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04/2022 journal articles

EDITORIAL: THE FUTURE IS NOW: ADVANCING BLOOD-BASED MARKERS

M.C. Carrillo, R.M. Edelmayer, H.M. Snyder

J Prev Alz Dis 2022;4(9):563-564

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CITATION:
M.C. Carrillo ; R.M. Edelmayer ; H.M. Snyder ; (2022): Editorial: The Future is Now: Advancing Blood-Based Markers . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.87

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EDITORIAL: BLOOD-BASED BIOMARKERS FOR ALZHEIMER’S DISEASE: ARE WE THERE YET?

P. Tariot

J Prev Alz Dis 2022;4(9):565-566

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CITATION:
P. Tariot ; (2022): Editorial: Blood-Based Biomarkers for Alzheimer’s Disease: Are We There Yet?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.88

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EDITORIAL: WHAT ARE THE REMAINING CHALLENGES BEFORE BLOODBASED BIOMARKERS FOR ALZHEIMER’S DISEASE CAN BE USED IN CLINICAL PRACTICE?

T. Bittner

J Prev Alz Dis 2022;4(9):567-568

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CITATION:
T. Bittner ; ; (2022): Editorial: What Are the Remaining Challenges before Blood-Based Biomarkers for Alzheimer’s Disease Can Be Used in Clinical Practice?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.89

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BLOOD BIOMARKERS FROM RESEARCH USE TO CLINICAL PRACTICE: WHAT MUST BE DONE? A REPORT FROM THE EU/US CTAD TASK FORCE

D. Angioni, J. Delrieu, O. Hansson, H. Fillit, P. Aisen, J. Cummings, J.R. Sims, J.B. Braunstein, M. Sabbagh, T. Bittner, M. Pontecorvo, S. Bozeat, J.L. Dage, E. Largent, S. Mattke, O. Correa, L.M. Gutierrez Robledo, V. Baldivieso, D.R. Willis, A. Atri, R.J. Bateman, P-J. Ousset, B. Vellas, M. Weiner, & EU/US/CTAD Task Force

J Prev Alz Dis 2022;4(9):569-579

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Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

CITATION:
D. Angioni ; J. Delrieu ; O. Hansson ; H. Fillit ; P. Aisen ; J. Cummings ; J.R. Sims ; J.B. Braunstein ; M. Sabbagh ; T. Bittner ; M. Pontecorvo ; S. Bozeat ; J.L. Dage ; E. Largent ; S. Mattke ; O. Correa ; L.M. Gutierrez Robledo ; V. Baldivieso ; D.R. Willis ; A. Atri ; R.J. Bateman ; P-J. Ousset ; B. Vellas ; M. Weiner ; & EU/US/CTAD Task Force ; (2022): Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.85

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

M. Tatar

J Prev Alz Dis 2022;4(9):580-588

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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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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

J Prev Alz Dis 2022;4(9):589-600

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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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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

J Prev Alz Dis 2022;4(9):601-616

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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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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

J Prev Alz Dis 2022;4(9):617-624

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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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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

J Prev Alz Dis 2022;4(9):625-634

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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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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

J Prev Alz Dis 2022;4(9):635-645

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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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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

J Prev Alz Dis 2022;4(9):646-654

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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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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

J Prev Alz Dis 2022;4(9):655-664

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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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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

J Prev Alz Dis 2022;4(9):665-671

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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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RECRUITMENT OF OLDER AFRICAN AMERICANS IN ALZHEIMER’S DISEASE CLINICAL TRIALS USING A COMMUNITY EDUCATION APPROACH

A.R. Shaw, J. Perales-Puchalt, T. Moore, P. Weatherspoon, M. Robinson, C.V. Hill, E.D. Vidoni

J Prev Alz Dis 2022;4(9):672-678

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Alzheimer’s disease and related dementias (ADRD) is two times more prevalent among compared to non-Hispanic Whites. Despite the higher prevalence of ADRD among older African Americans, recent estimates suggest research enrollment by those who identify as African American remains limited. The purpose of the study is to 1) explore how a culturally tailored community education program impacts clinical trial interest and enrollment in ADRD research studies and to 2) identify how applicable the African American community perceived the culturally tailored curriculum. Using a community-engaged research approach, we collaborated with predominately African American serving community-based organizations to support content development and delivery of Aging with Grace (AWG), a culturally tailored ADRD educational curriculum. A total of five AWG presentations were given to 66 attendees. Most attendees (67%) expressed interest in participating in clinical trials after attending AWG. Enrollment increased within an observational study (84%) and lifestyle prevention clinical trials (52%) from 2018 to 2019. Attendees (32%) also perceived an increase in ADRD knowledge from attending AWG and 89.1% believed more African Americans should participate in research. Our work demonstrates the effectiveness of a culturally tailored community education program to enhance knowledge, clinical trial interest, and recruitment into observational studies and lifestyle ADRD clinical trials among older African Americans. Education programs developed in partnership with the community can serve as bridge to research participation for underrepresented minorities in clinical research. Future studies should assess long-term retention of knowledge and research readiness.

