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EDITORIAL: ICOPE HEALTHY LONGEVITY INTEGRATIVE PREVENTIVE CARE, ALZHEIMER’S DISEASE PREVENTION AND EARLY DIAGNOSIS

L. Rouch, B. Vellas

J Prev Alz Dis 2024;6(11):1523-1524

CITATION:
L. Rouch ; B. Vellas ; (2024): Editorial: ICOPE Healthy Longevity Integrative Preventive Care, Alzheimer’s Disease Prevention and Early Diagnosis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.170

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UNIVERSAL PREVENTION OF DEMENTIA IN ITALY: A DOCUMENT ANALYSIS OF THE 21 ITALIAN REGIONAL PREVENTION PLANS

S. Salemme, D. Marconi, S.M. Pani, G. Zamboni, C. Sardu, G. Lazzeri, M. Corbo, E. Lacorte, N. Locuratolo, A. Ancidoni, N. Vanacore, G. Bellomo

J Prev Alz Dis 2024;6(11):1525-1533

BACKGROUND: Up to 40% of dementia cases are theoretically avoidable and population-level interventions (i.e., universal prevention) are a key component in facing the global public health challenge of dementia. However, information on the agenda for the universal prevention of dementia at the national and sub-national levels is still lacking. OBJECTIVES: We aim to provide a comprehensive description of the universal prevention strategies specific to dementia in Italian regions and autonomous provinces (APs). DESIGN: We conducted a document analysis of the 21 Italian Regional Prevention Plans (RPPs), with a focus on interventions that target potentially modifiable risk factors for dementia. We analysed the final version of the documents, which were previously downloaded from the dedicated section of the Italian Ministry of Health website in January 2023. We classified the interventions as direct, indirect, or absent. Additionally, we created a quality checklist to outline the essential programmatic elements and applied it to summarise the key findings of the RPPs. MEASUREMENTS: We reported the number of population-level interventions specific for dementia with sub-national detail. We reported information on the risk factor targeted by the interventions, the age groups and populations they were designed for. We summarized the presence or absence of 63 programmatic items using a four-domain checklist. RESULTS: We identified 248 interventions for dementia prevention among the assessed RPPs: 100% of the plans addressed physical inactivity; 30-35% addressed smoking, alcohol, obesity, and social isolation; 25% addressed hypertension, diabetes, and air pollution; only 5-10% addressed education, depression, and hearing loss. Most interventions targeted the general population. Quality checklist scores significantly varied among regions, with demographics and prevention strategies domains scoring higher than disease burden and intervention feasibility ones. CONCLUSIONS: The population-level interventions in the Italian Regional Prevention Programs dedicated to dementia prevention primarily focus on vascular risk factors, with limited coverage of dementia-specific factors such as traumatic brain injury and hearing loss. This data should be considered when planning future interventions for dementia prevention.

CITATION:
S. Salemme ; D. Marconi ; S.M. Pani ; G. Zamboni ; C. Sardu ; G. Lazzeri ; M. Corbo ; E. Lacorte ; N. Locuratolo ; A. Ancidoni ; N. Vanacore ; G. Bellomo (2024): Universal Prevention of Dementia in Italy: A Document Analysis of the 21 Italian Regional Prevention Plans. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.144

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EFFECTIVENESS OF A META-COGNITIVE GROUP INTERVENTION FOR OLDER ADULTS WITH SUBJECTIVE COGNITIVE DECLINE OR MILD COGNITIVE IMPAIRMENT: THE ASPIRE RANDOMIZED CONTROLLED TRIAL

S. Rotenberg, N.D. Anderson, M.A. Binns, E.R. Skidmore, A.K. Troyer, J. Richardson, F. Xie, E. Nalder, Y. Bar, N. Davids-Brumer, A. Bernick, D.R. Dawson

J Prev Alz Dis 2024;6(11):1534-1548

BACKGROUND: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) can lead to functional and cognitive decline, increasing dementia risk. There is a pressing need for interventions that prevent this deterioration. The ASPIRE (Adult Strategies Put Into Real-world Environments) intervention was developed to improve performance of daily activities. OBJECTIVES: The primary objective was to determine whether ASPIRE was more effective than a Brain Education control intervention in improving performance and satisfaction with daily life activities that were not specifically trained in the intervention. Secondary objectives were to explore: 1) whether ASPIRE was more effective in improving self-reported health and quality of life, and performance on cognitive tests; and 2) maintenance of change over six-months. DESIGN: Double-blind, two-armed, parallel randomized controlled trial, with a six-month follow-up period. SETTING: Community based, Greater Toronto Area. PARTICIPANTS: Two-hundred sixty-four older adults (aged 70.8 ± 6.6 years) with SCD or MCI, randomized to ASPIRE (n=131) or a Brain Education active control arm (n= 133). INTERVENTION: ASPIRE is a 10-week meta-cognitive group intervention focusing on strategy acquisition and application to improve performance of individualized daily activity identified by each participant as important. It involves setting goals, creating tailored plans, and iteratively modifying these plans with support from the group members and facilitator. MEASUREMENTS: Performance of and satisfaction with daily activities was rated on a 10-point Likert scale using the Canadian Occupational Performance Measure (COPM). Secondary outcome were subjective cognition, depression, anxiety, self-efficacy, quality of life, and cognitive tests of memory and executive functions. RESULTS: Post-intervention, clinically significant improvement of untrained activities (two points or more on the COPM) was found in 32.5% in ASPIRE; and 30.6% in the control arm, with no significant between group differences (Performance: (exp(β ̂) =0.96, z=-0.15, p=.879); Satisfaction: (exp(β ̂) =0.94, z=-0.29, p=.775). The improvements remained stable over six months in both arms. No significant group effects were found on the secondary outcomes, but improvements were found on subjective cognition and self-efficacy in both arms post intervention. CONCLUSION: Both a meta-cognitive strategy approach and an adult learning activity resulted in positive changes in subjective cognition, self efficacy, and, to a certain extent, engagement in daily activities.

CITATION:
S. Rotenberg ; N.D. Anderson ; M.A. Binns ; E.R. Skidmore ; A.K. Troyer ; J. Richardson ; F. Xie ; E. Nalder ; Y. Bar ; N. Davids-Brumer ; A. Bernick ; D.R. Dawson ; (2024): Effectiveness of a Meta-Cognitive Group Intervention for Older Adults with Subjective Cognitive Decline or Mild Cognitive Impairment: The ASPIRE Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.166

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INITIAL EXPERIENCE WITH LECANEMAB AND LESSONS LEARNED IN 71 PATIENTS IN A REGIONAL MEDICAL CENTER

L.B.E. Shields, H. Hust, S.D. Cooley, G.E. Cooper, R.N. Hart, B.C. Dennis, S.W. Freeman, J.F. Cain, W.Y. Shang, K.M. Wasz, A.T. Orr, C.B. Shields, S.S. Barve, K.G. Pugh

J Prev Alz Dis 2024;6(11):1549-1562

BACKGROUND AND OBJECTIVES: On July 6, 2023 the U.S. Food and Drug Administration approved the anti-amyloid monoclonal antibody lecanemab (Leqembi®) for treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD). Our early experience and lessons learned with lecanemab in a regional community medical center are described. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational study highlights the first 71 patients treated with lecanemab at our multidisciplinary Norton Neuroscience Institute Memory Center. All patients had positive cerebrospinal fluid biomarkers for AD and underwent at least 1 lecanemab infusion. Two patients had additional amyloid PET scans which were positive. RESULTS: The mean age was 72 years (49-90 years), and 44 (62%) patients were female. Most were Caucasian (68 [96%]), and 54 [76%] were referred to our Memory Center by their primary care provider. Comorbidities were common, including hypertension (34 [48%]), hypercholesterolemia (51 [72%]), diabetes mellitus (17 [24%]), and cardiovascular disease excluding hypertension (22 [31%]). The mean body mass index was 27.0 (range: 17.8-45.0). A total of 36 (51%) patients were heterozygous for the ApoE4 genotype, and 9 (13%) were homozygous. A total of 61 [86%] patients had been treated with donepezil; 40 (56%) patients had received memantine. Of the 50 patients who completed 1 or more safety monitoring brain MRIs following infusion, 12 (24%) had amyloid-related imaging abnormalities (ARIA) detected: solitary ARIA-H (hemorrhage) in 5, solitary ARIA-E (edema) in 3, and both ARIA-H and ARIA-E in 4. Of the 12 patients with ARIA, 9 were asymptomatic, 4 were homozygous for the ApoE4 genotype, and 6 were heterozygous for the ApoE4 genotype. Of the 9 who were homozygous for the ApoE4 genotype in this study, 4 (44%) had evidence of ARIA. Of the 36 who were heterozygous for the ApoE4 genotype, 6 (17%) were diagnosed with ARIA. Twenty-six (37%) patients experienced infusion reactions after their first lecanemab infusion: headaches (12 patients) and shaking/chills/rigors (11 patients) were most common. Twenty-three (88%) of these 26 patients reported the side effects either at the infusion center or within the first 24 hours post-infusion. One patient died shortly after the first lecanemab infusion of a myocardial infarction. It is uncertain whether or not this death was related to lecanemab treatment. CONCLUSION: Through our early experience with lecanemab, we have recognized several areas of improvement which have clarified and enhanced the lecanemab infusion experience.

