03/2022 journal articles
EDITORIAL: THE DAWN OF A NEW ERA OF ALZHEIMER’S RESEARCH AND DRUG DEVELOPMENT
Y. Hara, H.M. Fillit
J Prev Alz Dis 2022;3(9):385-386Show summaryHide summary
Y. Hara ; H.M. Fillit ; (2022): The Dawn of a New Era of Alzheimer’s Research and Drug Development. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.64
EDITORIAL: THE CLINICAL TRIALS ALZHEIMER’S DISEASE (CTAD) MEETING IN SAN FRANCISCO, FALL 2022, WILL BE A VERY EXCITING EVENT!
J Prev Alz Dis 2022;3(9):387Show summaryHide summary
M.W. Weiner (2022): The Clinical Trials Alzheimer’s Disease (Ctad) Meeting in San Francisco, Fall 2022, Will Be a Very Exciting Event!. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.65
TACKLING A MAJOR DEFICIENCY OF DIVERSITY IN ALZHEIMER’S DISEASE THERAPEUTIC TRIALS: AN CTAD TASK FORCE REPORT
R. Raman, P. Aisen, M.C. Carillo, M. Detke, J.D. Grill, O.C. Okonkwo, M. Rivera-Mindt, M. Sabbagh, B. Vellas, M. Weiner, R. Sperlin, and CTAD Task Force
J Prev Alz Dis 2022;3(9):388-392Show summaryHide summary
As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer’s Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials. New and innovative recruitment initiatives and enhanced infrastructure facilitate increased participant diversity in AD clinical studies.
R. Raman ; P. Aisen ; M.C. Carillo ; M. Detke ; J.D. Grill ; O.C. Okonkwo ; M. Rivera-Mindt ; M. Sabbagh ; B. Vellas ; M. Weiner ; R. Sperling ; and CTAD Task Force* ; (2022): Tackling a Major Deficiency of Diversity in Alzheimer’s Disease Therapeutic Trials: An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.50
THE FUTURE OF AD CLINICAL TRIALS WITH THE ADVENT OF ANTI-AMYLOID THERAPIES: AN CTAD TASK FORCE REPORT
J. Delrieu, R.J. Bateman, J. Touchon, M. Sabbagh, J. Cummings
J Prev Alz Dis 2022;3(9):393-399Show summaryHide summary
BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.
J. Delrieu ; R.J. Bateman ; J. Touchon ; M. Sabbagh ; J. Cummings ; (2022): The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.48
PREDICTION OF COGNITIVE DECLINE FOR ENRICHMENT OF ALZHEIMER’S DISEASE CLINICAL TRIALS
A. Tam, C. Laurent, S. Gauthier, C. Dansereau, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2022;3(9):400-409Show summaryHide summary
Background: A key issue to Alzheimer’s disease clinical trial failures is poor participant selection. Participants have heterogeneous cognitive trajectories and many do not decline during trials, which reduces a study’s power to detect treatment effects. Trials need enrichment strategies to enroll individuals who are more likely to decline.
Objectives: To develop machine learning models to predict cognitive trajectories in participants with early Alzheimer’s disease and presymptomatic individuals over 24 and 48 months respectively.
Design: Prognostic machine learning models were trained from a combination of demographics, cognitive tests, APOE genotype, and brain imaging data.
Setting: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), National Alzheimer’s Coordinating Center (NACC), Open Access Series of Imaging Studies (OASIS-3), PharmaCog, and a Phase 3 clinical trial in early Alzheimer’s disease were used for this study.
Participants: A total of 2098 participants who had demographics, cognitive tests, APOE genotype, and brain imaging data, as well as follow-up visits for 24-48 months were included.
