting to internal medicine and geriatrics outpatient clinics and a nursing home. Participants: 285 adults 65 and older with mild to moderate cognitive impairment. Measurements: QOL was assessed using LIFEAD and the QOL-AD. Demographic data were collected and level of depression was determined through a demographic questionnaire and the PHQ-8, respectively. Results: QOL-AD mean item scores ranged from 2.27-3.32 with an average scale total of 36.28 ± 6.48. LIFEAD mean item scores ranged from 2.26-2.51 with an average scale total of 14.28 ± 2.87. A majority (68%) of patients rated all items on LIFEAD as either average or good. The correlation between LIFEAD and the QOL-AD was 0.71 (p<0.001). Both LIFEAD and the QOL-AD showed strong internal consistency with a Cronbach’s alpha of 0.82 and 0.87, respectively. Conclusion: This study validated LIFEAD and exhibited LIFEAD can assess QOL in older adults with mild to moderate cognitive dysfunction in the clinic or nursing home. LIFEAD is a short, practical questionnaire and is easily administered in approximately 1 minute. Further research on LIFEAD could be done with larger samples, in different clinical populations, and including persons of other ethnic backgrounds.

CITATION:
K.Y. Yamashita ; E.S. Deol ; S.J. Elliott ; J.E. Morley ; T.K. Malmstrom ; (2022): Validation of the Saint Louis University Quality of Life Questionnaire in Older Adults with Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.60

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AMYLOID-RELATED IMAGING ABNORMALITIES AND OTHER MRI FINDINGS IN A COGNITIVELY UNIMPAIRED POPULATION WITH AND WITHOUT CEREBRAL AMYLOID

R. Yaari, K.C. Holdridge, J. Choi, M.C. Donohue, K. Kantarci, C.R. Jack Jr, S.M. Zuk, J.R. Sims, K.A. Johnson, P.S. Aisen, R.A. Sperling

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BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aβ+; n = 1250, A4) and without elevated cerebral amyloid (Aβ-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aβ+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aβ+ or Aβ- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aβ+ cohort compared with 8% in Aβ- (P < 0.001). In the Aβ+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aβ-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aβ+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aβ+ cohort compared with Aβ- (P < 0.001). Females showed reduced odds of MCH in the Aβ+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aβ+ and Aβ- populations prior to anti-amyloid drug intervention. ARIA-H in Aβ+ was greater than in Aβ- populations.

CITATION:
R. Yaari ; K.C. Holdridge ; J. Choi ; M.C. Donohue ; K. Kantarci ; C.R. Jack Jr ; S.M. Zuk ; J.R. Sims ; K.A. Johnson ; P.S. Aisen ; R.A. Sperling ; for the A4 Study Team ; (2022): Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.56

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EFFECTIVENESS OF PHYSICAL EXERCISE ON ALZHEIMER’S DISEASE. A SYSTEMATIC REVIEW

R. Cámara-Calmaestra, A. Martínez-Amat, A. Aibar-Almazán, F. Hita-Contreras, N. de Miguel Hernando, A. Achalandabaso-Ochoa

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Objective: A systematic review of randomized controlled trials was conducted to determine the effect of physical exercise on physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life in a population of older people with Alzheimer´s disease. Data sources: Pubmed, Scopus, PEDro, Web of Science, CINAHL, Cochrane Library, grey literature and a reverse search from inception to April 2021 were searched to identify documents. Study selection: Publications investigating the effect of any type of physical exercise-based intervention in any of its multiple modalities on physical-functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life were searched. Data Extraction: The data were extracted into predesigned data extraction tables. Risk of bias was evaluated through the PEDro scale and its internal validity scale. Data Synthesis: A total of 8 different randomized controlled trials with a total sample of 562 non-overlap Alzheimer disease patients between 50-90 years and a mean age of 75.2 ± 3.9 years were eligible for analyses. Physical-functional capacity was evaluated in 6 of 8 studies and cognitive performance was evaluated in 5 of 8 studies, all of them showed improvements in these variables when compared with the controls, except for two studies in physical-functional capacity and one study for cognitive performance. In the physical-functional capacity and cognitive performance variables, aerobic physical exercise was used in isolation, or in a multimodal way, combining aerobic, strength and balance exercise, from 2 to 7 weekly sessions with doses between 30 and 90 minutes, and a duration of the program comprised of 9 weeks to 6 months. Neuropsychiatric symptoms and quality of life were evaluated in 2 of 8 studies, which the intervention groups experienced significant improvements when compared with the control groups, except for one study that found similar differences in quality of life between both groups. In the neuropsychiatric symptoms and quality of life variables, only aerobic physical exercise was used, in a more homogeneous way, from 2 to 3 weekly sessions with doses of 30 to 60 minutes, and a total program duration of 9 to 16 weeks. Conclusions: Despite the scarcity of studies, especially those based on multimodal proposals, and the heterogeneity in the protocols, this systematic review found moderate to limited evidence that aerobic physical exercise on its own or combined in a multimodal program that also includes strength and balance exercise can be a useful tool in the management of patients with Alzheimer’s disease with the aim of maintaining and/or improving physical-functional capacity and cognitive performance. In addition, this review found moderate evidence of the positive impact that aerobic physical exercise could have in reducing neuropsychiatric symptoms and improving quality of life in patients with Alzheimer´s disease. PROSPERO registration number: CRD42021229891.