CITATION:
L.B.E. Shields ; H. Hust ; S.D. Cooley ; G.E. Cooper ; R.N. Hart ; B.C. Dennis ; S.W. Freeman ; J.F. Cain ; W.Y. Shang ; K.M. Wasz ; A.T. Orr ; C.B. Shields ; S.S. Barve ; K.G. Pugh (2024): Initial Experience with Lecanemab and Lessons Learned in 71 Patients in a Regional Medical Center. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.159

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VIEWS AND PERCEPTIONS OF AMYLOID IMAGING IN A PRECLINICAL ALZHEIMER’S DISEASE TRIAL

M. Ritchie, R. Raman, K. Ernstrom, S. Wang, M.C. Donohue, P. Aisen, D. Henley, G. Romano, G.P. Novak, H.R. Brashear, R.A. Sperling, J.D. Grill

J Prev Alz Dis 2024;6(11):1563-1571

BACKGROUND: Many cognitively unimpaired older adults are interested in learning their Alzheimer’s disease (AD) biomarker status, but little is known about motivations to undergo biomarker testing and result disclosure in the setting of preclinical AD trials. OBJECTIVES: Examine whether motivations to undergo AD biomarker testing and disclosure differ for individuals who have elevated amyloid compared to those with not elevated amyloid, and whether disclosure of amyloid results impacts participants’ motivations. DESIGN, SETTING, PARTICIPANTS: We conducted post-hoc analyses using data from the EARLY study, a preclinical AD trial of the beta-secretase inhibitor atabecestat. As part of the screening process of the trial, participants underwent biomarker testing and disclosure. We analyzed data from n=2241 participants. MEASUREMENTS: We analyzed data from the Views and Perceptions of Amyloid Imaging (VPAI), a 9-item questionnaire assessing how strongly participants agreed with motivating factors for undergoing amyloid testing. The VPAI was administered at the first screening visit and again after amyloid disclosure. RESULTS: Prior to amyloid disclosure, a greater proportion of participants in the elevated amyloid group responded at the two highest levels of endorsement for the items, “to confirm the feeling that I might already be developing symptoms of AD dementia” (p<0.001) and “to prepare my family for my possible illness in the future” (p=0.008), compared to participants in the not elevated amyloid group. Following disclosure, the not elevated amyloid group had higher odds of positive change in categorical VPAI item level scores for the items “to put mind at ease” (OR: 0.54; p<0.001), “to confirm the feeling that I might already be developing symptoms of AD dementia” (OR: 0.79; p=0.049), and “to prepare my family for my possible illness in the future” (OR: 0.67; p=<0.001), while the elevated amyloid group had higher odds of positive change for the item “curiosity” (OR:1.32; p=0.014). CONCLUSIONS: Investigators might consider adjusting recruitment strategies for future trials to align with the motivations to undergo biomarker testing and disclosure most strongly endorsed by participants with elevated amyloid.

CITATION:
M. Ritchie ; R. Raman ; K. Ernstrom ; S. Wang ; M.C. Donohue ; P. Aisen ; D. Henley ; G. Romano ; G.P. Novak ; H.R. Brashear ; R.A. Sperling ; J.D. Grill ; (2024): Views and Perceptions of Amyloid Imaging in a Preclinical Alzheimer’s Disease Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.157

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INFORMING ALZHEIMER’S BIOMARKER COMMUNICATION: CONCERNS AND UNDERSTANDING OF COGNITIVELY UNIMPAIRED ADULTS DURING AMYLOID RESULTS DISCLOSURE

F.B. Ketchum, C.M. Erickson, K.E. Basche, N.A. Chin, M.L. Eveler, C.E. Conway, D.M. Coughlin, L.R. Clark

J Prev Alz Dis 2024;6(11):1572-1580

in research and clinical settings, but less is known about how individuals interpret their results or concerns raised during the disclosure visit that may need to be addressed by clinicians to ensure appropriate disclosure. METHODS: Fifty-two cognitively unimpaired older adults aged 65 to 89 years old from the Wisconsin Registry for Alzheimer’s Prevention, who had undergone an amyloid PET scan in the previous 18 months, were enrolled in the disclosure substudy. After ensuring psychological readiness, trained study clinicians disclosed amyloid PET results using a structured protocol. We assessed participants’ level of understanding, concerns, and the perceived personal significance of their biomarker results during the disclosure visit through a series of question prompts in real-time. RESULTS: Thirty-four received a non-elevated amyloid result and 18 received an elevated result. The average age was 72.2 years (range 65-81); most were women (64%) and non-Hispanic White (92%). Participants understood their results (98%), and both non-elevated and elevated groups provided similar responses around topics of sharing with others, privacy, accuracy of testing, and risk. Participants with elevated results were significantly more likely than those with non-elevated results to want to change their lifestyle (78% vs 12%, p=<0.01) and have questions about their results (61% vs 30%, p=0.05). Participants interpreted the personal significance of results in terms of several themes relating to individual risk status, emotional impact, whether the result was expected, and prevention/planning. CONCLUSION: Results show that participants understand their biomarker results, and have a number of concerns during the disclosure process that clinical and research protocols could address. en These findings could be important considerations as effective processes are developed for widespread biomarker disclosure in clinical and research settings.

CITATION:
F.B. Ketchum ; C.M. Erickson ; K.E. Basche ; N.A. Chin ; M.L. Eveler ; C.E. Conway ; D.M. Coughlin ; L.R. Clark ; (2024): Informing Alzheimer’s Biomarker Communication: Concerns and Understanding of Cognitively Unimpaired Adults During Amyloid Results Disclosure . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.151

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DIAGNOSTIC ACCURACY OF PLASMA P-TAU217 FOR DETECTING PATHOLOGICAL CEREBROSPINAL FLUID CHANGES IN COGNITIVELY UNIMPAIRED SUBJECTS USING THE LUMIPULSE PLATFORM

F. Martínez-Dubarbie, A. Guerra-Ruiz, S. López-García, C. Lage, M. Fernández-Matarrubia, J. Infante, A. Pozueta-Cantudo, M. García-Martínez, A. Corrales-Pardo, M. Bravo, M. López-Hoyos, J. Irure-Ventura, E. Valeriano-Lorenzo, M.T. García-Unzueta, P. Sánchez-Juan, E. Rodríguez-Rodríguez

J Prev Alz Dis 2024;6(11):1581-1591

BACKGROUND: Plasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice. OBJECTIVES: To evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD. DESIGN: Cross-sectional analyses from a prospective cohort. SETTING: A population-based study. PARTICIPANTS: Volunteers over 55 years without cognitive impairment or contraindications for complementary tests. MEASUREMENTS: Plasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Aβ40, Aβ42, p-tau181, and t-tau levels. We correlated plasma p-tau217 with CSF Aβ40, Aβ42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A-/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor. RESULTS: We screened 209 cognitively unimpaired volunteers with a mean age 64 years (60-69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho=-0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85. CONCLUSIONS: Plasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology.

CITATION:
F. Martínez-Dubarbie ; A. Guerra-Ruiz ; S. López-García ; C. Lage ; M. Fernández-Matarrubia ; J. Infante ; A. Pozueta-Cantudo ; M. García-Martínez ; A. Corrales-Pardo ; M. Bravo ; M. López-Hoyos ; J. Irure-Ventura ; E. Valeriano-Lorenzo ; M.T. García-Unzueta ; P. Sánchez-Juan ; E. Rodríguez-Rodríguez ; (2024): Diagnostic Accuracy of Plasma p-tau217 for Detecting Pathological Cerebrospinal Fluid Changes in Cognitively Unimpaired Subjects Using the Lumipulse Platform. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.152

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PHASE 1 STUDIES OF THE ANTI-TAU MONOCLONAL ANTIBODY JNJ-63733657 IN HEALTHY PARTICIPANTS AND PARTICIPANTS WITH ALZHEIMER’S DISEASE

W.R. Galpern, G. Triana-Baltzer, L. Li, K. Van Kolen, M. Timmers, K. Haeverans, L. Janssens, H. Kolb, P. Nandy, K. Aida, H. Shimizu, M. Mercken, H. Sun