Measurements: Baseline magnetic resonance imaging, cognitive tests, demographics, and APOE genotype were used to separate decliners, defined as individuals whose CDR-Sum of Boxes scores increased during a predefined time window, from stable individuals. A prognostic model to predict decline at 24 months in early Alzheimer’s disease was trained on 1151 individuals who had baseline diagnoses of mild cognitive impairment and Alzheimer’s dementia from ADNI and NACC. This model was validated on 115 individuals from a placebo arm of a Phase 3 clinical trial and 76 individuals from the PharmaCog dataset. A second prognostic model to predict decline at 48 months in presymptomatic populations was trained on 628 individuals from ADNI and NACC who were cognitively unimpaired at baseline. This model was validated on 128 individuals from OASIS-3.
Results: The models achieved up to 79% area under the curve (cross-validated and out-of-sample). Power analyses showed that using prognostic models to recruit enriched cohorts of predicted decliners can reduce clinical trial sample sizes by as much as 51% while maintaining the same detection power.
Conclusions: Prognostic tools for predicting cognitive decline and enriching clinical trials with participants at the highest risk of decline can improve trial quality, derisk endpoint failures, and accelerate therapeutic development in Alzheimer’s disease.
A. Tam ; C. Laurent ; S. Gauthier ; C. Dansereau ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2022): Prediction of Cognitive Decline for Enrichment of Alzheimer’s Disease Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.49
EFFECTS OF NON-INVASIVE BRAIN STIMULATION ON ALZHEIMER’S DISEASE
L. Gu, H. Xu, F. Qian
J Prev Alz Dis 2022;3(9):410-424Show summaryHide summary
Background: Previous meta-analyses did not explore the immediate and long-term effect of non-invasive brain stimulation (NIBS) on different cognitive domains in Alzheimer’s disease (AD). The meta-analysis aimed to assess the therapy effect of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on different cognitive domains in AD in randomized controlled trials (RCTs).
Methods: Studies published before December 2021 and exploring therapy effect of rTMS, tDCS on different cognitive domains in AD were searched in the following databases: PubMed and Web of Science. We used STATA 12.0 software to compute the standard mean difference (SMD) and a 95% confidence interval (CI).
Results: The present study included 16 articles (including 372 AD patients treated with rTMS and 310 treated with sham rTMS) for rTMS and 11 articles (including 152 AD patients treated with tDCS and 134 treated with sham tDCS) for tDCS. The present study showed better immediate and long-term general cognitive function increase effects in AD given rTMS, compared to those given sham rTMS with random effects models (immediate effect: SMD = 2.07, 95% CI = 0.37 to 3.77, I2 = 97.8%, p < 0.001; long-term effect: SMD = 5.04, 95% CI = 2.25 to 7.84, I2 = 97.8%, p < 0.001). The present study showed no significant immediate and long-term effects of rTMS on attention, executive, language and memory functions. In addition, the present study showed no significant difference in immediate or long-term effects of tDCS on general cognitive function, attention, language or memory functions between tDCS group and sham tDCS group.
Conclusions: RTMS was an effective treatment technique for general cognitive function in AD, whereas tDCS showed no significant therapy effect on cognitive function in AD. More large-scale studies were essential to explore the effect of NIBS on various cognitive function in AD.
L. Gu ; H. Xu ; F. Qian : Effects of Non-Invasive Brain Stimulation on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad..40
EVALUATION OF THE FEASIBILITY, SAFETY AND EFFICACY OF THE USE OF INTRAVENOUS INFUSIONS OF ADENOSINE TRIPHOSPHATE (ATP) IN PEOPLE AFFECTED BY MODERATE TO SEVERE ALZHEIMER\'S DISEASE: A DOUBLE-BLIND MASKED CLINICAL TRIAL FOR DOSE FINDING
A. Ruiz, D. Sánchez, A. Lafuente, G. Ortega, M. Buendía, J. Papasey, S.Y. Jimeno, F.P. Badia, M.E. Palacio, C. Abdelnour, F. Ramírez-Toraño, F. Maestú, M.E. Sáez, L. Tárraga, P.C. Dagnelie, M. Boada
J Prev Alz Dis 2022;3(9):425-434Show summaryHide summary
Background: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer’s disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented.
Objectives: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion.
Design: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates.
Participants: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions.
Results: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables.