CITATION:
A.R. Shaw ; J. Perales-Puchalt ; T. Moore ; P. Weatherspoon ; M. Robinson ; C.V. Hill ; E.D. Vidoni ; (2022): Recruitment of Older African Americans in Alzheimer’s Disease Clinical Trials Using a Community Education Approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.82

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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

J Prev Alz Dis 2022;4(9):679-691

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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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SEX MODERATES THE ASSOCIATION BETWEEN FRAILTY AND MILD BEHAVIORAL IMPAIRMENT

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

J Prev Alz Dis 2022;4(9):692-700

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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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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

J Prev Alz Dis 2022;4(9):701-707

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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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AGE, SEX, HYPERTENSIONANDHDL-CALTERSERUMBACE1ACTIVITY IN COGNITIVELY NORMAL SUBJECTS: IMPLICATIONS FOR ALZHEIMER’S DISEASE

C. Cervellati, A. Vergallo, A. Trentini, G. Campo, F. Vieceli Dalla Sega, P. Rizzo, G. Bonaccorsi, V. Rosta, C. Renzini, S. Pacifico, A. Passaro, H. Hampel, G. Zuliani

J Prev Alz Dis 2022;4(9):708-714

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Background: Increasing evidence indicates that β-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer’s disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs. Objectives: To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity. Design: prospective analysis of serum samples, clinical, biological, and demographic variables. Setting: Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. Participants: 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51-73) and 175 patients with AD (78 years, 74-82). Measurements: serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities. Results: Age was the strongest independent predictor of sBACE1 variance (β=0.425, p<0.0001), followed by sex (β=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (β=-0.168, p<0.0001) and hypertension (β=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men. Conclusions: We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age.

CITATION:
C. Cervellati ; A. Vergallo ; A. Trentini ; G. Campo ; F. Vieceli Dalla Sega ; P. Rizzo ; G. Bonaccorsi ; V. Rosta ; C. Renzini ; S. Pacifico ; A. Passaro ; H. Hampel ; G. Zuliani ; ; (2022): Age, Sex, Hypertension and HDL-C Alter Serum BACE1 Activity in Cognitively Normal Subjects: Implications for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.78

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ANTIHYPERTENSIVE AGENTS AND INCIDENT ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF OBSERVATIONAL STUDIES

M. Adesuyan, Y.H. Jani, D. Alsugeir, E.C.L. Cheung, C.S.L. Chui, R. Howard, I.C.K. Wong, R. Brauer

J Prev Alz Dis 2022;4(9):715-724

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Background: Hypertension is a recognized risk factor for dementia. However, evidence for using antihypertensive agents to reduce the risk of Alzheimer’s disease in people with hypertension is inconclusive. OBJECTIVE: To examine the association between antihypertensive agents and the incidence of Alzheimer’s disease in adults with hypertension and normal cognition. DESIGN: We conducted a systemic review and performed meta-analyses using Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Web of science and Scopus, from inception to 18th February 2022. SETTING: Cohort and case-control studies. PARTICIPANTS: Adults ≥ 40 years with hypertension and normal cognition. INTERVENTION: Antihypertensive agents. MEASUREMENTS: We performed two separate meta-analyses, pooling the adjusted relative risk (RR) of non-antihypertensive comparator and antihypertensive comparator study design. RESULTS: We included nine studies, totalling 1,527,410 individuals. Meta-analysis of non-antihypertensive user comparator studies found that the use of antihypertensive agents is associated with a reduced risk of incident Alzheimer’s disease (RR= 0.94, 95% CI 0.90-0.99; p=0.01). Meta-analysis of antihypertensive comparator studies found evidence that angiotensin II receptor blocker users are associated with a reduction in the risk of Alzheimer’s disease compared to other antihypertensive agents (RR= 0.78, 95% CI 0.68-0.88; p< 0.001). CONCLUSION: Our review provides evidence that the use of antihypertensive agents is associated with a lower incidence of Alzheimer’s disease. The use of angiotensin II receptor blockers may provide the most benefit among antihypertensive agents. Lowering raised blood pressure may not be the only mechanism for cognitive protection and further investigation of the effects of angiotensin II on cognition is indicated.

CITATION:
M. Adesuyan ; Y.H. Jani ; D. Alsugeir ; E.C.L. Cheung ; C.S.L. Chui ; R. Howard ; I.C.K. Wong ; R. Brauer ; (2022): Antihypertensive Agents and Incident Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Observational Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.77

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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

J Prev Alz Dis 2022;4(9):725-730

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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-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

J Prev Alz Dis 2022;4(9):731-742

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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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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

J Prev Alz Dis 2022;4(9):743-751

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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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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

J Prev Alz Dis 2022;4(9):752-757

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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

J Prev Alz Dis 2022;4(9):758-768

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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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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

J Prev Alz Dis 2022;4(9):769-779

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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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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

J Prev Alz Dis 2022;4(9):780-790

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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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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

J Prev Alz Dis 2022;4(9):791-800

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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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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

J Prev Alz Dis 2022;4(9):801-808

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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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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

J Prev Alz Dis 2022;4(9):809-812

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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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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

J Prev Alz Dis 2022;4(9):813-815

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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

J Prev Alz Dis 2022;4(9):816-817

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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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