CITATION:
R. Cámara-Calmaestra ; A. Martínez-Amat ; A. Aibar-Almazán ; F. Hita-Contreras ; N. de Miguel Hernando ; A. Achalandabaso-Ochoa ; (2022): Effectiveness of Physical Exercise on Alzheimer’s disease. A Systematic Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.57

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SALIVARY ALPHA-AMYLASE ACTIVITY AND MILD COGNITIVE IMPAIRMENT AMONG JAPANESE OLDER ADULTS: THE TOON HEALTH STUDY

N. Yamane, A. Ikeda, K. Tomooka, I. Saito, K. Maruyama, E. Eguchi, K. Suyama, A. Fujii, T. Shiba, K. Tanaka, A. Kooka, S. Nakamura, M. Kajita, R. Kawamura, Y. Takata, H. Osawa, A. Steptoe, T. Tanigawa

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objective markers for early identification and behavioral intervention to prevent dementia and mild cognitive impairment in clinical and community settings. Objective: To investigate the association between salivary alpha-amylase as an objective measure of psychological stress response and mild cognitive impairment for the implication of psychological stress in the development of mild cognitive impairment. Design, Setting, and Participants: This cross-sectional study involved 865 participants aged ≥ 65 years. A saliva sample was collected in the morning, and the levels of salivary alpha-amylase were assayed. Mild cognitive impairment was evaluated using the Japanese version of the Montreal Cognitive Assessment; a score < 26 was indicative of mild cognitive impairment. A multivariable logistic regression model was used to examine the association of salivary alpha-amylase and mild cognitive impairment after adjusting for age, sex, current drinking status, current smoking status, body mass index, hypertension, diabetes mellitus, physical activity, education, social support, social network, and heart rate variability. Results: Salivary alpha-amylase was associated with mild cognitive impairment (the multivariable-adjusted odds ratio [95% confidence interval] for the 1-standard deviation increment of log-transformed salivary alpha-amylase was 1.24 [1.07–1.44]). This significant association persisted after adjusting for various confounding factors. Conclusion: Elevation of salivary alpha-amylase was associated with mild cognitive impairment among Japanese community-dwelling older adults. This suggests that salivary alpha-amylase is a useful objective marker of psychological stress responses associated with mild cognitive impairment.

CITATION:
N. Yamane ; A. Ikeda ; K. Tomooka ; I. Saito ; K. Maruyama ; E. Eguchi ; K. Suyama ; A. Fujii ; T. Shiba ; K. Tanaka ; A. Kooka ; S. Nakamura ; M. Kajita ; R. Kawamura ; Y. Takata ; H. Osawa ; A. Steptoe ; T. Tanigawa ; (2022): Salivary Alpha-Amylase Activity and Mild Cognitive Impairment among Japanese Older Adults: The Toon Health Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.51

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EVALUATION OF THE FISCAL COSTS AND CONSEQUENCES OF ALZHEIMER’S DISEASE IN GERMANY: MICROSIMULATION OF PATIENTS’ AND CAREGIVERS’ PATHWAYS

R. Martins, N. Kotsopoulos, B. Michalowsky, P. Pemberton-Ross, M. Urbich, M.P. Connolly

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Background: Alzheimer’s disease is a severe condition, impacting individual’s wellbeing and independence in daily activities. Informal care provision is common and of great value to societies but is not without negative externalities to households and the broader economy. Objectives: Estimate the lifetime incremental fiscal consequences of Alzheimer’s disease in community-based individuals and their informal caregivers. Setting: The fiscal consequences of Alzheimer’s disease was modeled using the German government and social security perspective. Participants: Synthetic cohort containing 1,000 pairs of people with Alzheimer’s disease and their informal caregivers, compared to 1,000 demographically identical pairs from the general population. Design: Disease progression was modeled using published equations and a state-transition microsimulation framework. Labor participation, financial support and paid taxes were estimated according to cognitive decline and caregiving responsibilities using German labor statistics and tax rates. Healthcare costs were sourced from several German publications. Costs and life-years were discounted at 3% annually. Measurements: Results are reported as lifetime incremental differences in total tax revenue and transfer payments between the cohort affected by Alzheimer’s disease and their general population analogues. Results: The Alzheimer’s disease-affected pair was associated with net incremental fiscal losses of €74,288 ($85,037) to the German government and social security over the lifetime of people with Alzheimer’s disease. Most costs were lost taxes on employment earnings (48.4%) due to caregivers working reduced hours. Caregivers were estimated to earn €56,967 ($65,209) less than their general population analogues. Financial support for informal and formal care accounted for 20.4%, and medical healthcare costs represented 24.0% of the incremental fiscal losses. Sensitivity analyses confirmed the robustness of the model results. In a cohort with early onset Alzheimer’s disease, incremental fiscal losses were predicted to be €118,533 ($114,209) over the lifetime of people with Alzheimer’s disease. Conclusions: Alzheimer’s disease externalities profoundly impact public economics for governments and should be considered to inform policy making and healthcare planning.

CITATION:
R. Martins ; N. Kotsopoulos ; B. Michalowsky ; P. Pemberton-Ross ; M. Urbich ; M.P. Connolly ; (2022): Evaluation of the Fiscal Costs and Consequences of Alzheimer’s Disease in Germany: Microsimulation of Patients’ and Caregivers’ Pathways. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.53

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INTERVENTION FOR COGNITIVE RESERVE ENHANCEMENT IN DELAYING THE ONSET OF ALZHEIMER’S SYMPTOMATIC EXPRESSION (INCREASE) STUDY: RESULTS FROM A RANDOMIZED CONTROLLED STUDY OF MEDICATION THERAPY MANAGEMENT TARGETING A DELAY IN PRODROMAL DEMENTIA SYMPTOM PROGRESSION

D.C. Moga, E.L. Abner, F.A. Schmitt, L. Eckmann, M. Huffmyer, A.I. Martinez, B.F. Beech, R. George, R.H. El Khouli, D. Ali, G.A. Jicha