Conclusions: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.
A. Ruiz ; D. Sánchez ; A. Lafuente ; G. Ortega ; M. Buendía ; J. Papasey ; S.Y. Jimeno ; F.P. Badia ; M.E. Palacio ; C. Abdelnour ; F. Ramírez-Toraño ; F. Maestú ; M.E. Sáez ; L. Tárraga ; P.C. Dagnelie ; M. Boada ; (2022): Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.38
SUBJECTIVE COGNITIVE DECLINE IN A REGISTRY SAMPLE: RELATION TO PSYCHIATRIC HISTORY, LONELINESS, AND PERSONALITY
G.O. Reynolds, L. Manning, D. Kirn, H. Klein, O. Hampton, O. Burke Jr., R. Buckley, D. Rentz, R. Sperling, G.A. Marshall, R.E. Amariglio
J Prev Alz Dis 2022;3(9):435-440Show summaryHide summary
BACKGROUND: With the increasing focus on prevention of Alzheimer’s disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline.
OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia).
DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor’s degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality.
RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years.
CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.
G.O. Reynolds ; L. Manning ; D. Kirn ; H. Klein ; O. Hampton ; O. Burke Jr. ; R. Buckley ; D. Rentz ; R. Sperling ; G.A. Marshall ; R.E. Amariglio ; (2022): Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.31
INCREASED INCIDENT ALZHEIMER’S DISEASE AMONG INDIVIDUALS WITH VARICOSE VEINS: A POPULATION-BASED COHORT STUDY
J Prev Alz Dis 2022;3(9):441-448Show summaryHide summary
Background: Varicose vein may be related to increased risk of comorbidities and decreased cognitive function in the elderly, but little is known about the association between varicose vein and Alzheimer’s disease.
Objectives: To evaluate whether there is an association between varicose veins and Alzheimer’s disease.
Design: The study subjects of this cohort study were selected based on Chang Gung Research Database from January 1, 2003, to December 31, 2012. Follow-up ended December 31, 2017.
Setting: A population-based study
Participants: Patients aged 45 years and older with varicose veins were enrolled, and the participants of control group were selected by matching with gender, age, and index date at a 4:1 ratio.
Measurements: The hazard ratios associated with varicose veins were estimated using Cox regression analysis with competitive risk model. Incidence rates of Alzheimer’s disease, was assessed in people with and without varicose veins.
Results: A total of 9,601 patients with varicose veins and 38,404 matched controls were enrolled in the study. The varicose veins group had higher incidence rates than the control group for Alzheimer’s disease (12.60 vs 6.24 per 10,000 person-years; Hazard ratio, 1.647 [95% confidence interval, 1.326- 2.045, p<0.001]). Patients with complicated varicose veins had increased incidence of Alzheimer’s disease than uncomplicated cases (adjusted HR, 1.474; 95% CI, 1.034-2.101, P=0.032).
Conclusion: The present study demonstrated a positive association between the varicose veins and Alzheimer’s disease. Physicians should be alerted to cognitive function in patients with varicose veins, especially those with presence of inflammation and ulcerations.
C.-Y. Cheng (2022): Increased Incident Alzheimer’s Disease among Individuals with Varicose Veins: A Population-Based Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.23
ASSOCIATION BETWEEN DIETARY THEOBROMINE AND COGNITIVE FUNCTION IN A REPRESENTATIVE AMERICAN POPULATION: A CROSS-SECTIONAL STUDY
L. Gao, W. Ge, C. Peng, J. Guo, N. Chen, L. He
J Prev Alz Dis 2022;3(9):449-457Show summaryHide summary
Background: Despite reports on neuroprotective effects of dietary theobromine intake, whether dietary theobromine has beneficial effects on cognitive function is unclear.
Objectives: To investigate the association between dietary theobromine and cognitive function.
Design: A cross-sectional study.
Setting: Data were collected from the 2011-2014 cycles of the National Health and Nutrition Examination Survey conducted by the Centers for Disease Control and Prevention of the USA.
