01/2019 journal articles
Point of View
REVISITING THE CHOLINERGIC HYPOTHESIS IN ALZHEIMER’S DISEASE: EMERGING EVIDENCE FROM TRANSLATIONAL AND CLINICAL RESEARCH
H. Hampel, M.-M. Mesulam, A.C. Cuello, A.S. Khachaturian, A. Vergallo, M.R. Farlow, P.J. Snyder, E. Giacobini, Z.S. Khachaturian, for the Cholinergic System Working Group, and for the Alzheimer Precision Medicine Initiative (APMI)
J Prev Alz Dis 2019;6(1):2-15Show summaryHide summary
Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer’s disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the “Cholinergic Hypothesis of AD” and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.
H. Hampel ; M.-M. Mesulam ; A.C. Cuello ; A.S. Khachaturian ; A. Vergallo ; M.R. Farlow ; P.J. Snyder ; E. Giacobini ; Z.S. Khachaturian ; for the Cholinergic System Working Group, and for the Alzheimer Precision Medicine Initiative (APMI) (2018): Revisiting the Cholinergic Hypothesis in Alzheimer’s Disease: Emerging Evidence from Translational and Clinical Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.43
POLYGENIC RISK SCORE ANALYSIS OF ALZHEIMER’S DISEASE IN CASES WITHOUT APOE4 OR APOE2 ALLELES
V. Escott-Price, A. Myers, M. Huentelman, M. Shoai, J. Hardy
J Prev Alz Dis 2019;6(1):16-19Show summaryHide summary
The We and others have previously shown that polygenic risk score analysis (PRS) has considerable predictive utility for identifying those at high risk of developing Alzheimer’s disease (AD) with an area under the curve (AUC) of >0.8. However, by far the greatest determinant of this risk is the apolipoprotein E locus with the E4 allele alone giving an AUC of ~0.68 and the inclusion of the protective E2 allele increasing this to ~0.69 in a clinical cohort. An important question is to determine how good PRS is at predicting risk in those who do not carry the E4 allele (E3 homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e. E3 homozygotes). Previous studies have shown that PRS remains a significant predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier status. In this study we assess the accuracy of PRS prediction in a cohort of pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has surprisingly little effect on the PRS prediction accuracy (AUC ~0.83 [95% CI: 0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with APOE included as a predictor. From a practical perspective this suggests that PRS analysis will have predictive utility even in E4 negative individuals and may be useful in clinical trial design.
V. Escott-Price ; A. Myers ; M. Huentelman ; M. Shoai ; J. Hardy (2018): Polygenic Risk Score Analysis of Alzheimer’s Disease in Cases without APOE4 or APOE2 Alleles. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.46
Point of View
THE ROLE OF FUTILITY ANALYSES IN AD CLINICAL TRIALS
J Prev Alz Dis 2020;7(1):7Show summaryHide summary
R. Doody (2020): The Role of Futility Analyses in AD Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.1
DESIGNING TRIALS OF DISEASE MODIFYING AGENTS FOR EARLY AND PRECLINICAL ALZHEIMER’S DISEASE INTERVENTION: WHAT EVIDENCE IS MEANINGFUL TO PATIENTS, PROVIDERS, AND PAYERS?
D.A. Messner, P. Rabins, A.C. Downing, M. Irizarry, N.L. Foster, J. Al Naber, O. Dabbous, H. Fillit, S. Gabler, H. Fillit, S. Gabler, R. Krakauer, D. Lotz, E. Payzant, L. Schneider, J. Tyrone, D. Van Amerongen, D. Wuest
J Prev Alz Dis 2019;6(1):20-26Show summaryHide summary
Background: Drug development for disease modifying agents in Alzheimer’s disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer’s. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs.
Objective: to create multi-stakeholder–vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer’s disease (AD).
Design: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members.
Setting: The in-person meeting was held in Baltimore, MD.
Participants: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers.
Results: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer’s prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include “digital independence.”
Conclusions: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.
D.A. Messner ; P. Rabins ; A.C. Downing ; M. Irizarry ; N.L. Foster ; J. Al Naber ; O. Dabbous ; H. Fillit ; S. Gabler ; R. Krakauer ; D. Lotz ; E. Payzant ; L. Schneider ; J. Tyrone ; D. Van Amerongen ; D. Wuest (2018): Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer’s Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.42
PIMAVANSERIN IN ALZHEIMER’S DISEASE PSYCHOSIS: EFFICACY IN PATIENTS WITH MORE PRONOUNCED PSYCHOTIC SYMPTOMS
C. Ballard, J.M. Youakim, B. Coate, S. Stankovic
J Prev Alz Dis 2019;6(1):27-33Show summaryHide summary
Background: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
Objective: Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer’s disease (AD).