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Background: Cognitive reserve has been hypothesized as a mechanism to explain differences in individual risk for symptomatic expression of Alzheimer’s Disease (AD). Inappropriate medications may diminish cognitive reserve, precipitating the transition from preclinical AD (pAD) to a symptomatic state. To date, there is limited data on the potential impact of medication optimization as a potential tool for slowing the symptomatic expression of AD. Objectives: (1) To test the efficacy of a medication therapy management intervention designed to bolster cognitive reserve in community-dwelling older adults without dementia. (2) To evaluate the efficacy of intervention by baseline pAD status. Design: A 1-year randomized controlled trial was conducted in community-dwelling older adults without dementia. Randomization was stratified by amyloid β positron emission tomography levels. Setting: Community-based, Lexington, Kentucky. Participants: Adults 65 years or older with no evidence of dementia and reporting at least one potentially inappropriate medication as listed in the Beers 2015 criteria were recruited. The study aimed to enroll 90 participants based on the a priori sample size calculation. Intervention: Medication therapy management versus standard of care. Measurements: Primary outcomes were: (1) one-year changes in the Medication Appropriateness Index; (2) one-year changes in Trail Making Test B under scopolamine challenge. Results: The medication therapy management intervention resulted in significant improvement in Medication Appropriateness Index scores. Overall, there was no beneficial effect of the medication therapy management on Trail Making Test B scores, however stratified analysis demonstrated improvement in Trail Making Test B challenged scores associated with the medication therapy management for those with elevated amyloid β positron emission tomography levels consistent with pAD. Conclusions: Medication therapy management can reduce inappropriate medication use in older adults at risk for AD. Our study indicated beneficial cognitive effects in those with preclinical Alzheimer’s Disease. No statistically significant effects were evident in the study group as a whole, or in those without preclinical cerebral amyloidosis. Further work designed to improve the effectiveness of the medication therapy management approach and defining other preclinical pathologic states that may benefit from medication optimization are readily achievable goals for promoting improved cognitive health and potentially delaying the onset of symptomatic AD.

CITATION:
D.C. Moga ; E.L. Abner ; F.A. Schmitt ; L. Eckmann ; M. Huffmyer ; A.I. Martinez ; B.F. Beech ; R. George ; R.H. El Khouli ; D. Ali ; G.A. Jicha ; (2022): Intervention for Cognitive Reserve Enhancement in Delaying the Onset of Alzheimer’s Symptomatic Expression (INCREASE) Study: Results from a Randomized Controlled Study of Medication Therapy Management Targeting a Delay in Prodromal Dementia Symptom Progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.55

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SEX-DRIVEN DIFFERENCES IN THE EFFECTIVENESS OF INDIVIDUALIZED CLINICAL MANAGEMENT OF ALZHEIMER’S DISEASE RISK

N. Saif, H. Hristov, K. Akiyoshi, K. Akiyoshi, I.E. Ariza, N. Malviya, P. Lee, J. Melendez, G. Sadek, K. Hackett, A. Rahman, J. Meléndez-Cabrero, C.E. Greer, L. Mosconi, R. Krikorian, R.S. Isaacson

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Background: The Comparative Effectiveness Dementia & Alzheimer’s Registry (CEDAR) trial demonstrated that individualized, multi-domain interventions improved cognition and reduced the risk of Alzheimer’s disease (AD). As biological sex is a significant risk factor for AD, it is essential to explore the differential effectiveness of targeted clinical interventions in women vs. men. Methods: Patients were recruited from an Alzheimer’s Prevention Clinic. Subjects with normal cognition, subjective cognitive decline, or asymptomatic preclinical AD were classified as “Prevention”. Subjects with mild cognitive impairment due to AD or mild AD were classified as “Early Treatment.” The primary outcome was the change from baseline to 18-months on the modified-Alzheimer’s Prevention Cognitive Composite. Secondary outcomes included a cognitive aging composite, AD and cardiovascular (CV) risk scales, and serum biomarkers. Subjects who adhered to >60% of recommendations in the CEDAR trial were included in this a priori sub-group analysis to examine whether individualized intervention effects were modified by sex (n=80). Results: In the Prevention group, both women (p=0.0205) and men (p=0.0044) demonstrated improvements in cognition with no sex differences (p=0.5244). In the Early Treatment group, there were also no significant sex differences in cognition (p=0.3299). In the Prevention group, women demonstrated greater improvements in the Multi-Ethnic Study of Atherosclerosis risk score (MESA-RS) than men (difference=1.5, p=0.0013). Women in the Early Treatment group demonstrated greater improvements in CV Risk Factors, Aging and Incidence of Dementia (CAIDE) risk score (difference=2.3, p=0.0067), and the MESA-RS (difference=4.1, p<0.001). Conclusions: Individualized multi-domain interventions are equally effective at improving cognition in women and men. However, personally-tailored interventions led to greater improvements in calculated AD and CV risk, and CV blood biomarkers, in women compared to men. Future study in larger cohorts is necessary to further define sex differences in AD risk reduction in clinical practice.

CITATION:
N. Saif ; H. Hristov ; K. Akiyoshi ; K. Akiyoshi ; I.E. Ariza ; N. Malviya ; P. Lee ; J. Melendez ; G. Sadek ; K. Hackett ; A. Rahman ; J. Meléndez-Cabrero ; C.E. Greer ; L. Mosconi ; R. Krikorian ; R.S. Isaacson ; (2022): Sex-Driven Differences in the Effectiveness of Individualized Clinical Management of Alzheimer’s Disease Risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.44

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JPAD Volume 9, N°03 - 2022

 

EDITORIAL: THE DAWN OF A NEW ERA OF ALZHEIMER’S RESEARCH AND DRUG DEVELOPMENT

Y. Hara, H.M. Fillit

J Prev Alz Dis 2022;3(9):385-386

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CITATION:
Y. Hara ; H.M. Fillit ; (2022): The Dawn of a New Era of Alzheimer’s Research and Drug Development. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.64

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EDITORIAL: THE CLINICAL TRIALS ALZHEIMER’S DISEASE (CTAD) MEETING IN SAN FRANCISCO, FALL 2022, WILL BE A VERY EXCITING EVENT!

M.W. Weiner

J Prev Alz Dis 2022;3(9):387

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CITATION:
M.W. Weiner (2022): The Clinical Trials Alzheimer’s Disease (Ctad) Meeting in San Francisco, Fall 2022, Will Be a Very Exciting Event!. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.65

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TACKLING A MAJOR DEFICIENCY OF DIVERSITY IN ALZHEIMER’S DISEASE THERAPEUTIC TRIALS: AN CTAD TASK FORCE REPORT

R. Raman, P. Aisen, M.C. Carillo, M. Detke, J.D. Grill, O.C. Okonkwo, M. Rivera-Mindt, M. Sabbagh, B. Vellas, M. Weiner, R. Sperlin, and CTAD Task Force

J Prev Alz Dis 2022;3(9):388-392

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As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer’s Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials. New and innovative recruitment initiatives and enhanced infrastructure facilitate increased participant diversity in AD clinical studies.