Participants: A representative American population aged ≥60 years.
Measurements: L-theobromine was treated as a log transform and dichotomous form (the highest quantile vs. others). Cognitive function was measured using four tests: Consortium to Establish a Registry for Alzheimer's Disease Word Learning tests, Consortium to Establish a Registry for Alzheimer's Disease delayed recall test, animal fluency test, and digit symbol substitution test. We conducted multiple regression analyses and subgroup analyses to study the association between theobromine and cognitive performance. Basic characteristics, lifestyle factors, disease history, and nutritional intake were adjusted for in these models.
Results: A total of 2,845 participants were included in the study. The highest quantile of L-theobromine intake was positively associated with sores of delayed recall, animal fluency, and digit symbol substitution tests (β, 95% confidence interval, P: 0.11, -0.00-0.30, 0.049; 0.50, 0.02-0.99, 0.043; 1.55, 0.33-2.77, 0.015; respectively) in the fully adjusted model, but not with immediate recall score (β=0.13, 95% confidence interval -0.16-0.43, P=0.361). Subgroup analyses showed that L-theobromine intake was associated with cognitive performance in the highest quantile of caffeine intake.
Conclusions: Daily theobromine intake was associated with cognitive performance in a large nationally representative population. However, further research is needed to corroborate our findings.
L. Gao ; W. Ge ; C. Peng ; J. Guo ; N. Chen ; L. He (2022): Association between Dietary Theobromine and Cognitive Function in a Representative American Population: A Cross-Sectional Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.39
MESENCHYMAL STEM CELLS MODULATE SIRT1/MIR-134/ GSK3Β SIGNALING PATHWAY IN A RAT MODEL OF ALZHEIMER\'S DISEASE
O.A.R. Abozaid, M.W. Sallam, E.S.A. Ahmed
J Prev Alz Dis 2022;3(9):458-468Show summaryHide summary
Prolonged exposure to environmental aluminum-containing substances is associated with the development of Alzheimer's disease (AD). AD is a brain disorder associated with a gradual weakening in neurocognitive functions. Mesenchymal stem cells (MSCs) transplant as a promising and safe approach is used to treat AD through countless mechanisms. Therefore, this study aims to elucidate how MSCs improve biochemical and histopathological approaches associated with the AD model in rats. MSCs treatment restores the redox status impairment through a notable decline in the malondialdehyde (MDA) levels along with antioxidant enrichment. The anti-inflammatory effect of MSCs through conversion of microglial cells from M1 to M2 and inhibition of pro-inflammatory mediator’s release work in with de-activated GSK-3β. Additionally, the alleviation of autophagy and lysosomal clearance of Aβ and tau aggregates was accompanied by a down-regulation of the mTOR. Moreover, MSCs upregulate the expression of SIRT1 together with a limited expression of miR-134 thereby, improve neurite outgrowth and synaptic loss. Overall, the obtained data confirm the novelty of MSCs in the treatment of AD not only by their antioxidant, anti-inflammatory effect but also by restoring the neural integrity, neurogenesis, improving the neurocognitive function, and modulation of the signal pathways linked to the Aβ hypothesis.
O.A.R. Abozaid ; M.W. Sallam ; E.S.A. Ahmed ; (2022): Mesenchymal Stem Cells Modulate SIRT1/MiR-134/ GSK3β Signaling Pathway in a Rat Model of Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.26
A CONFORMATIONAL VARIANT OF P53 (U-P53AZ) AS BLOODBASED BIOMARKER FOR THE PREDICTION OF THE ONSET OF SYMPTOMATIC ALZHEIMER’S DISEASE
S. Piccirella, L. Van Neste, C. Fowler, C.L. Master, J. Fripp, J.D. Doeck, C. Xiong, D. Uberti, P. Kinnon
J Prev Alz Dis 2022;3(9):469-479Show summaryHide summary
Background: Ongoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer’s disease (AD).
Objective: The unfolded conformational variant of p53 (U-p53AZ), previously observed in AD individuals, was evaluated in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort for diagnostic and prognostic assessment, validated on a neuropsychological-based diagnosis, over the course of six years.