J Prev Alz Dis 2024;6(11):1592-1603

BACKGROUND: JNJ-63733657 (posdinemab) is a humanized IgG1/kappa monoclonal anti-phospho tau antibody that binds with high affinity to phosphorylated amino acid 217 (pT217) in the proline-rich domain. The parent molecule, PT3, was raised against Alzheimer’s disease brain purified paired helical filament, and preclinical studies with the humanized version, JNJ-63733657, have demonstrated reductions in tau seeding. The results of the first-in-human clinical trial of JNJ-63733657 and a separate single ascending dose study in Japanese participants are presented. OBJECTIVES: To evaluate the safety and tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of JNJ-63733657 after single and multiple intravenous dose administrations in healthy participants and participants with prodromal or mild Alzheimer’s disease. DESIGN: A two part first-in-human, phase 1, randomized, double-blind, placebo-controlled trial: Single ascending dose (Part 1) and multiple ascending dose (Part 2). And a phase 1, randomized, double-blind, placebo-controlled single ascending dose trial in healthy Japanese participants. SETTING: 7 sites in Belgium, Netherlands, Spain, and Germany; 1 site in Japan. PARTICIPANTS: A total of 40 healthy participants aged 55-75 were enrolled in Part 1 of the first-in-human study; a total of 16 healthy participants and 13 participants with prodromal or mild AD aged 55-80 years were enrolled in Part 2. In the Japanese trial, a total of 24 participants aged 55-75 were enrolled. INTERVENTION: In Part 1, single doses of 1, 3, 10, 30, or 60 mg/kg of JNJ-63733657 or placebo were administered to healthy participants. In Part 2, two dose levels of JNJ-63733657 (5 mg/kg or 50 mg/kg) or placebo were evaluated in healthy participants, and 2 dose levels (15 mg/kg or 30 mg/kg) or placebo were evaluated in participants with Alzheimer’s disease; doses were administered on Days 1, 29, and 57. In the Japanese trial, single doses of 3, 15, or 60 mg/kg of JNJ-63733675 or placebo were administered. All doses were administered intravenously. MEASUREMENTS: Safety assessments, serum and cerebrospinal fluid pharmacokinetic parameters, immunogenicity, and cerebrospinal fluid pharmacodynamic changes in free and total p217+tau, total tau, and p181tau were evaluated. RESULTS: JNJ-63733657 was generally safe and well-tolerated in healthy participants and participants with Alzheimer’s disease. In healthy participants and participants with Alzheimer’s disease, JNJ-63733657 demonstrated linear PK, and serum Cmax and AUC were approximately dose proportional following single and multiple doses. Dose-dependent reductions in free and total p217+tau in cerebrospinal fluid were observed. No changes in total tau or p181tau were observed in healthy participants whereas Alzheimer’s disease participants showed decreases in these tau species following administration of JNJ-63733657. CONCLUSION: In these Phase 1 trials, no safety or tolerability concerns were identified, and dose dependent reductions in p217+tau in the cerebrospinal fluid were demonstrated following administration of JNJ-63733657. The safety and biomarker profiles support the continued investigation of this compound for the slowing of disease progression in Alzheimer’s disease.

CITATION:
W.R. Galpern ; G. Triana-Baltzer ; L. Li ; K. Van Kolen ; M. Timmers ; K. Haeverans ; L. Janssens ; H. Kolb ; P. Nandy ; K. Aida ; H. Shimizu ; M. Mercken ; H. Sun (2024): Phase 1 Studies of the Anti-Tau Monoclonal Antibody JNJ-63733657 in Healthy Participants and Participants with Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.163

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MULTIDOMAIN INTERVENTION TRIAL FOR PREVENTING COGNITIVE DECLINE AMONG OLDER ADULTS WITH TYPE 2 DIABETES: J-MIND-DIABETES

T. Sugimoto, A. Araki, H. Fujita, K. Fujita, K. Honda, N. Inagaki, T. Ishida, J. Kato, M. Kishi, Y. Kishino, K. Kobayashi, K. Kouyama, Y. Kuroda, S. Kuwahata, N. Matsumoto, T. Murakami, H. Noma, J. Ogino, M. Ogura, M. Ohishi, H. Shimada, K. Sugimoto, T. Takenaka, Y. Tamura, H. Tokuda, K. Uchida, H. Umegaki, T. Sakurai, J-MIND-Diabetes study group

J Prev Alz Dis 2024;6(11):1604-1614

BACKGROUND: No multidomain intervention trials have been designed for the prevention of cognitive decline in older adults with type 2 diabetes. OBJECTIVES: To investigate the efficacy of a multidomain intervention in preventing cognitive decline in older adults with type 2 diabetes and cognitive impairment. DESIGN: Eighteen-month, multi-centered, randomized controlled trial. SETTING: Twelve hospitals in Japan. PARTICIPANTS: Outpatients with type 2 diabetes aged 70–85 years with cognitive impairment. INTERVENTION: The multidomain intervention program includes management of metabolic and vascular risk factors, exercise, nutritional counseling, and promotion of social participation. Participants in the control group received usual care and treatment for type 2 diabetes. MEASUREMENTS: The primary outcome was the change in a composite score combining several neuropsychological tests from baseline to the 18-month follow-up. To assess the differences in cognitive changes between the intervention and control groups, a mixed-effects model for repeated measures was used. RESULTS: Between March 13, 2019, and May 8, 2020, 361 participants were screened, and 154 were randomly assigned to either the intervention group (n = 81) or the control group (n = 73). Finally, 110 participants completed the trial. The between-group difference in the composite score changes was 0.068 (95% confidence interval, −0.091 to 0.226). Analyses for secondary outcomes indicated a positive impact of the intervention on memory and indicated that the intervention led to changes in dietary habits with increased intakes of niacin and meat, along with weight reduction compared to the control group. CONCLUSION: The multidomain intervention did not demonstrate efficacy in preventing cognitive decline. However, this trial provided proof-of-concept evidence that multidomain interventions may offer cognitive benefits and contribute to changes in dietary behavior and weight reduction in older adults with type 2 diabetes and cognitive impairment. These findings should be confirmed in future studies.

CITATION:
T. Sugimoto ; A. Araki ; H. Fujita ; K. Fujita ; K. Honda ; N. Inagaki ; T. Ishida ; J. Kato ; M. Kishi ; Y. Kishino ; K. Kobayashi ; K. Kouyama ; Y. Kuroda ; S. Kuwahata ; N. Matsumoto ; T. Murakami ; H. Noma ; J. Ogino ; M. Ogura ; M. Ohishi ; H. Shimada ; K. Sugimoto ; T. Takenaka ; Y. Tamura ; H. Tokuda ; K. Uchida ; H. Umegaki ; T. Sakurai ; J-MIND-Diabetes study group ; (2024): Multidomain Intervention Trial for Preventing Cognitive Decline among Older Adults with Type 2 Diabetes: J-MIND-Diabetes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.117

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HYPOTHETICAL INTERVENTIONS ON CARDIOVASCULAR HEALTH METRICS FOR ABNORMAL COGNITIVE AGING: AN APPLICATION OF THE PARAMETRIC G-FORMULA IN THE CLHLS COHORT STUDY WITH 12 YEARS FOLLOW-UP

S. Huang, Z. Zhao, S. Wang, Y. Xu, Z. Wang, J. Wang, H. Wang, X. Yu, X. Lv

J Prev Alz Dis 2024;6(11):1615-1625

BACKGROUND: Abnormal cognitive aging is closely related to dementia. OBJECTIVES: This study aimed to estimate the effect of cardiovascular health (CVH) metrics on abnormal cognitive aging. DESIGN: A longitudinal cohort study. SETTING: Participants were recruited from the Chinese Longitudinal Health Longevity Survey. PARTICIPANTS: A total of 3298 participants aged ≥65 years with normal cognitive performance at baseline were included. MEASUREMENTS: Cognitive performance was measured by the Chinese version of the Mini-Mental State Examination (MMSE). CVH was assessed with six metrics, including hypertension, diabetes, exercise, body mass index (BMI), diet, and smoking. Group-based trajectory model was used to identify the trajectory groups of cognitive aging over 12 years (2002-2014 and 2005-2018). The parametric g-formula was applied to estimate the effect of each single six CVH metrics and their combinations on the 12-year cognitive aging trajectory. RESULTS: Four trajectory groups of cognitive aging were identified: Stable-high (77.4%), Unstable (4.9%), Slow decline (11.1%), and Rapid decline (6.6%). Unstable, Slow decline, and Rapid decline trajectory groups were considered as abnormal cognitive aging (22.6%). Single interventions on hypertension, exercise, BMI, and diet could reduce the risk of abnormal cognitive aging. Moreover, the risk ratios of joint intervention on exercise, BMI, and diet for Unstable, Slow decline, and Rapid decline trajectory groups were 0.38 (95% CI: 0.30-0.48), 0.45 (95% CI: 0.37-0.54), and 0.3 (95% CI: 0.23-0.41), respectively. CONCLUSION: A considerable proportion of the participants experienced abnormal cognitive aging during their aging process. Interventions on these CVH metrics (i.e., exercise, BMI, and diet), which are fairly practical and feasible for older adults, may be effective strategies for preventing abnormal cognitive aging.

CITATION:
S. Huang ; Z. Zhao ; S. Wang ; Y. Xu ; Z. Wang ; J. Wang ; H. Wang ; X. Yu ; X. Lv (2024): Hypothetical Interventions on Cardiovascular Health Metrics for Abnormal Cognitive Aging: An Application of the Parametric g-formula in the CLHLS Cohort Study with 12 Years Follow-Up. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.143

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EFFECTS OF VITAMIN D3 COMBINED WITH FOLIC ACID ON DOMAIN AND SPECIFIC COGNITIVE FUNCTION AMONG PATIENTS WITH MILD COGNITIVE IMPAIRMENT: A RANDOMIZED CLINICAL TRIAL

W. Liu, D. Zheng, X. Li, T. Wang, L. Wang, L. Hao, M. Ju, W. Feng, Z. Guo, X. Sun, H. Yu, Z. Qin, R. Xiao

J Prev Alz Dis 2024;6(11):1626-1633

INTRODUCTION: To investigate the effect of vitamin D3 (VD3) combined with folic acid (FA) intervention on the cognitive function among patients with mild cognitive impairment (MCI) and vitamin D deficiency. METHODS: Our study is a single-center, randomized, controlled trial. A total of 402 patients were randomly assigned to the placebo group (n=135), FA group (n=134), and FA+1600IU VD3 group (n=133). The intervention period was 24 weeks. The primary endpoint was the mean change in Montreal Cognitive Assessment (MoCA) compared to baseline. Secondary endpoints included other cognitive functions, serum vitamin D, folic acid, and homocysteine levels. RESULTS: The Intention-to-Treat analysis results of MoCA showed that the adjusted Least Squares Means (LSM) differences between the FA+1600IU VD3 group and the placebo or FA group were 0.456 (95% CI -0.198 to 1.11; p=0.171) and 0.038 (95% CI -0.600 to 0.676; p=0.907), respectively, and the Per-protocol set analysis results showed that the adjusted LSM differences between the FA+1600IU VD3 group and the placebo or FA group were 0.659 (95% CI 0.005 to 1.313; p=0.048) and 0.251 (95% CI -0.387 to 0.889; p=0.44), respectively. CONCLUSION: The effect of FA+1600IU VD3 intervention for 6 months on overall cognitive function in MCI patients with vitamin D deficiency was not significant, but its role may be underestimated and requires further long-term studies to confirm.