CITATION:
R. Raman ; P. Aisen ; M.C. Carillo ; M. Detke ; J.D. Grill ; O.C. Okonkwo ; M. Rivera-Mindt ; M. Sabbagh ; B. Vellas ; M. Weiner ; R. Sperling ; and CTAD Task Force* ; (2022): Tackling a Major Deficiency of Diversity in Alzheimer’s Disease Therapeutic Trials: An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.50

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THE FUTURE OF AD CLINICAL TRIALS WITH THE ADVENT OF ANTI-AMYLOID THERAPIES: AN CTAD TASK FORCE REPORT

J. Delrieu, R.J. Bateman, J. Touchon, M. Sabbagh, J. Cummings

J Prev Alz Dis 2022;3(9):393-399

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BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.

CITATION:
J. Delrieu ; R.J. Bateman ; J. Touchon ; M. Sabbagh ; J. Cummings ; (2022): The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.48

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PREDICTION OF COGNITIVE DECLINE FOR ENRICHMENT OF ALZHEIMER’S DISEASE CLINICAL TRIALS

A. Tam, C. Laurent, S. Gauthier, C. Dansereau, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2022;3(9):400-409

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Background: A key issue to Alzheimer’s disease clinical trial failures is poor participant selection. Participants have heterogeneous cognitive trajectories and many do not decline during trials, which reduces a study’s power to detect treatment effects. Trials need enrichment strategies to enroll individuals who are more likely to decline. Objectives: To develop machine learning models to predict cognitive trajectories in participants with early Alzheimer’s disease and presymptomatic individuals over 24 and 48 months respectively. Design: Prognostic machine learning models were trained from a combination of demographics, cognitive tests, APOE genotype, and brain imaging data. Setting: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), National Alzheimer’s Coordinating Center (NACC), Open Access Series of Imaging Studies (OASIS-3), PharmaCog, and a Phase 3 clinical trial in early Alzheimer’s disease were used for this study. Participants: A total of 2098 participants who had demographics, cognitive tests, APOE genotype, and brain imaging data, as well as follow-up visits for 24-48 months were included. Measurements: Baseline magnetic resonance imaging, cognitive tests, demographics, and APOE genotype were used to separate decliners, defined as individuals whose CDR-Sum of Boxes scores increased during a predefined time window, from stable individuals. A prognostic model to predict decline at 24 months in early Alzheimer’s disease was trained on 1151 individuals who had baseline diagnoses of mild cognitive impairment and Alzheimer’s dementia from ADNI and NACC. This model was validated on 115 individuals from a placebo arm of a Phase 3 clinical trial and 76 individuals from the PharmaCog dataset. A second prognostic model to predict decline at 48 months in presymptomatic populations was trained on 628 individuals from ADNI and NACC who were cognitively unimpaired at baseline. This model was validated on 128 individuals from OASIS-3. Results: The models achieved up to 79% area under the curve (cross-validated and out-of-sample). Power analyses showed that using prognostic models to recruit enriched cohorts of predicted decliners can reduce clinical trial sample sizes by as much as 51% while maintaining the same detection power. Conclusions: Prognostic tools for predicting cognitive decline and enriching clinical trials with participants at the highest risk of decline can improve trial quality, derisk endpoint failures, and accelerate therapeutic development in Alzheimer’s disease.

CITATION:
A. Tam ; C. Laurent ; S. Gauthier ; C. Dansereau ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2022): Prediction of Cognitive Decline for Enrichment of Alzheimer’s Disease Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.49

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EFFECTS OF NON-INVASIVE BRAIN STIMULATION ON ALZHEIMER’S DISEASE

L. Gu, H. Xu, F. Qian

J Prev Alz Dis 2022;3(9):410-424

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Background: Previous meta-analyses did not explore the immediate and long-term effect of non-invasive brain stimulation (NIBS) on different cognitive domains in Alzheimer’s disease (AD). The meta-analysis aimed to assess the therapy effect of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on different cognitive domains in AD in randomized controlled trials (RCTs). Methods: Studies published before December 2021 and exploring therapy effect of rTMS, tDCS on different cognitive domains in AD were searched in the following databases: PubMed and Web of Science. We used STATA 12.0 software to compute the standard mean difference (SMD) and a 95% confidence interval (CI). Results: The present study included 16 articles (including 372 AD patients treated with rTMS and 310 treated with sham rTMS) for rTMS and 11 articles (including 152 AD patients treated with tDCS and 134 treated with sham tDCS) for tDCS. The present study showed better immediate and long-term general cognitive function increase effects in AD given rTMS, compared to those given sham rTMS with random effects models (immediate effect: SMD = 2.07, 95% CI = 0.37 to 3.77, I2 = 97.8%, p < 0.001; long-term effect: SMD = 5.04, 95% CI = 2.25 to 7.84, I2 = 97.8%, p < 0.001). The present study showed no significant immediate and long-term effects of rTMS on attention, executive, language and memory functions. In addition, the present study showed no significant difference in immediate or long-term effects of tDCS on general cognitive function, attention, language or memory functions between tDCS group and sham tDCS group. Conclusions: RTMS was an effective treatment technique for general cognitive function in AD, whereas tDCS showed no significant therapy effect on cognitive function in AD. More large-scale studies were essential to explore the effect of NIBS on various cognitive function in AD.