Design: Retrospective Longitudinal Prognostic biomarker study.
Setting: Single-center study based on the AIBL cohort.
Participants: 482 participants of the AIBL cohort, aged 60-85 years, without uncontrolled diabetes, vascular disease, severe depression or psychiatric illnesses.
Measurements: The AlzoSure® Predict test, consisting of immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), was performed to quantify the AZ 284® peptide as readout of U-p53AZ and compared with an independent neuropsychological diagnosis. The amyloid load via amyloid β-positron emission tomography (Aβ-PET) and supporting clinical information were included where possible.
Results: U-p53AZ diagnostic and prognostic performance was assessed in both time-independent and time-dependent (36, 72 and 90 months following initial sampling) analyses. Prognostic performance of Aβ-PET and survival analyses with different risk factors (gender, Aβ-PET and APOE ε4 allele status) were also performed. U-p53AZ differentiated neuropsychologically graded AD from non-AD samples, and its detection at intermediate/high levels precisely identified present and future symptomatic AD. In both time-independent and time-dependent prognostic analyses U-p53AZ achieved area under the curve (AUC) >98%, significantly higher than Aβ-PET AUCs (between 84% and 93%, P respectively <0.0001 and <0.001). As single factor, U-p53AZ could clearly determine the risk of AD neuropsychological diagnosis over time (low versus intermediate/high U-p53AZ hazard ratio=2.99). Proportional hazards regression analysis identified U-p53AZ levels as a major independent predictor of AD onset.
Conclusions: These findings support use of U-p53AZ as blood-based biomarker predicting whether individuals would reach neuropsychologically-defined AD within six years prior to AD diagnosis. Integration of U-p53AZ in screening processes could support refined participant stratification for interventional studies.
S. Piccirella ; L. Van Neste ; C. Fowler ; C.L. Masters ; J. Fripp ; J.D. Doecke ; C. Xiong ; D. Uberti ; P. Kinnon ; (2022): A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.52
CEREBRAL PHOSPHO-TAU ACTS SYNERGISTICALLY WITH SOLUBLE AΒ42 LEADING TO MILD COGNITIVE IMPAIRMENT IN AAV-AD RATS
B. Souchet, M. Audrain, Y. Gu, M.F. Lindberg, N.S. Orefice, E. Rey, N. Cartier, N. Janel, L. Meijer, J. Braudeau
J Prev Alz Dis 2022;3(9):480-490Show summaryHide summary
BACKGROUND: Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear.
OBJECTIVES: We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer's disease (LOAD) predementia.
METHODS: We specifically reduced the phosphorylation level of tau while leaving Aβ42 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer's disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age.
RESULTS: Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aβ42 levels but prevented MCI onset in 10-month-old AAV-AD rats.
CONCLUSIONS: The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aβ42 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aβ42 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action.
B. Souchet ; M. Audrain ; Y. Gu ; M.F. Lindberg ; N.S. Orefice ; E. Rey ; N. Cartier ; N. Janel ; L. Meijer ; J. Braudeau (2022): Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.18
ELECSYS CEREBROSPINAL FLUID ASSAYS ACCURATELY DISTINGUISH ALZHEIMER’S DISEASE FROM FRONTOTEMPORAL LOBAR DEGENERATION
M. Ortner, O. Goldhardt, J. Diehl-Schmid, I. Yakushev, K. Lanz, D.M. Hedderich
J Prev Alz Dis 2022;3(9):491-498Show summaryHide summary
BACKGROUND: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy.
OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD.
DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank.
PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography.
MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aβ42 ≤1000 pg/mL, pTau181/Aβ42 ratio >0.024, and tTau/Aβ42 ratio >0.28) and optimized cut-offs based on Youden’s index.