CITATION:
W. Liu ; D. Zheng ; X. Li ; T. Wang ; L. Wang ; L. Hao ; M. Ju ; W. Feng ; Z. Guo ; X. Sun ; H. Yu ; Z. Qin ; R. Xiao (2024): Effects of Vitamin D3 Combined with Folic Acid on Domain and Specific Cognitive Function among Patients with Mild Cognitive Impairment: A Randomized Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.165

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ANTI-HYPERTENSIVES REDUCE THE RATE OF ALZHEIMER’S DISEASE PROGRESSION: A COHORT STUDY LINKED WITH GENETIC AND NEUROPATHOLOGICAL ANALYSES

Z. Sternberg, R. Podolsky, J. Yu, S. Hua, S. Halvorsen, D. Hojnacki, B.J. Schaller

J Prev Alz Dis 2024;6(11):1634-1646

BACKGROUND: Arterial hypertension contributes to both the development and progression of dementia due to both Alzheimer’s disease (A.D.) and vascular pathology. However, the effects of different classes of anti-hypertensives (A.H.T.s), on the rate of dementia progression and brain neuropathology are unknown. OBJECTIVE: To investigate the effect of each class of A.H.T., both as single and combined, on the rate of dementia progression. In addition, we analyzed the effect of A.H.T.s on brain neuropathology in AD participants, indicated by Braak staging, hippocampal atrophy, and baseline CSF levels of A-β42, total (T) tau, and P-181 tau. METHODS: We have used the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS). RESULTS: A.H.T.s were associated with reduced yearly increase in the CDR-SOB scores of 1.025 during a 10-year follow-up (P<0.001). The overall survival rate was higher in A.H.T. users than non-users [HR: 0.912: 0.860, 0.967) P=0.002]. These trends continued when stratifying participants by age, gender, and APOE4 allele. Participants who did not use A.H.T.s had a mean yearly increase of 1.71±1.7 in the CDR-SOB scores. This value was reduced to 1.48±1.6, P=0.006 and 1.45±1.6, P=0.024 for participants with documented use of βB and A.R.B.s, respectively. Combining diuretics with α1-AB or ACEI led to synergistic effects in reducing the rise in CDR-SOB scores. The proportion of participants who were diagnosed having AD postmortem with severe Braak staging was significantly lower in A.H.T.-users than non-users. The severity of Braak staging, and hippocampal atrophy differed in participants> 70 vs. <70 years old, in both males and females. A significant relationship was observed between hippocampal atrophy and Braak staging; and between hippocampal atrophy and baseline CSF levels of P-181 tau. CONCLUSION: Our results could have implications for halting the progression of dementia regardless of the etiology being related to AD or vascular pathology. The choice of combination of A.H.T. therapy should also consider the combination which would lead to an optimum benefit in slowing the progression of dementia. Additionally, our results underline a more complex A.D. disease model than previously thought, which opens new treatment options.

CITATION:
Z. Sternberg ; R. Podolsky ; J. Yu ; S. Hua ; S. Halvorsen ; D. Hojnacki ; B.J. Schaller ; (2024): Anti-Hypertensives Reduce the Rate of Alzheimer’s Disease Progression: A Cohort Study Linked with Genetic and Neuropathological Analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.156

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EXAMINING THE ROLE OF COMMUNITY ENGAGEMENT IN ENHANCING THE PARTICIPATION OF RACIAL AND ETHNIC MINORITIZED COMMUNITIES IN ALZHEIMER’S DISEASE CLINICAL TRIALS; A RAPID REVIEW

S. Dabiri, R. Raman, J. Grooms, D. Molina-Henry

J Prev Alz Dis 2024;6(11):1647-1672

BACKGROUND: Despite higher dementia prevalence in racial and ethnic minoritized communities, they are underrepresented in Alzheimer’s disease clinical trials. Community-based recruitment strategies are believed to yield positive outcomes in various fields, such as cancer and cardiovascular clinical trials, but their outcomes in Alzheimer’s disease and Related Dementias (AD/ADRD) require further study. In this systematic rapid review, we synthesized the available evidence on community-engaged recruitment strategies in enhancing participation in AD/ADRD clinical trials and observational study participation. METHODS: We searched and identified studies describing a community-based recruitment approach for racial and ethnic minoritized communities across seven databases (Pubmed, OVID MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, PsychINFO, Web of Science, and EMBASE). RESULTS: Out of 1915 screened studies, 49 met the inclusion criteria. Most studies employed multiple community-based recruitment approaches, including educational presentations, collaborations with community-based faith organizations, community advisory boards, and engagement with local clinics or health professionals. 52% of studies targeted more than one racial and ethnic minoritized population, primarily African Americans and then Hispanic/Latino. Gaps in knowledge about AD/ADRD, its increased risk among minoritized populations, distrust, and stigma were noted as barriers to research participation. Approximately 50% of the studies specified whether they evaluated their recruitment approaches, and in studies where approaches were evaluated, there was substantial heterogeneity in methods utilized. CONCLUSION: The quality of available evidence on the use of community-based recruitment approaches to include racial and ethnic minoritized populations in AD/ADRD research, particularly in clinical trials, is limited. Systematic assessment of recruitment strategies is urgently needed to increase the evidence base around community-engaged recruitment approaches.

CITATION:
S. Dabiri ; R. Raman ; J. Grooms ; D. Molina-Henry ; (2024): Examining the Role of Community Engagement in Enhancing the Participation of Racial and Ethnic Minoritized Communities in Alzheimer’s Disease Clinical Trials; A Rapid Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.149

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DEVELOPMENT AND VALIDATION THE MOBILE TOOLBOX (MTB) SPELLING TEST

E. LaForte, S.R. Young, E.M. Dworak, M.A. Novack, A.J. Kaat, H. Adam, C.J. Nowinski, Z. Hosseinian, J. Slotkin, S. Amagai, M.V. Diaz, A.A. Correa, K. Alperin, M. Camacho, B. Landavazo, R. Nosheny, M.W. Weiner, R.M. Gershon

J Prev Alz Dis 2024;6(11):1673-1681

BACKGROUND: Spelling assessments can provide a valuable marker of cognitive change in Alzheimer’s disease and related dementias (ADRD) and play an important role in ADRD research. However, most commercial assessments are not well-suited to the needs of researchers or participants; they are expensive and often require face-to-face administration by a trained examiner. To help overcome these barriers and foster progress in ADRD research, the National Institute on Aging (NIA)-funded Mobile Toolbox (MTB) offers a library of cognitive measures that can be self-administered remotely on a participant’s own smartphone, including a brand-new Spelling test. OBJECTIVE: The goal of this paper is to describe the design, piloting, calibration, and validation of the MTB Spelling test. DESIGN: We describe a pilot study, calibration study, and three validation studies, all of which use a cross-sectional design. SETTING: The pilot study, calibration study, and validation studies 2 and 3 were conducted remotely, while validation study 1 was conducted in the lab. PARTICIPANTS: Participants for all of the studies were recruited from the general population by a thirdparty market research firm and the samples were stratified by age, gender, race, ethnicity, and education to represent the U.S. population. The pilot sample included 1,950 participants and the calibration study included 1335 participants over the age of 8. Validation study 1 included 92 participants ages 20 to 84, validation study 2 included 1021 participants ages 18 to 90, and validation study 3 included 168 participants ages 28 to 87. MEASUREMENTS: Participants in each of the studies completed the MTB Spelling test. Participants in validation studies 1 and 2 completed measures from the NIH Toolbox including Oral Reading Recognition as a measure of convergent validity, and Visual Reasoning and the Rey Auditory Verbal Learning as measures of divergent validity. As an additional measure of convergent validity, participants in study 1 also completed the Spelling subtest from the Wechsler Individual Achievement Test, 4th Edition. RESULTS: The MTB Spelling test demonstrated evidence of internal consistency (r=.79 to .83) convergent validity (r=.56 to .81, p<.01), discriminant validity (r = .23 to .36, p <.01), test-retest reliability ( ICC=.63 ), and correlations with normal cognitive aging (r = -.06 to -.04, p >.01). CONCLUSION: Findings suggest the MTB Spelling test is a reliable and valid measure of English spelling abilities in general population samples, and has potential in ADRD research.