CITATION:
L. Gu ; H. Xu ; F. Qian : Effects of Non-Invasive Brain Stimulation on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad..40

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EVALUATION OF THE FEASIBILITY, SAFETY AND EFFICACY OF THE USE OF INTRAVENOUS INFUSIONS OF ADENOSINE TRIPHOSPHATE (ATP) IN PEOPLE AFFECTED BY MODERATE TO SEVERE ALZHEIMER\'S DISEASE: A DOUBLE-BLIND MASKED CLINICAL TRIAL FOR DOSE FINDING

A. Ruiz, D. Sánchez, A. Lafuente, G. Ortega, M. Buendía, J. Papasey, S.Y. Jimeno, F.P. Badia, M.E. Palacio, C. Abdelnour, F. Ramírez-Toraño, F. Maestú, M.E. Sáez, L. Tárraga, P.C. Dagnelie, M. Boada

J Prev Alz Dis 2022;3(9):425-434

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Background: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer’s disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. Objectives: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. Design: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. Participants: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. Results: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. Conclusions: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

CITATION:
A. Ruiz ; D. Sánchez ; A. Lafuente ; G. Ortega ; M. Buendía ; J. Papasey ; S.Y. Jimeno ; F.P. Badia ; M.E. Palacio ; C. Abdelnour ; F. Ramírez-Toraño ; F. Maestú ; M.E. Sáez ; L. Tárraga ; P.C. Dagnelie ; M. Boada ; (2022): Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.38

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SUBJECTIVE COGNITIVE DECLINE IN A REGISTRY SAMPLE: RELATION TO PSYCHIATRIC HISTORY, LONELINESS, AND PERSONALITY

G.O. Reynolds, L. Manning, D. Kirn, H. Klein, O. Hampton, O. Burke Jr., R. Buckley, D. Rentz, R. Sperling, G.A. Marshall, R.E. Amariglio

J Prev Alz Dis 2022;3(9):435-440

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BACKGROUND: With the increasing focus on prevention of Alzheimer’s disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor’s degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

CITATION:
G.O. Reynolds ; L. Manning ; D. Kirn ; H. Klein ; O. Hampton ; O. Burke Jr. ; R. Buckley ; D. Rentz ; R. Sperling ; G.A. Marshall ; R.E. Amariglio ; (2022): Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.31

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INCREASED INCIDENT ALZHEIMER’S DISEASE AMONG INDIVIDUALS WITH VARICOSE VEINS: A POPULATION-BASED COHORT STUDY

C.-Y. Cheng

J Prev Alz Dis 2022;3(9):441-448

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Background: Varicose vein may be related to increased risk of comorbidities and decreased cognitive function in the elderly, but little is known about the association between varicose vein and Alzheimer’s disease. Objectives: To evaluate whether there is an association between varicose veins and Alzheimer’s disease. Design: The study subjects of this cohort study were selected based on Chang Gung Research Database from January 1, 2003, to December 31, 2012. Follow-up ended December 31, 2017. Setting: A population-based study Participants: Patients aged 45 years and older with varicose veins were enrolled, and the participants of control group were selected by matching with gender, age, and index date at a 4:1 ratio. Measurements: The hazard ratios associated with varicose veins were estimated using Cox regression analysis with competitive risk model. Incidence rates of Alzheimer’s disease, was assessed in people with and without varicose veins. Results: A total of 9,601 patients with varicose veins and 38,404 matched controls were enrolled in the study. The varicose veins group had higher incidence rates than the control group for Alzheimer’s disease (12.60 vs 6.24 per 10,000 person-years; Hazard ratio, 1.647 [95% confidence interval, 1.326- 2.045, p<0.001]). Patients with complicated varicose veins had increased incidence of Alzheimer’s disease than uncomplicated cases (adjusted HR, 1.474; 95% CI, 1.034-2.101, P=0.032). Conclusion: The present study demonstrated a positive association between the varicose veins and Alzheimer’s disease. Physicians should be alerted to cognitive function in patients with varicose veins, especially those with presence of inflammation and ulcerations.

CITATION:
C.-Y. Cheng (2022): Increased Incident Alzheimer’s Disease among Individuals with Varicose Veins: A Population-Based Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.23

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ASSOCIATION BETWEEN DIETARY THEOBROMINE AND COGNITIVE FUNCTION IN A REPRESENTATIVE AMERICAN POPULATION: A CROSS-SECTIONAL STUDY

L. Gao, W. Ge, C. Peng, J. Guo, N. Chen, L. He

J Prev Alz Dis 2022;3(9):449-457

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Background: Despite reports on neuroprotective effects of dietary theobromine intake, whether dietary theobromine has beneficial effects on cognitive function is unclear. Objectives: To investigate the association between dietary theobromine and cognitive function. Design: A cross-sectional study. Setting: Data were collected from the 2011-2014 cycles of the National Health and Nutrition Examination Survey conducted by the Centers for Disease Control and Prevention of the USA. Participants: A representative American population aged ≥60 years. Measurements: L-theobromine was treated as a log transform and dichotomous form (the highest quantile vs. others). Cognitive function was measured using four tests: Consortium to Establish a Registry for Alzheimer's Disease Word Learning tests, Consortium to Establish a Registry for Alzheimer's Disease delayed recall test, animal fluency test, and digit symbol substitution test. We conducted multiple regression analyses and subgroup analyses to study the association between theobromine and cognitive performance. Basic characteristics, lifestyle factors, disease history, and nutritional intake were adjusted for in these models. Results: A total of 2,845 participants were included in the study. The highest quantile of L-theobromine intake was positively associated with sores of delayed recall, animal fluency, and digit symbol substitution tests (β, 95% confidence interval, P: 0.11, -0.00-0.30, 0.049; 0.50, 0.02-0.99, 0.043; 1.55, 0.33-2.77, 0.015; respectively) in the fully adjusted model, but not with immediate recall score (β=0.13, 95% confidence interval -0.16-0.43, P=0.361). Subgroup analyses showed that L-theobromine intake was associated with cognitive performance in the highest quantile of caffeine intake. Conclusions: Daily theobromine intake was associated with cognitive performance in a large nationally representative population. However, further research is needed to corroborate our findings.