RESULTS: AUC-based performance was similarly good for the pTau181/Aβ42 ratio (AUC=0.841; 95% CI: 0.759−0.923), pTau181/Aβ40 ratio (AUC=0.837; 95% CI: 0.754−0.919), Aβ42/Aβ40 ratio (AUC=0.829; 95% CI: 0.746−0.912), tTau/Aβ42 ratio (AUC=0.822; 95% CI: 0.736−0.908), pTau181/Aβ42/Aβ40 ratio (AUC=0.817; 95% CI: 0.734–0.901), and Aβ42 (AUC=0.812; 95% CI: 0.722−0.902). Performance was slightly lower for the tTau/Aβ42/Aβ40 ratio (AUC=0.799; 95% CI: 0.713−0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707−0.880), tTau/Aβ40 ratio (AUC=0.751; 95% CI: 0.657−0.844), and tTau alone (AUC=0.706; 95% CI: 0.613−0.799). The highest qualitative performance was observed with the pTau181/Aβ42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively.
CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.
M. Ortner ; O. Goldhardt ; J. Diehl-Schmid ; I. Yakushev ; K. Lanz ; D.M. Hedderich ; E. Manuilova ; M. Simon ; J.-P. Weinberger ; T. Grimmer (2022): Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer’s Disease from Frontotemporal Lobar Degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.27
DECREASED GRAY–WHITE MATTER CONTRAST OF [11C]-PIB UPTAKE IN COGNITIVELY UNIMPAIRED SUBJECTS WITH SEVERE OBSTRUCTIVE SLEEP APNEA
S. Ylä-Herttuala, M. Hakulinen, P. Poutiainen, J. Lötjönen, M. Könönen, H. Gröhn, R. Vanninen, H. Mussalo, T. Laitinen, E. Mervaala
J Prev Alz Dis 2022;3(9):499-506Show summaryHide summary
Background: Very recently, cognitively normal, middle-aged adults with severe obstructive sleep apnea (OSA) were shown to have regional cortical amyloid-β deposits. In the normal brain, amyloid tracer (e.g., [11C]-PiB) uptake is observed in white matter (WM) but not in cortical gray matter (GM), resulting in clear GM–WM contrast. There are no reports on possible changes in this contrast in severe OSA.
Objectives: Evaluate changes in the global [11C]-PiB GM–WM contrast and study if factors reflecting clinical and imaging characteristics are associated with them.
Design and setting: Cross-sectional imaging study.
Participants: 19 cognitively intact middle-aged (mean 44 years) patients with severe OSA (Apnea–Hypopnea Index >30/h), carefully selected to exclude any other possible factors that could alter brain health.
Measurements: Detailed neuroimaging (amyloid PET, MRI). Signs of possible alterations in amyloid tracer GM–WM contrast and kinetics were studied with static and dynamic [11C]-PiB PET and WM structures with detailed 3.0T MRI.
Results: Static [11C]-PiB PET uptake showed significantly decreased GM–WM contrast in 5 out of 19 patients. This was already clearly seen in visual evaluation and also detected quantitatively using retention indexes. Dynamic imaging revealed decreased contrast due to alterations in trace accumulation in the late phase of [11C]-PiB kinetics. Decreased GM–WM contrast in the late phase was global in nature. MRI revealed no corresponding alterations in WM structures. Importantly, decreased GM–WM contrast was associated with smoking (p = 0.007) and higher Apnea–Hypopnea Index (p = 0.001).
Conclusions: Severe OSA was associated with decreased GM–WM contrast in amyloid tracer uptake, with significant correlation with clinical parameters of smoking and AHI. The results support and further extend the current understanding of the deleterious effect of severe OSA on proper amyloid clearance, possibly reflecting dysfunction of the brain glymphatic system.
S. Ylä-Herttuala ; M. Hakulinen ; P. Poutiainen ; J. Lötjönen ; M. Könönen ; H. Gröhn ; R. Vanninen ; H. Mussalo ; T. Laitinen ; E. Mervaala ; (2022): Decreased Gray–White Matter Contrast of [11C]-PiB Uptake in Cognitively Unimpaired Subjects with Severe Obstructive Sleep Apnea. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.24
CLINICAL TRIAL ENDPOINTS AND THEIR CLINICAL MEANINGFULNESS IN EARLY STAGES OF ALZHEIMER’S DISEASE
S. Cohen, J. Cummings, S. Knox, M. Potashman, J. Harrison
J Prev Alz Dis 2022;3(9):507-522Show summaryHide summary
As the focus of Alzheimer’s disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.