CITATION:
E. LaForte ; S.R. Young ; E.M. Dworak ; M.A. Novack ; A.J. Kaat ; H. Adam ; C.J. Nowinski ; Z. Hosseinian ; J. Slotkin ; S. Amagai ; M.V. Diaz ; A.A. Correa ; K. Alperin ; M. Camacho ; B. Landavazo ; R. Nosheny ; M.W. Weiner ; R.M. Gershon (2024): Development and Validation the Mobile Toolbox (MTB) Spelling Test. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.158

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ROLES OF TREM2 IN THE PATHOLOGICAL MECHANISM AND THE THERAPEUTIC STRATEGIES OF ALZHEIMER’S DISEASE

M. Lin, J.-X. Yu, W.-X. Zhang, F.-X. Lao, H.-C. Huang

J Prev Alz Dis 2024;6(11):1682-1695

Alzheimer’s disease (AD) is an age-related degenerative disease, which is characteristic by the deposition of senile plaques (SP) outside the cells, the neurofibrillary tangles (NFTs) inside the neurons, and the loss of synapse and neurons. Neuroinflammation may play an important role in the pathogenesis of AD. Microglia are the immune cells in the central nervous system. However, microglia might become disease-related microglia (DAMs) when stimulated by the external environment. DAMs have been shown to be involved in a series of events of AD development including Aβ accumulation and tau phosphorylation. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor that is mainly expressed by microglia in the central nervous system (CNS). TREM2 plays an important role in the physiological function of microglia, and the dyshomeostasis of TREM2 is related to the development of late-onset AD. This article summarized the latest advances in TREM2 biology and its impact on the roles of microglia in AD development, with a particular emphasis on the structure, ligands, signal transduction, and the agonistic antibodies of TREM2 for AD treatment. We further discussed the survival, migration, phagocytosis, inflammation, and cellular metabolism of microglia, as well as the role of sTREM2 in neuroprotection and as a biomarker for AD. It provides a reference for further research on the molecular mechanism of microglial TREM2 in the occurrence and development of AD and on the therapeutic strategies targeted on the microglial TREM2.

CITATION:
M. Lin ; J.-X. Yu ; W.-X. Zhang ; F.-X. Lao ; H.-C. Huang (2024): Roles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.164

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FREE RECALL OUTPERFORMS STORY RECALL IN ASSOCIATIONS WITH PLASMA BIOMARKERS IN PRECLINICAL ALZHEIMER DISEASE

A.J. Aschenbrenner, J.J. Hassenstab, S.E. Schindler, S. Janelidze, O. Hansson, J.C. Morris, E. Grober

J Prev Alz Dis 2024;6(11):1696-1702

BACKGROUND: A decline in episodic memory is one of the earliest cognitive characteristics of Alzheimer disease and memory tests are heavily featured in cognitive composite endpoints that are used to demonstrate treatment efficacy. Assessments of episodic memory can take many forms including free recall, associate learning, and paragraph or story recall. Plasma biomarkers of Alzheimer disease are now widely available and will likely form the backbone of cohort enrichment strategies for future clinical trials. Thus, it is critical to evaluate which episodic memory measures are most sensitive to plasma markers of Alzheimer disease pathology. OBJECTIVES: To compare the associations of common episodic memory tests with plasma biomarkers of Alzheimer disease. DESIGN: Longitudinal cohort study. SETTING: Academic medical center in the midwestern United States. PARTICIPANTS: A total of 161 cognitively normal older adults with at least one plasma biomarker assessment and two or more annual clinical and cognitive assessments which included up to three different tests of episodic memory. MEASUREMENTS: Episodic memory performance using free recall, paired associates recall or paragraph recall. Plasma Aβ42, Aβ40, ptau217, and neurofilament light chain were measured. RESULTS: Free recall on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) was substantially more sensitive to longitudinal cognitive change associated with abnormal baseline plasma Aβ42/Aβ40 and ptau217 compared to other measures of episodic memory. A cognitive composite that included only free recall showed larger decline associated with baseline Aβ42/Aβ40 when compared to those that included paragraph recall. Differences in decline across composites were minimal when considering baseline ptau217 or NfL. CONCLUSION: Episodic memory is a critical domain to assess in preclinical Alzheimer disease. Methods of assessing memory are not equal and longitudinal change in free recall substantially outperformed both paired associates and paragraph recall. Clinical trial results will depend critically on the episodic memory test(s) that are chosen for a composite endpoint and free recall from the FCSRT + IR is an optimal memory measure to include rather than paired associates or paragraph recall.

CITATION:
A.J. Aschenbrenner ; J.J. Hassenstab ; S.E. Schindler ; S. Janelidze ; O. Hansson ; J.C. Morris ; E. Grober (2024): Free Recall Outperforms Story Recall in Associations with Plasma Biomarkers in Preclinical Alzheimer Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.130

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EFFECTS OF THE COVID-19 PANDEMIC ON THE NUMBER OF NEW DEMENTIA DIAGNOSES AND THE QUALITY OF DEMENTIA DIAGNOSTICS AND TREATMENT

M.T. Hoang, P.G. Jurado, T. Abzhandadze, S. Mostafaei, M. Mo, M. Åkerman, K. Vestling, C. Chen, H. Xu, M. Eriksdotter, S. Garcia-Ptacek

J Prev Alz Dis 2024;6(11):1703-1711

BACKGROUND: Care trajectories were disrupted during the COVID-19 pandemic. However, how COVID-19 influenced the number of new dementia diagnoses, and the quality of dementia work-ups, and treatment is understudied. OBJECTIVE: To investigate the change in new dementia registrations, diagnostics, and treatment in the pre-, COVID-19 and post-COVID-19 pandemic periods. DESIGN: A nationwide cohort study. SETTING: This population-based study used data from the Swedish Registry for Cognitive/Dementia disorders – SveDem, and other nationwide registries in Sweden. PARTICIPANTS: Persons with dementia diagnosed between 2019 and 2021 were divided into three groups based on the date of diagnosis: the pre-COVID-19 period (01 January 2019 - 29 February 2020), the COVID-19 period (01 March 2020 – 31 December 2020), and the post-COVID-19 period (01 January 2021 – 31 August 2021). MEASUREMENTS: Outcomes included dementia diagnostics and treatments. RESULTS: The monthly average number of new dementia cases registered in SveDem was 595, 415 and 470, respectively in the pre-COVID-19, COVID-19 and post-COVID-19 period. Compared to the pre-COVID-19 period, the monthly number of registrations decreased, but provision of the basic diagnostic work-up, its individual tests, and the use of cholinesterase inhibitors, memantine and antipsychotics were not significantly different in the COVID-19 period. Compared to the pre-COVID-19 period, new dementia diagnoses continued to be low in the post-COVID-19 period, but diagnosed individuals were more likely to receive the complete basic diagnostic work-up (OR 1.14, 95% CI 1.00 – 1.29), blood analysis (OR 1.88, 95% CI 1.44 – 2.49), computed tomography and magnetic resonance imaging (OR 1.22, 95% CI 1.01 – 1.48), occupational therapy assessment (OR 1.13, 95% CI 1.04 – 1.22), and memantine (OR 1.19, 95% CI 1.07 – 1.31). CONCLUSION: The quantity of new dementia registrations in SveDem decreased in the COVID-19 period and has not returned to pre-COVID-19 levels, but the quality of the work-ups which were conducted and registered in SveDem was similar or higher than in the pre-COVID-19 period. It is imperative to implement policies to increase SveDem registration with the aim of matching or exceeding pre-COVID-19 levels.

CITATION:
M.T. Hoang ; P.G. Jurado ; T. Abzhandadze ; S. Mostafaei ; M. Mo ; M. Åkerman ; K. Vestling ; C. Chen ; H. Xu ; M. Eriksdotter ; S. Garcia-Ptacek ; (2024): Effects of the COVID-19 Pandemic on the Number of New Dementia Diagnoses and the Quality of Dementia Diagnostics and Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.150

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ASSOCIATION BETWEEN COGNITIVE RESERVE INDICATOR AND CHRONIC DISEASE-FREE SURVIVAL: A LARGE COMMUNITYBASED LONGITUDINAL STUDY

P. Li, W. Yang, J. Wang, H. Zhu, A. Dove, W. Xu

J Prev Alz Dis 2024;6(11):1712-1720

BACKGROUND: Cognitive reserve (CR) has been linked to dementia and might be a predictor of aged-related outcomes. However, the association between CR and risk of other chronic diseases and mortality remains unclear. OBJECTIVES: We aimed to investigate the association of CR with survival free from major chronic diseases. DESIGN, SETTING AND PARTICIPANTS: This community-based longitudinal study used data from the UK Biobank. A total of 412,509 participants (mean age 55.71+8.10) free of major chronic disease (including dementia, diabetes, cardiovascular diseases, chronic obstructive pulmonary disease, and cancer) completed the baseline examination between 2006 to 2010 and were followed for changes in health status. MEASUREMENTS: Latent class analysis was used to generate an indicator of CR (categorized as low, moderate, or high) based on education, occupation, television viewing time, confiding, social connection, and leisure activities. Major chronic diseases and survival status were ascertained through self-reported history and/or linkages to medical and death records. Chronic disease-free survival was defined as survival without any of the aforementioned chronic diseases. Effect modifications and interactions between the CR indicator and sex, age, and lifestyle factors (including smoking status, alcohol consumption, physical activity, and body mass index) were explored. RESULTS: Over a median follow-up of 12.49 (interquartile range 11.42-13.41, range 0.01-15.87) years, 112,190 (27.2%) participants died or developed at least one chronic disease. High CR indicator was associated with lower risk of chronic disease/death (hazard ratio 0.82, 95% confidence interval: 0.80-0.83) compared to low CR indicator. Chronic disease-free survival was prolonged by 1.33 (1.21-1.44) years among participants with high CR compared to low CR indicator. Furthermore, the association between the CR indicator and chronic disease-free survival was strengthened among individuals aged <60 years and current smokers. CONCLUSION: High CR indicator is associated with a lower risk of chronic disease/death and may prolong chronic disease-free survival. Our findings underscore the importance of CR-enhancing lifestyle and experiences in health longevity, especially for younger individuals and current smokers.