CITATION:
L. Gao ; W. Ge ; C. Peng ; J. Guo ; N. Chen ; L. He (2022): Association between Dietary Theobromine and Cognitive Function in a Representative American Population: A Cross-Sectional Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.39

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MESENCHYMAL STEM CELLS MODULATE SIRT1/MIR-134/ GSK3Β SIGNALING PATHWAY IN A RAT MODEL OF ALZHEIMER\'S DISEASE

O.A.R. Abozaid, M.W. Sallam, E.S.A. Ahmed

J Prev Alz Dis 2022;3(9):458-468

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Prolonged exposure to environmental aluminum-containing substances is associated with the development of Alzheimer's disease (AD). AD is a brain disorder associated with a gradual weakening in neurocognitive functions. Mesenchymal stem cells (MSCs) transplant as a promising and safe approach is used to treat AD through countless mechanisms. Therefore, this study aims to elucidate how MSCs improve biochemical and histopathological approaches associated with the AD model in rats. MSCs treatment restores the redox status impairment through a notable decline in the malondialdehyde (MDA) levels along with antioxidant enrichment. The anti-inflammatory effect of MSCs through conversion of microglial cells from M1 to M2 and inhibition of pro-inflammatory mediator’s release work in with de-activated GSK-3β. Additionally, the alleviation of autophagy and lysosomal clearance of Aβ and tau aggregates was accompanied by a down-regulation of the mTOR. Moreover, MSCs upregulate the expression of SIRT1 together with a limited expression of miR-134 thereby, improve neurite outgrowth and synaptic loss. Overall, the obtained data confirm the novelty of MSCs in the treatment of AD not only by their antioxidant, anti-inflammatory effect but also by restoring the neural integrity, neurogenesis, improving the neurocognitive function, and modulation of the signal pathways linked to the Aβ hypothesis.

CITATION:
O.A.R. Abozaid ; M.W. Sallam ; E.S.A. Ahmed ; (2022): Mesenchymal Stem Cells Modulate SIRT1/MiR-134/ GSK3β Signaling Pathway in a Rat Model of Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.26

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A CONFORMATIONAL VARIANT OF P53 (U-P53AZ) AS BLOODBASED BIOMARKER FOR THE PREDICTION OF THE ONSET OF SYMPTOMATIC ALZHEIMER’S DISEASE

S. Piccirella, L. Van Neste, C. Fowler, C.L. Master, J. Fripp, J.D. Doeck, C. Xiong, D. Uberti, P. Kinnon

J Prev Alz Dis 2022;3(9):469-479

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Background: Ongoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer’s disease (AD). Objective: The unfolded conformational variant of p53 (U-p53AZ), previously observed in AD individuals, was evaluated in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort for diagnostic and prognostic assessment, validated on a neuropsychological-based diagnosis, over the course of six years. Design: Retrospective Longitudinal Prognostic biomarker study. Setting: Single-center study based on the AIBL cohort. Participants: 482 participants of the AIBL cohort, aged 60-85 years, without uncontrolled diabetes, vascular disease, severe depression or psychiatric illnesses. Measurements: The AlzoSure® Predict test, consisting of immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), was performed to quantify the AZ 284® peptide as readout of U-p53AZ and compared with an independent neuropsychological diagnosis. The amyloid load via amyloid β-positron emission tomography (Aβ-PET) and supporting clinical information were included where possible. Results: U-p53AZ diagnostic and prognostic performance was assessed in both time-independent and time-dependent (36, 72 and 90 months following initial sampling) analyses. Prognostic performance of Aβ-PET and survival analyses with different risk factors (gender, Aβ-PET and APOE ε4 allele status) were also performed. U-p53AZ differentiated neuropsychologically graded AD from non-AD samples, and its detection at intermediate/high levels precisely identified present and future symptomatic AD. In both time-independent and time-dependent prognostic analyses U-p53AZ achieved area under the curve (AUC) >98%, significantly higher than Aβ-PET AUCs (between 84% and 93%, P respectively <0.0001 and <0.001). As single factor, U-p53AZ could clearly determine the risk of AD neuropsychological diagnosis over time (low versus intermediate/high U-p53AZ hazard ratio=2.99). Proportional hazards regression analysis identified U-p53AZ levels as a major independent predictor of AD onset. Conclusions: These findings support use of U-p53AZ as blood-based biomarker predicting whether individuals would reach neuropsychologically-defined AD within six years prior to AD diagnosis. Integration of U-p53AZ in screening processes could support refined participant stratification for interventional studies.

CITATION:
S. Piccirella ; L. Van Neste ; C. Fowler ; C.L. Masters ; J. Fripp ; J.D. Doecke ; C. Xiong ; D. Uberti ; P. Kinnon ; (2022): A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.52

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CEREBRAL PHOSPHO-TAU ACTS SYNERGISTICALLY WITH SOLUBLE AΒ42 LEADING TO MILD COGNITIVE IMPAIRMENT IN AAV-AD RATS

B. Souchet, M. Audrain, Y. Gu, M.F. Lindberg, N.S. Orefice, E. Rey, N. Cartier, N. Janel, L. Meijer, J. Braudeau

J Prev Alz Dis 2022;3(9):480-490

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BACKGROUND: Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear. OBJECTIVES: We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer's disease (LOAD) predementia. METHODS: We specifically reduced the phosphorylation level of tau while leaving Aβ42 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer's disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age. RESULTS: Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aβ42 levels but prevented MCI onset in 10-month-old AAV-AD rats. CONCLUSIONS: The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aβ42 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aβ42 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action.