S. Cohen ; J. Cummings ; S. Knox ; M. Potashman ; J. Harrison ; (2022): Clinical Trial Endpoints and Their Clinical Meaningfulness in Early Stages of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.41
AGING, SENESCENCE, AND DEMENTIA
Q. Behfar, A. Ramirez Zuniga, P.V. Martino-Adami
J Prev Alz Dis 2022;3(9):523-531Show summaryHide summary
The underlying processes occurring in aging are complex, involving numerous biological changes that result in chronic cellular stress and sterile inflammation. One of the main hallmarks of aging is senescence. While originally the term senescence was defined in the field of oncology, further research has established that also microglia, astrocytes and neurons become senescent. Since age is the main risk factor for neurodegenerative diseases, it is reasonable to argue that cellular senescence might play a major role in Alzheimer’s disease. Specific cellular changes seen during Alzheimer’s disease are similar to those observed during senescence across all resident brain cell types. Furthermore, increased levels of senescence-associated secretory phenotype proteins such as IL-6, IGFBP, TGF-β and MMP-10 have been found in both CSF and plasma samples from Alzheimer’s disease patients. In addition, genome-wide association studies have identified that individuals with Alzheimer’s disease carry a high burden of genetic risk variants in genes known to be involved in senescence, including ADAM10, ADAMTS4, and BIN1. Thus, cellular senescence is emerging as a potential underlying disease process operating in Alzheimer’s disease. This has also attracted more attention to exploiting cellular senescence as a therapeutic target. Several senolytic compounds with the capability to eliminate senescent cells have been examined in vivo and in vitro with notable results, suggesting they may provide a novel therapeutic avenue. Here, we reviewed the current knowledge of cellular senescence and discussed the evidence of senescence in various brain cell types and its putative role in inflammaging and neurodegenerative processes.
Q. Behfar ; A. Ramirez Zuniga ; P.V. Martino-Adami ; (2022): Aging, Senescence, and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.42
CLINICAL RESEARCH INVESTIGATING ALZHEIMER’S DISEASE IN CHINA: CURRENT STATUS AND FUTURE PERSPECTIVES TOWARD PREVENTION
Q. Wang, F. Gao, L. Dai, J. Zhang, D. Bi, Y. Shen
J Prev Alz Dis 2022;3(9):532-541Show summaryHide summary
Based on the background of research investigating brain aging and neurodegenerative diseases in China, the present review addresses Alzheimer’s disease (AD), one of the most common types of neurodegenerative diseases, clinical research progress, and prospects for future development in China.
Q. Wang ; F. Gao ; L. Dai ; J. Zhang ; D. Bi ; Y. Shen ; (2022): Clinical Research Investigating Alzheimer’s Disease in China: Current Status and Future Perspectives Toward Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.46
SITE READINESS FRAMEWORK TO IMPROVE HEALTH SYSTEM PREPAREDNESS FOR A POTENTIAL NEW ALZHEIMER’S DISEASE TREATMENT PARADIGM
M. Anderson, N. Sathe, C. Polacek, J. Vawter, T. Fritz, M. Mann, P. Hernandez, M.C. Nguyen, J. Thompson, J. Penderville, M. Arling, S. Safo, R. Christopher
J Prev Alz Dis 2022;3(9):542-549Show summaryHide summary
New therapies that address the underlying pathophysiology of Alzheimer’s Disease (AD), coupled with the growth of the AD population, will transform the AD care pathway and present significant challenges to health systems. We explored real-world challenges health systems may face in delivering potential new AD therapies with diverse stakeholders. Key challenges in care included integrating primary care providers into assessment and management, availability of memory care specialists, understanding payment and coverage issues and training mid-level providers to help coordinate care and serve as a shared resource across the system. This input informed a novel Site Readiness Framework for AD, comprising self-assessment exercises to identify health system capabilities and gaps and a framework of core strategies and responsive tools to help prepare to integrate new AD therapies. These resources may help health systems improve readiness to modify care pathways to integrate new therapies for AD.