CITATION:
P. Li ; W. Yang ; J. Wang ; H. Zhu ; A. Dove ; W. Xu ; (2024): Association between Cognitive Reserve Indicator and Chronic Disease-Free Survival: A Large Community-Based Longitudinal Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.160

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QUANTIFYING PERSONALIZED SHIFT-WORK MOLECULAR PORTRAITS UNDERLYING ALZHEIMER’S DISEASE THROUGH COMPUTATIONAL BIOLOGY

Y. Xu, G. Zhang, L. Yang, H. Qin, Z. Zhou, Q. Li, H. Liu, R. Wang, Z. Cai, L. Jing, Y. Li, Y. Yao, Z. Gong, P. Yuan, T. Fu, X. Zhao, T. Peng, Y. Jia

J Prev Alz Dis 2024;6(11):1721-1733

BACKGROUND: Shift work, the proven circadian rhythm-disrupting behavior, has been linked to the increased risk of Alzheimer’s disease (AD). However, the putative causal effect and potential mechanisms of shift work for AD were still unclear. METHODS: Mendelian randomization (MR) analysis was performed to discover the putative causal effect of shift work for AD. Expression quantitative trait loci (eQTLs) and transcriptome data were integrated to identify genes causally associated with AD from circadian-related genes. An in vitro experiment was also conducted to validate the expression of target genes. Based on the identified genes, a novel integrative program and 4,077 samples from 16 microarray datasets were leveraged to assess the extent of circadian rhythm disruption (CRD), defined as the clock deviation level (CDL). FINDINGS/RESULTS: Shift work causally increased the risk of AD [odds ratio (OR) = 2.49, 95% CI = 1.79 - 3.19, p = 0.01]. Seven circadian-related genes were causally associated with AD, including CCS, CDS2, MYRIP, NRP1, PLEKHA5, POLR1D, and PPP4C. These genes were significantly correlated with the circadian rhythm pathway. CDL was higher in CRD mice group, shift work group, sleep restriction group, and AD patients compared to control mice group (p = 0.043), non-shift group (p = 0.004), sleep extension group (p = 0.025), and health controls (multiple cohorts, p < 0.05). Additionally, CDL was also significantly correlated with AD’s clinical biomarkers. INTERPRETATIONS/CONCLUSION: By combining GWAS and transcriptome data, this study demonstrated the causal role of CRD behavior in AD, identified the potential target genes in shift work-induced AD, and generated CDL to characterize CRD status, which provided evidence and prospects for disease prevention and future therapeutic interventions.

CITATION:
Y. Xu ; G. Zhang ; L. Yang ; H. Qin ; Z. Zhou ; Q. Li ; H. Liu ; R. Wang ; Z. Cai ; L. Jing ; Y. Li ; Y. Yao ; Z. Gong ; P. Yuan ; T. Fu ; X. Zhao ; T. Peng ; Y. Jia (2024): Quantifying Personalized Shift-Work Molecular Portraits Underlying Alzheimer’s Disease through Computational Biology. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.161

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CORRELATES OF SUBJECTIVE COGNITIVE DECLINE IN BLACK AMERICAN MEN

D.K. Esiaka, C. Nwakasi, A.Q. Briggs, D.F. Conserve, R.J. Thorpe Jr

J Prev Alz Dis 2024;6(11):1734-1740

BACKGROUND: Past research suggests that subjective cognitive decline serves as an early and potentially important indicator that individuals may be at risk for future cognitive decline or neurodegenerative conditions. However, there is a dearth of studies on factors influencing the experience of subjective cognitive decline in Black Americans, especially in Black American men. OBJECTIVE: The current study explored correlates of subjective cognitive decline in Black American men. PARTICIPANTS: A total of 117 Black American men, with a mean age of 38.5 (SD = 7.14) years, participated in the study. MEASUREMENT: Participants completed a survey that assessed their demographic characteristics, self-rated health, neighborhood problems, length of residency in neighborhood, bodily symptoms, sleep comorbidities, sleep difficulties, and subjective cognitive decline. Linear regression analyses was performed and standardized beta coefficients were reported to describe the estimated independent effect of the predictor variables. RESULTS: We found that socioecomic status (β = -.222, p=.003), bodily symptoms (β = .246, p=.005), length of residency in neighborhood (β = .157, p=.029), and sleep difficulties (β = .305, p<.001) were significant correlates of subjective cognitive decline among Black American men. CONCLUSION: These findings underscore the intricate roles of socioeconomic status, bodily symptoms, neighborhood factors, and sleep health in shaping subjective cognitive experiences in this population. Research on subjective cognitive decline can contribute to the early identification of individuals at risk for cognitive decline, allowing for timely interventions, lifestyle modifications, and potential preventive measures.

CITATION:
D.K. Esiaka ; C. Nwakas ; A.Q. Briggs ; D.F. Conserve ; R.J. Thorpe Jr (2024): Correlates of Subjective Cognitive Decline in Black American Men. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.162

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PERFORMANCE OF A SHORT VERSION OF THE EVERYDAY COGNITION SCALE (ECOG-12) TO DETECT COGNITIVE IMPAIRMENT

M. Manjavong, A. Diaz, M.T. Ashford, A. Aaronson, M.J. Miller, J.M. Kang, S. Mackin, R. Tank, B. Landavazo, D. Truran, S.T. Farias, M. Weiner, R. Nosheny, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2024;6(11):1741-1750

BACKGROUND: The Everyday Cognition (ECog) 12-item scale, a functional decline measurement, can distinguish dementia from cognitively unimpaired (CU). Limited data compare ECog-12 performance by raters (self vs. informant) and scoring systems (average numeric vs. categorical grouping) to differentiate cognitive statuses. OBJECTIVES: To evaluate the performance of ECog-12 in differentiation cognitive statuses. DESIGN: A cross-sectional diagnostic test study. SETTING AND PARTICIPANTS: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study are analyzed. Participants were aged 55-90 years old divided into subgroups based on diagnostic criteria. MEASUREMENTS: We evaluated ECog-12 performance across different diagnostic groups, such as CU vs cognitive impairment (CI; mild cognitive impairment (MCI), and dementia), and the association between ECog-12 and CI. This procedure was repeated for self- and partner (informant)-reports. Additionally, types of ECog scores were also assessed, where an average ECog score was calculated (continuous numeric) as well as a categorical grouping (“any occasional declined” or “any consistently declined”) based on item-level responses to ECog questions. RESULTS: ECog-12 cut-off scores of 1.36 (self-reported) and 1.45 (partner-reported) distinguish CU from CI with AUC 0.7 and 0.78, respectively. Adding a memory-concern question improved self-reported-ECog AUC to 0.79. Self- and partner-reported “consistently-declined” ECog-12 categorical grouping provided AUC 0.69 and 0.78. The study partner reported ECog-12 showed a greater association with CI than self-reported, with odds ratios of 35.45 and 8.79, respectively. CONCLUSION: Study partner-reported ECog scores performed better than self-reported ECog-12 in differentiating cognitive statuses, and a higher study partner reported ECog score was a higher prognostic risk for CI. A memory concern question could enhance self-reported ECog-12 performance. This further emphasizes the need to obtain data from study partners for research and clinical practice.

CITATION:
M. Manjavong ; A. Diaz ; M.T. Ashford ; A. Aaronson ; M.J. Miller ; J.M. Kang ; S. Mackin ; R. Tank ; B. Landavazo ; D. Truran ; S.T. Farias ; M. Weiner ; R. Nosheny ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Performance of a Short Version of the Everyday Cognition Scale (ECog-12) to Detect Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.109

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DEVELOPMENT AND CONCURRENT VALIDITY OF THE SHORTFORM COGDRISK DEMENTIA RISK ASSESSMENT TOOL

K.J. Anstey, M.H. Huque, S. Kootar, R. Eramudugolla, M. Li

J Prev Alz Dis 2024;6(11):1751-1758

Evidence-based dementia risk assessment is required to inform individual and policy-level dementia risk reduction interventions. We developed the CogDrisk Short Form (CogDrisk-SF) to assess dementia risk factors, for situations where time and resources are limited. To evaluate concurrent validity with the original CogDrisk, we conducted an online survey using a repeated-measures, counterbalanced design. Community dwelling participants (n = 647, 50.1% were female, mean age 62.2 years, age range 40-89) completed the survey. The mean(sd) score for CogDrisk-SF and the CogDrisk was 9.7 (5.3) and 9.9 (5.5), respectively. The intraclass correlation between the risk score obtained from CogDrisk and CogDrisk-SF was 0.92. Fish intake, insomnia and depression had percentage agreements of 79%, 87% and 89% respectively. Other items had >95% agreement except for loneliness (94%), hypertension (94%), cholesterol (93%), atrial fibrillation (91%) and cognitive activity (90%). Very high agreement between the CogDrisk-SF and original CogDrisk shows that CogDrisk-SF is valid for use in research and clinical practice.