CITATION:
B. Souchet ; M. Audrain ; Y. Gu ; M.F. Lindberg ; N.S. Orefice ; E. Rey ; N. Cartier ; N. Janel ; L. Meijer ; J. Braudeau (2022): Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.18

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ELECSYS CEREBROSPINAL FLUID ASSAYS ACCURATELY DISTINGUISH ALZHEIMER’S DISEASE FROM FRONTOTEMPORAL LOBAR DEGENERATION

M. Ortner, O. Goldhardt, J. Diehl-Schmid, I. Yakushev, K. Lanz, D.M. Hedderich

J Prev Alz Dis 2022;3(9):491-498

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BACKGROUND: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy. OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD. DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank. PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography. MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aβ42 ≤1000 pg/mL, pTau181/Aβ42 ratio >0.024, and tTau/Aβ42 ratio >0.28) and optimized cut-offs based on Youden’s index. RESULTS: AUC-based performance was similarly good for the pTau181/Aβ42 ratio (AUC=0.841; 95% CI: 0.759−0.923), pTau181/Aβ40 ratio (AUC=0.837; 95% CI: 0.754−0.919), Aβ42/Aβ40 ratio (AUC=0.829; 95% CI: 0.746−0.912), tTau/Aβ42 ratio (AUC=0.822; 95% CI: 0.736−0.908), pTau181/Aβ42/Aβ40 ratio (AUC=0.817; 95% CI: 0.734–0.901), and Aβ42 (AUC=0.812; 95% CI: 0.722−0.902). Performance was slightly lower for the tTau/Aβ42/Aβ40 ratio (AUC=0.799; 95% CI: 0.713−0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707−0.880), tTau/Aβ40 ratio (AUC=0.751; 95% CI: 0.657−0.844), and tTau alone (AUC=0.706; 95% CI: 0.613−0.799). The highest qualitative performance was observed with the pTau181/Aβ42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively. CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.

CITATION:
M. Ortner ; O. Goldhardt ; J. Diehl-Schmid ; I. Yakushev ; K. Lanz ; D.M. Hedderich ; E. Manuilova ; M. Simon ; J.-P. Weinberger ; T. Grimmer (2022): Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer’s Disease from Frontotemporal Lobar Degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.27

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DECREASED GRAY–WHITE MATTER CONTRAST OF [11C]-PIB UPTAKE IN COGNITIVELY UNIMPAIRED SUBJECTS WITH SEVERE OBSTRUCTIVE SLEEP APNEA

S. Ylä-Herttuala, M. Hakulinen, P. Poutiainen, J. Lötjönen, M. Könönen, H. Gröhn, R. Vanninen, H. Mussalo, T. Laitinen, E. Mervaala

J Prev Alz Dis 2022;3(9):499-506

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Background: Very recently, cognitively normal, middle-aged adults with severe obstructive sleep apnea (OSA) were shown to have regional cortical amyloid-β deposits. In the normal brain, amyloid tracer (e.g., [11C]-PiB) uptake is observed in white matter (WM) but not in cortical gray matter (GM), resulting in clear GM–WM contrast. There are no reports on possible changes in this contrast in severe OSA. Objectives: Evaluate changes in the global [11C]-PiB GM–WM contrast and study if factors reflecting clinical and imaging characteristics are associated with them. Design and setting: Cross-sectional imaging study. Participants: 19 cognitively intact middle-aged (mean 44 years) patients with severe OSA (Apnea–Hypopnea Index >30/h), carefully selected to exclude any other possible factors that could alter brain health. Measurements: Detailed neuroimaging (amyloid PET, MRI). Signs of possible alterations in amyloid tracer GM–WM contrast and kinetics were studied with static and dynamic [11C]-PiB PET and WM structures with detailed 3.0T MRI. Results: Static [11C]-PiB PET uptake showed significantly decreased GM–WM contrast in 5 out of 19 patients. This was already clearly seen in visual evaluation and also detected quantitatively using retention indexes. Dynamic imaging revealed decreased contrast due to alterations in trace accumulation in the late phase of [11C]-PiB kinetics. Decreased GM–WM contrast in the late phase was global in nature. MRI revealed no corresponding alterations in WM structures. Importantly, decreased GM–WM contrast was associated with smoking (p = 0.007) and higher Apnea–Hypopnea Index (p = 0.001). Conclusions: Severe OSA was associated with decreased GM–WM contrast in amyloid tracer uptake, with significant correlation with clinical parameters of smoking and AHI. The results support and further extend the current understanding of the deleterious effect of severe OSA on proper amyloid clearance, possibly reflecting dysfunction of the brain glymphatic system.

CITATION:
S. Ylä-Herttuala ; M. Hakulinen ; P. Poutiainen ; J. Lötjönen ; M. Könönen ; H. Gröhn ; R. Vanninen ; H. Mussalo ; T. Laitinen ; E. Mervaala ; (2022): Decreased Gray–White Matter Contrast of [11C]-PiB Uptake in Cognitively Unimpaired Subjects with Severe Obstructive Sleep Apnea. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.24

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CLINICAL TRIAL ENDPOINTS AND THEIR CLINICAL MEANINGFULNESS IN EARLY STAGES OF ALZHEIMER’S DISEASE

S. Cohen, J. Cummings, S. Knox, M. Potashman, J. Harrison

J Prev Alz Dis 2022;3(9):507-522

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As the focus of Alzheimer’s disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.

CITATION:
S. Cohen ; J. Cummings ; S. Knox ; M. Potashman ; J. Harrison ; (2022): Clinical Trial Endpoints and Their Clinical Meaningfulness in Early Stages of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.41

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AGING, SENESCENCE, AND DEMENTIA

Q. Behfar, A. Ramirez Zuniga, P.V. Martino-Adami

J Prev Alz Dis 2022;3(9):523-531

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The underlying processes occurring in aging are complex, involving numerous biological changes that result in chronic cellular stress and sterile inflammation. One of the main hallmarks of aging is senescence. While originally the term senescence was defined in the field of oncology, further research has established that also microglia, astrocytes and neurons become senescent. Since age is the main risk factor for neurodegenerative diseases, it is reasonable to argue that cellular senescence might play a major role in Alzheimer’s disease. Specific cellular changes seen during Alzheimer’s disease are similar to those observed during senescence across all resident brain cell types. Furthermore, increased levels of senescence-associated secretory phenotype proteins such as IL-6, IGFBP, TGF-β and MMP-10 have been found in both CSF and plasma samples from Alzheimer’s disease patients. In addition, genome-wide association studies have identified that individuals with Alzheimer’s disease carry a high burden of genetic risk variants in genes known to be involved in senescence, including ADAM10, ADAMTS4, and BIN1. Thus, cellular senescence is emerging as a potential underlying disease process operating in Alzheimer’s disease. This has also attracted more attention to exploiting cellular senescence as a therapeutic target. Several senolytic compounds with the capability to eliminate senescent cells have been examined in vivo and in vitro with notable results, suggesting they may provide a novel therapeutic avenue. Here, we reviewed the current knowledge of cellular senescence and discussed the evidence of senescence in various brain cell types and its putative role in inflammaging and neurodegenerative processes.