M. Anderson ; N. Sathe ; C. Polacek ; J. Vawter ; T. Fritz ; M. Mann ; P. Hernandez ; M.C. Nguyen ; J. Thompson ; J. Penderville ; M. Arling ; S. Safo ; R. Christopher ; (2022): Site Readiness Framework to Improve Health System Preparedness for a Potential New Alzheimer’s Disease Treatment Paradigm. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.32
WHAT MATTERS TO PATIENTS WITH ALZHEIMER’S DISEASE AND THEIR CARE PARTNERS? IMPLICATIONS FOR UNDERSTANDING THE VALUE OF FUTURE INTERVENTIONS
F. Jessen, J. Georges, M. Wortmann, S. Benham-Hermetz
J Prev Alz Dis 2022;3(9):550-555Show summaryHide summary
Alzheimer's Disease (AD) is the most common cause of dementia. Recent thinking portrays AD as a continuum consisting of three stages: an asymptomatic preclinical period, a mild cognitive impairment phase, and dementia, which can be further classified as mild, moderate or severe. While many studies explore the cognitive and functional aspects of AD, fully understanding AD pathophysiology, as well as the potential value of pharmacological and psycho-social interventions, requires a deeper understanding of patient and care partner priorities, particularly in the early stages where such interventions may have the greatest impact in slowing or delaying progression. Available studies highlight a diverse range of patient and care partner priorities, including impacts on their emotions, moods, and social lives. These priorities have not been systematically incorporated in the clinical and value assessments of potential interventions. We propose approaches to better understand the humanistic impact of AD including conducting additional research into the impacts of interventions from the point of view of patients and care partners, expanding notions of ‘value’ and improving health system capacity for diagnosis.
F. Jessen ; J. Georges ; M. Wortmann ; S. Benham-Hermetz ; (2022): What Matters to Patients with Alzheimer’s Disease and Their Care Partners? Implications for Understanding the Value of Future Interventions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.22
STANDARDIZING ELECTRONIC HEALTH RECORD DATA ON AD/ADRD TO ACCELERATE HEALTH EQUITY IN PREVENTION, DETECTION, AND TREATMENT
C.G. Lyketsos, S.B. Roberts, E.K. Swift, A. Quina, G. Moon, I. Kremer, P. Tariot, H. Fillit, D.E. Bovenkamp, P.P. Zandi, J.G. Haaga
J Prev Alz Dis 2022;3(9):556-560Show summaryHide summary
Improving the prevention, detection, and treatment of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced “shared”) for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.
C.G. Lyketsos ; S.B. Roberts ; E.K. Swift ; A. Quina ; G. Moon ; I. Kremer ; P. Tariot ; H. Fillit ; D.E. Bovenkamp ; P.P. Zandi ; J.G. Haaga ; (2022): Standardizing Electronic Health Record Data on AD/ADRD to Accelerate Health Equity in Prevention, Detection, and Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.47
LETTER TO THE EDITOR: EARLY-ONSET TYPE 2 DIABETES AND RISK OF DEMENTIA
J Prev Alz Dis 2022;3(9):561Show summaryHide summary
T. Kawada (2022): Letter to the Editor: Early-Onset Type 2 Diabetes and Risk of Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.43
REPLY TO LETTER TO THE EDITOR: “EARLY-ONSET TYPE 2 DIABETES AND RISK OF DEMENTIA”
K. Wang, H. Liu
J Prev Alz Dis 2022;3(9):562Show summaryHide summary
K. Wang ; H. Liu ; (2022): Reply to Letter to the Editor: “Early-Onset Type 2 Diabetes and Risk of Dementia”. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.45