CITATION:
K.J. Anstey ; M.H. Huque ; S. Kootar ; R. Eramudugolla ; M. Li (2024): Development and Concurrent Validity of the Short-Form CogDrisk Dementia Risk Assessment Tool. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.108

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UNVEILING POTENTIAL BIOMARKERS IN CEREBROSPINAL FLUID FOR AMYLOID PATHOLOGICAL POSITIVITY IN NON-DEMENTED INDIVIDUALS

F. Meng, X. Zhang, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

J Prev Alz Dis 2024;6(11):1759-1766

BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque accumulation and neurofibrillary tangles. The recent approval of anti-amyloid therapeutic medications highlights the crucial need for early detection of Aβ pathological abnormalities in individuals without dementia to facilitate timely intervention and treatment. OBJECTIVE: The primary aim of this study was to identify cerebrospinal fluid (CSF) biomarkers strongly associated with Aβ pathological positivity in a non-demented cohort and evaluate their clinical values. METHODS: A comprehensive analysis was conducted on 51 CSF proteins (excluding Aβ42, pTau, and Tau) obtained from 474 non-demented participants sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. By utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) regression, we identified potential proteins indicative of Aβ pathological positivity and evaluated their performance in tracking longitudinal pathological progression. RESULTS: Our LASSO analysis unveiled three candidates: apolipoprotein E (APOE), chitinase-3-like protein 1 (CHI3L1), and SPARC-related modular calcium-binding protein 1 (SMOC1). While SMOC1 did not correlate with Aβ42-related cognitive alterations, it displayed better abilities in discriminating both CSF-Aβ positivity and Aβ-positron emission tomography (PET) positivity than the other two candidates. It could precisely predict longitudinal Aβ-PET status conversion. Notably, SMOC1 was the only protein showing associations with longitudinal Aβ-PET trajectory and enhancing the diagnostic accuracy of Aβ42. The assessment of combined Aβ42 and SMOC1 yielded valuable clinical insights. CONCLUSION: Our findings elucidated SMOC1 as a potential biomarker for detecting Aβ abnormalities. Aβ42 combining SMOC1 offered critical implications in AD pathological diagnosis and management.

CITATION:
F. Meng ; X. Zhang ; for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) ; (2024): Unveiling Potential Biomarkers in Cerebrospinal Fluid for Amyloid Pathological Positivity in Non-Demented Individuals. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.129

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MODULATORY EFFECT OF BLOOD LDL CHOLESTEROL ON THE ASSOCIATION BETWEEN CEREBRAL AΒ AND TAU DEPOSITION IN OLDER ADULTS

S.M. Han, M.S. Byun, D. Yi, J.H. Jung, N. Kong, Y.Y. Chang, M. Keum, G.J. Jung, J.-Y. Lee, Y.-S. Lee, Y.K. Kim, K.M. Kang, C.-H. Sohn, D.Y. Lee, and for the KBASE Research Group

J Prev Alz Dis 2024;6(11):1767-1774

BACKGROUND: This study investigates the synergistic relationship between blood low-density lipoprotein cholesterol (LDL-C) and cerebral beta-amyloid (Aβ) in relation to tau deposition, a key factor in the pathology of Alzheimer’s disease (AD), in older adults across a diverse cognitive spectrum. OBJECTIVES: To examine whether higher levels of LDL-C in the blood moderate the association of cerebral Aβ with tau deposition in older adults, including those with normal cognition, mild cognitive impairment, and Alzheimer’s disease dementia. DESIGN: Cross-sectional design. Setting: The study was conducted as a part of a prospective cohort study. All assessments were done at the Seoul National University Hospital, Seoul, South Korea. Participants: A total of 136 older adults (aged 60-85 years) with normal cognition, mild cognitive impairment or Alzheimer’s disease (AD) dementia were included. MEASUREMENTS: Serum lipid measurements, [11C] Pittsburgh Compound B-positron emission tomography (PET), [18F] AV-1451 PET, and magnetic resonance imaging were performed on all participants. RESULTS: There was a significant Aβ x LDL-C interaction effect on tau deposition indicating a synergistic moderation effect of LDL-C on the relationship between Aβ and tau deposition. Subsequent subgroup analysis showed that the positive association between Aβ and tau deposition was stronger in higher LDL-C group than in lower LDL-C group. In contrast, other lipids, such as total cholesterol, high-density lipoprotein cholesterol, and triglycerides, did not show a similar moderation effect on the relationship between Aβ deposition and tau deposition. CONCLUSION: Our findings suggest that blood LDL-C synergistically enhances the influence of Aβ deposition on tau pathology, emphasizing the need for greater attention to the role of LDL-C in AD progression.

CITATION:
S.M. Han ; M.S. Byun ; D. Yi ; J.H. Jung ; N. Kong ; Y.Y. Chang ; M. Keum ; G.J. Jung ; J.-Y. Lee ; Y.-S. Lee ; Y.K. Kim ; K.M. Kang ; C.-H. Sohn ; D.Y. Lee ; and for the KBASE Research Group ; (2024): Modulatory Effect of Blood LDL Cholesterol on the Association between Cerebral Aβ and Tau Deposition in Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.131

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LEVERAGING DIVERSE REGULATED CELL DEATH PATTERNS TO IDENTIFY DIAGNOSIS BIOMARKERS FOR ALZHEIMER’S DISEASE

L. Ren, Q. Zhang, J. Zhou, X. Wang, D. Zhu, X. Chen

J Prev Alz Dis 2024;6(11):1775-1788

BACKGROUND: The functions of regulated cell death (RCD) are closely related to Alzheimer’s disease (AD). However, very few studies have systematically investigated the diagnosis and immunologic role of RCD-related genes in AD patients. METHODS: 8 multicenter AD cohorts were included in this study, and then were merged into a meta cohort. Then, an unsupervised clustering analysis was carried out to detect unique subtypes of AD based on RCD-related genes. Subsequently, differently expressed genes (DEGs) and weighted correlation network analysis (WGCNA) between subtypes were identified. Finally, to establish an optimal risk model, an RCD.score was constructed by using computational algorithm (10 machine-learning algorithms, 113 combinations). RESULTS: We identified two distinct subtypes based on RCD-related genes, each exhibiting distinct hallmark pathway activity and immunologic landscape. Specifically, cluster.A patients had a higher immune infiltration, a higher immune modulators and poor AD progression. Utilizing the shared DEGs and WGCNA of these subtypes, we constructed an RCD.score that demonstrated excellent predictive ability in AD across multiple datasets. Furthermore, RCD.score was identified to exhibit the strongest association with poor AD progression. Mechanistically, we observed activation of signaling pathways and effective immune infiltration and immune modulators in the high RCD.score group, thus leading to a poor AD progression. Additionally, Mendelian randomization screening revealed four genes (CXCL1, ENTPD2, METTL7A, and SERPINB6) as feature genes for AD. CONCLUSION: The RCD model is a valuable tool in categorizing AD patients. This model can be of great assistance to clinicians in determining the most suitable personalized treatment plan for each individual AD patient.

CITATION:
L. Ren ; Q. Zhang ; J. Zhou ; X. Wang ; D. Zhu ; X. Chen (2024): Leveraging Diverse Regulated Cell Death Patterns to Identify Diagnosis Biomarkers for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.119

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ACOUSTIC SPEECH ANALYSIS IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

S. Saeedi, S. Hetjens, M.O.W. Grimm, B. Barsties v. Latoszek

J Prev Alz Dis 2024;6(11):1789-1797

BACKGROUND: The potential of biomarkers in the detection of Alzheimer’s disease (AD) is prominent. Acoustics may be useful in this context but the evaluation and weighting for specific acoustic parameters on continuous speech is missing. This meta-analysis aimed to explore the significance of acoustic parameters from acoustic speech analysis on continuous speech, as a diagnostic tool for clinical AD. METHODS: Applying PRISMA protocol, a comprehensive search was done in MEDLINE, Scopus, Web of Science, and CENTRAL, from 1960 to January 2024. Cross-sectional studies comparing the acoustic speech analysis between AD patients and healthy controls (HC), were taken into account. The bias risk of the included studies were examined via JBI checklist. Using Review Manager v.5.4.1, the mean differences of acoustic speech parameters among AD and HC were weighted, and the pooled analysis and the heterogeneity statistics were conducted. RESULTS: In total, 1112 records (without duplicates) were obtained, and 11 papers with 7 acoustic parameters were included for this study, and 8 from 11 studies were identified with a low level of bias. Five from 7 acoustic parameters revealed significant differences among the two groups (p-values ≤ 0.01), in which for all rate-related and interruption-related acoustic parameters were the most prominent and less in temporal-related acoustic parameters. CONCLUSIONS: Although a small number of acoustic parameters on continuous speech could be evaluated in the detection of clinical AD, the greatest potential of acoustic biomarkers for AD appeared to exist in two of three categories. Further contributions of high-quality studies are needed to support evidence for acoustics as biomarkers for AD.