CITATION:
Q. Behfar ; A. Ramirez Zuniga ; P.V. Martino-Adami ; (2022): Aging, Senescence, and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.42

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CLINICAL RESEARCH INVESTIGATING ALZHEIMER’S DISEASE IN CHINA: CURRENT STATUS AND FUTURE PERSPECTIVES TOWARD PREVENTION

Q. Wang, F. Gao, L. Dai, J. Zhang, D. Bi, Y. Shen

J Prev Alz Dis 2022;3(9):532-541

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Based on the background of research investigating brain aging and neurodegenerative diseases in China, the present review addresses Alzheimer’s disease (AD), one of the most common types of neurodegenerative diseases, clinical research progress, and prospects for future development in China.

CITATION:
Q. Wang ; F. Gao ; L. Dai ; J. Zhang ; D. Bi ; Y. Shen ; (2022): Clinical Research Investigating Alzheimer’s Disease in China: Current Status and Future Perspectives Toward Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.46

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SITE READINESS FRAMEWORK TO IMPROVE HEALTH SYSTEM PREPAREDNESS FOR A POTENTIAL NEW ALZHEIMER’S DISEASE TREATMENT PARADIGM

M. Anderson, N. Sathe, C. Polacek, J. Vawter, T. Fritz, M. Mann, P. Hernandez, M.C. Nguyen, J. Thompson, J. Penderville, M. Arling, S. Safo, R. Christopher

J Prev Alz Dis 2022;3(9):542-549

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New therapies that address the underlying pathophysiology of Alzheimer’s Disease (AD), coupled with the growth of the AD population, will transform the AD care pathway and present significant challenges to health systems. We explored real-world challenges health systems may face in delivering potential new AD therapies with diverse stakeholders. Key challenges in care included integrating primary care providers into assessment and management, availability of memory care specialists, understanding payment and coverage issues and training mid-level providers to help coordinate care and serve as a shared resource across the system. This input informed a novel Site Readiness Framework for AD, comprising self-assessment exercises to identify health system capabilities and gaps and a framework of core strategies and responsive tools to help prepare to integrate new AD therapies. These resources may help health systems improve readiness to modify care pathways to integrate new therapies for AD.

CITATION:
M. Anderson ; N. Sathe ; C. Polacek ; J. Vawter ; T. Fritz ; M. Mann ; P. Hernandez ; M.C. Nguyen ; J. Thompson ; J. Penderville ; M. Arling ; S. Safo ; R. Christopher ; (2022): Site Readiness Framework to Improve Health System Preparedness for a Potential New Alzheimer’s Disease Treatment Paradigm. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.32

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WHAT MATTERS TO PATIENTS WITH ALZHEIMER’S DISEASE AND THEIR CARE PARTNERS? IMPLICATIONS FOR UNDERSTANDING THE VALUE OF FUTURE INTERVENTIONS

F. Jessen, J. Georges, M. Wortmann, S. Benham-Hermetz

J Prev Alz Dis 2022;3(9):550-555

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Alzheimer's Disease (AD) is the most common cause of dementia. Recent thinking portrays AD as a continuum consisting of three stages: an asymptomatic preclinical period, a mild cognitive impairment phase, and dementia, which can be further classified as mild, moderate or severe. While many studies explore the cognitive and functional aspects of AD, fully understanding AD pathophysiology, as well as the potential value of pharmacological and psycho-social interventions, requires a deeper understanding of patient and care partner priorities, particularly in the early stages where such interventions may have the greatest impact in slowing or delaying progression. Available studies highlight a diverse range of patient and care partner priorities, including impacts on their emotions, moods, and social lives. These priorities have not been systematically incorporated in the clinical and value assessments of potential interventions. We propose approaches to better understand the humanistic impact of AD including conducting additional research into the impacts of interventions from the point of view of patients and care partners, expanding notions of ‘value’ and improving health system capacity for diagnosis.

CITATION:
F. Jessen ; J. Georges ; M. Wortmann ; S. Benham-Hermetz ; (2022): What Matters to Patients with Alzheimer’s Disease and Their Care Partners? Implications for Understanding the Value of Future Interventions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.22

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STANDARDIZING ELECTRONIC HEALTH RECORD DATA ON AD/ADRD TO ACCELERATE HEALTH EQUITY IN PREVENTION, DETECTION, AND TREATMENT

C.G. Lyketsos, S.B. Roberts, E.K. Swift, A. Quina, G. Moon, I. Kremer, P. Tariot, H. Fillit, D.E. Bovenkamp, P.P. Zandi, J.G. Haaga

J Prev Alz Dis 2022;3(9):556-560

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Improving the prevention, detection, and treatment of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced “shared”) for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.

CITATION:
C.G. Lyketsos ; S.B. Roberts ; E.K. Swift ; A. Quina ; G. Moon ; I. Kremer ; P. Tariot ; H. Fillit ; D.E. Bovenkamp ; P.P. Zandi ; J.G. Haaga ; (2022): Standardizing Electronic Health Record Data on AD/ADRD to Accelerate Health Equity in Prevention, Detection, and Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.47

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LETTER TO THE EDITOR: EARLY-ONSET TYPE 2 DIABETES AND RISK OF DEMENTIA

T. Kawada

J Prev Alz Dis 2022;3(9):561

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CITATION:
T. Kawada (2022): Letter to the Editor: Early-Onset Type 2 Diabetes and Risk of Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.43

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REPLY TO LETTER TO THE EDITOR: “EARLY-ONSET TYPE 2 DIABETES AND RISK OF DEMENTIA”

K. Wang, H. Liu

J Prev Alz Dis 2022;3(9):562

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CITATION:
K. Wang ; H. Liu ; (2022): Reply to Letter to the Editor: “Early-Onset Type 2 Diabetes and Risk of Dementia”. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.45

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