CITATION:
S. Saeedi ; S. Hetjens ; M.O.W. Grimm ; B. Barsties v. Latoszek (2024): Acoustic Speech Analysis in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.132

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DAYTIME SLEEPINESS, APNEA, NEUROIMAGING CORRELATES AND CORTISOL DYSREGULATION IN A MEMORY CLINIC COHORT

C. Sørensen, I. Kåreholt, G. Kalpouzos, C.T. Udeh-Momoh, J. Holleman, M. Aspö, G. Hagman, G. Spulber, M. Kivipelto, A. Solomon, S. Sindi

J Prev Alz Dis 2024;6(11):1798-1808

BACKGROUND: Sleep disturbances as well as cortisol hypersecretion are increasingly acknowledged as risk factors for Alzheimer’s disease (AD). However, the mechanisms underlying the association, and the interplay with cortisol abnormalities, remain unclear. OBJECTIVES: This study aims to identify how self-reported sleep disturbances are associated with structural brain measures and diurnal cortisol dysregulation among memory clinic patients. DESIGN: A cross-sectional study performed at Karolinska University Hospital Memory Clinic, Sweden. PARTICIPANTS: The study was based on 146 memory clinic patients diagnosed with either subjective cognitive impairment or mild cognitive impairment. MEASUREMENTS: Self-reported sleep was measured using the Karolinska Sleep Questionnaire. MRI or CT was used to quantify structural brain measures using four visual rating scales (Scheltens, Pasquier, Koedam, and Fazekas scales), and salivary cortisol was sampled to measure diurnal cortisol patterns through measures of cortisol immediately after awakening, cortisol awakening response, bedtime cortisol, total cortisol from awakening to bedtime, and the AM/PM cortisol ratio. RESULTS: Increased sleep apnea index (OR=1.20, 95% CI=1.04:1.39, p=0.015) was associated with greater odds of posterior brain atrophy, measured by the Koedam visual rating scale, and reduced awakening cortisol (β=-0.03, 95% CI=-0.07:0.00, p=0.045). Increased daytime sleepiness was associated with both reduced awakening cortisol (β=-0.03, 95% CI=-0.06:0.00, p=0.025) and a reduced AM/PM cortisol ratio (β=-0.04, CI=-0.08:-0.01, p= 0.021). CONCLUSION: In a memory clinic cohort self-reported sleep disturbances are associated with both worse structural brain tissue integrity and altered diurnal cortisol profiles. These findings may add insights into possible mechanisms behind sleep disturbances in aging with subjective and cognitive impairment.

CITATION:
C. Sørensen ; I. Kåreholt ; G. Kalpouzos ; C.T. Udeh-Momoh ; J. Holleman ; M. Aspö ; G. Hagman ; G. Spulber ; M. Kivipelto ; A. Solomon ; S. Sindi ; (2024): Daytime Sleepiness, Apnea, Neuroimaging Correlates and Cortisol Dysregulation in a Memory Clinic Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.145

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A PILOT ELECTROENCEPHALOGRAPHY STUDY OF THE EFFECT OF CT1812 TREATMENT ON SYNAPTIC ACTIVITY IN PATIENTS WITH MILD TO MODERATE ALZHEIMER’S DISEASE

E. Vijverberg, W. de Haan, E. Scheijbeler, M.E. Hamby, S. Catalano, P. Scheltens, M. Grundman, A.O. Caggiano

J Prev Alz Dis 2024;6(11):1809-1817

BACKGROUND: CT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity. OBJECTIVES: Evaluate CT1812 impact on synaptic function using qEEG measurements. DESIGN: Phase 2, randomized, double-blind, placebo-controlled, 4-week crossover study. SETTING: VU University Medical Center and Brain Research Center Amsterdam, The Netherlands. PARTICIPANTS: Adults with mild or moderate Alzheimer’s disease (AD). INTERVENTION: A daily 300 mg dose of CT1812 or placebo for 4 weeks. MEASUREMENTS: A resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4-8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed. RESULTS: 16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo - most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported. CONCLUSION: CT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.

CITATION:
E. Vijverberg ; W. de Haan ; E. Scheijbeler ; M.E. Hamby ; S. Catalano ; P. Scheltens ; M. Grundman ; A.O. Caggiano (2024): A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.154

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NO ASSOCIATION FOUND: ADVERSE CHILDHOOD EXPERIENCES AND COGNITIVE IMPAIRMENT IN OLDER AUSTRALIAN ADULTS

J. Lian, K.M. Kiely, B.L. Callaghan, R. Eramudugolla, M. Mortby, K.J. Anstey

J Prev Alz Dis 2024;6(11):1818-1825

OBJECTIVE: This study aimed to investigate the relationship between childhood adversity and cognitive impairment in older adults. METHODS: We analysed data from 1568 participants aged 72-79 (M = 75.1, SD = 1.5, % male = 52.6%) from Wave 4 of the Personality and Total Health (PATH) Through Life Project. The outcome variable was the presence of mild cognitive impairment (MCI) or dementia, determined through a clinically validated algorithmic diagnostic criteria. Childhood adversity was assessed using a 17-item scale covering various domestic adversities such as poverty, neglect, physical abuse, and verbal abuse. Adversity was operationalised using cumulative analysis, dichotomisation (<3 adversities; 3+ adversities), and latent class analysis. Multiple logistic regressions were employed to estimate the association between childhood adversity and cognitive impairment, while controlling for covariates including education, gender, ethnicity, and APOE ε4 status. RESULTS: Our analyses revealed no significant association between childhood adversity and the presence of MCI or dementia across all tested models. Sensitivity analyses, exploring alternative scenarios, consistently failed to yield statistically significant findings. CONCLUSION: In contrast to prevailing research findings, this study does not support a link between childhood domestic adversity and late-life cognitive outcomes. These results underscore the mixed results on adversity and cognition, highlighting the need for further research. Future investigations should consider the roles of potential mediating and protective factors within this complex relationship.

CITATION:
J. Lian ; K.M. Kiely ; B.L. Callaghan ; R. Eramudugolla ; M. Mortby ; K.J. Anstey (2024): No Association Found: Adverse Childhood Experiences and Cognitive Impairment in Older Australian Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.133

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THE CAUSAL RELATIONSHIP BETWEEN GENETICALLY PREDICTED BIOLOGICAL AGING, ALZHEIMER’S DISEASE AND COGNITIVE FUNCTION: A MENDELIAN RANDOMISATION STUDY

Y. Hao, W. Tian, B. Xie, X. Fu, S. Wang, Y. Yang

J Prev Alz Dis 2024;6(11):1826-1833

Aging is one of the most important risk factors for Alzheimer’s disease (AD). Biological aging is a better indicator of the body’s functional state than age (chronological aging). Leukocyte telomere length (LTL) and epigenetic clocks constructed from DNA methylation patterns have emerged as reliable markers of biological aging. Recent studies have shown that it may be possible to slow down or even reverse biological aging, offering promising prospects for treating AD. Several observational studies have reported an association between biological aging, AD, and cognitive function, but the causality behind this association and the effects of different biological aging markers on AD risk and cognitive function remain unclear. Therefore, we explored the causal relationship between them by Mendelian randomization (MR) study. Inverse-variance weighted (IVW) method is the most dominant analytical method in MR studies, which is a weighted average of estimates from different genotype combinations, and this weighted average provides an overall estimate of the causal effect. The results of the IVW analyses showed that HannumAge acceleration and LTL shortening were able to increase the risk of late-onset AD (LOAD), but not early-onset AD (EOAD). Excellent prospective memory and fluid intelligence are potentially protective against GrimAge acceleration. GrimAge acceleration and HorvathAge acceleration increase the risk of LOAD through effects on LTL. Our findings provide important insights into the role of biological aging in the pathogenesis of AD, while also highlighting the interplay of different biological aging markers and their complexity in different AD subtypes.

CITATION:
Y. Hao ; W. Tian ; B. Xie ; X. Fu ; S. Wang ; Y. Yang (2024): The Causal Relationship between Genetically Predicted Biological Aging, Alzheimer’s Disease and Cognitive Function: A Mendelian Randomisation Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.128

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BLOOD CATHEPSINS ON THE RISK OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGICAL BIOMARKERS: RESULTS FROM OBSERVATIONAL COHORT AND MENDELIAN RANDOMIZATION STUDY

X.-H. Qian, G.-Y. Ding, S.-Y. Chen, X.-L. Liu, M. Zhang, H.-D. Tang

J Prev Alz Dis 2024;6(11):1834-1842

BACKGROUND: Alzheimer’s disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD. METHODS: This study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer’s disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers. RESULTS: Using MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ- cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants. CONCLUSION: This study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.

CITATION:
X.-H. Qian ; G.-Y. Ding ; S.-Y. Chen ; X.-L. Liu ; M. Zhang ; H.-D. Tang (2024): Blood Cathepsins on the Risk of Alzheimer’s Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.107

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EVALUATING CAUSAL EFFECTS OF GUT MICROBIOME ON ALZHEIMER’S DISEASE

Q. Zhao, A. Baranova, H. Cao, F. Zhang

J Prev Alz Dis 2024;6(11):1843-1848

BACKGROUND: The preceding evidence indicates a close correlation between imbalances in the gut microbiome and Alzheimer’s disease (AD), yet the direct causal relationship remains unclear. Our objective is to investigate this potential causal connection. METHODS: We obtained summary results from two significant genome-wide association studies (GWAS) on gut microbiota (the MibioGen consortium and the Dutch Microbiome Project), along with one GWAS summary result for AD. Using a two-sample Mendelian randomization (TSMR) analysis, we examined the potential causal effects of gut microbiota on AD. RESULTS: Our TSMR analysis revealed that 16 gut bacterial taxa were linked to a reduced risk of AD. These included phylum Tenericutes, classes Bacilli and Clostridia along with its order Clostridiales, family Bacteroidaceae, genus Bacteroides, and species Bifidobacterium bifidum (OR: 0.867~0.971, P ≤ 0.045). Conversely, the presence of 12 taxa correlated with an increased risk of AD. These comprised class Actinobacteria and its family Coriobacteriaceae, as well as class Betaproteobacteria, its order Burkholderiales, and its family Sutterellaceae (OR: 1.042~1.140, P ≤ 0.035). CONCLUSION: Our research uncovered evidence suggesting certain gut bacterial species might play a causal role in AD risk, providing a fresh angle for AD treatment strategies.

CITATION:
Q. Zhao ; A. Baranova ; H. Cao ; F. Zhang ; (2024): Evaluating Causal Effects of Gut Microbiome on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.113

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