Design: Randomized, double-blind, placebo-controlled trial
Setting: Nursing home residents
Participants: Patients with AD psychosis
Interventions: Pimavanserin 34 mg or placebo daily for 12 weeks
Measurements: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated.
Results: Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen’s d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks.
Conclusions: Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.
C. Ballard ; J.M. Youakim ; B. Coate ; S. Stankovic (2018): Pimavanserin in Alzheimer’s Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.30
PLASMA A?42/40 RATIO DETECTS EARLY STAGES OF ALZHEIMER’S DISEASE AND CORRELATES WITH CSF AND NEUROIMAGING BIOMARKERS IN THE AB255 STUDY
V. Pérez-Grijalba, J. Romero, P. Pesini, L. Sarasa, I. Monleón, I. San-José, J. Arbizu, P. Martínez-Lage, J. Munuera, A. Ruiz, L. Tárraga, M. Boada, M. Sarasa, on behalf of The AB255 Study Group
J Prev Alz Dis 2019;6(1):34-41Show summaryHide summary
Background: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer’s disease (AD) in large population screening strategies.
Objectives: This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years.
Design: Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern.
Results: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF).
Conclusions: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.
V. Pérez-Grijalba ; J. Romero ; P. Pesini ; L. Sarasa ; I. Monleón ; I. San-José ; J. Arbizu ; P. Martínez-Lage ; J. Munuera ; A. Ruiz ; L. Tárraga ; M. Boada ; M. Sarasa ; on behalf of The AB255 Study Group ; (2018): Plasma Aβ42/40 Ratio Detects Early Stages of Alzheimer’s Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.41
TREATABLE VASCULAR RISK AND COGNITIVE PERFORMANCE IN PERSONS AGED 35 YEARS OR OLDER: LONGITUDINAL STUDY OF SIX YEARS
M.E.A. van Eersel, H. Joosten, R.T. Gansevoort, J.P.J. Slaets, G.J. Izaks
J Prev Alz Dis 2019;6(1):42-49Show summaryHide summary
Background: Poor cognitive performance is associated with high vascular risk. However, this association is only investigated in elderly. As neuropathological changes precede clinical symptoms of cognitive impairment by several decades, it is likely that cognitive performance is already associated with vascular risk at middle-age.
OBJECTIVES: To investigate the association of cognitive performance with treatable vascular risk in middle-aged and old persons.
DESIGN: Longitudinal study with three measurements during follow-up period of 5.5 years.
SETTING: City of Groningen, the Netherlands.
PARTICIPANTS: Cohort of 3,572 participants (age range, 35-82 years; mean age, 54 years; men, 52%).
EXPOSURE: Treatable vascular risk as defined by treatable components of the Framingham Risk Score for Cardiovascular Disease at the first measurement (diabetes mellitus, smoking, hypercholesterolemia and hypertension).
MEASUREMENTS: Change in cognitive performance during follow-up. Cognitive performance was measured with Ruff Figural Fluency Test (RFFT) and Visual Association Test (VAT), and calculated as the average of the standardized RFFT and VAT score per participant.
RESULTS: The mean (SD) cognitive performance changed from 0.00 (0.79) at the first measurement to 0.15 (0.83) at second measurement and to 0.39 (0.82) at the third measurement (Ptrend<0.001). This change was negatively associated with treatable vascular risk: the change in cognitive performance between two measurements decreased with 0.004 per one-point increment of treatable vascular risk (95%CI, -0.008 to 0.000; P=0.05) and with 0.006 per one-year increment of age (95%CI, -0.008 to -0.004; P<0.001).
CONCLUSIONS: Change in cognitive performance was associated with treatable vascular risk in persons aged 35 years or older.
M.E.A. van Eersel ; H. Joosten ; R.T. Gansevoort ; J.P.J. Slaets ; G.J. Izaks (2018): Treatable Vascular Risk and Cognitive Performance in Persons Aged 35 Years or Older: Longitudinal Study of Six Years. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.47
DIET AS A RISK FACTOR FOR COGNITIVE DECLINE IN AFRICAN AMERICANS AND CAUCASIANS WITH A PARENTAL HISTORY OF ALZHEIMER’S DISEASE: A CROSS- SECTIONAL PILOT STUDY DIETARY PATTERNS
A.C. Nutaitis, S.D. Tharwani, M.C. Serra, F.C. Goldstein, L. Zhao, S.S. Sher, D.D. Verble, W. Wharton
J Prev Alz Dis 2019;6(1):50-55Show summaryHide summary
Background: African Americans (AA) are more likely to develop Alzheimer’s disease (AD) than Caucasians (CC). Dietary modification may have the potential to reduce the risk of developing AD.
Objective: The objective of this study is to investigate the relationship between Southern and Prudent diet patterns and cognitive performance in individuals at risk for developing AD.
Design: Cross-sectional observational study.
Participants: Sixty-six cognitively normal AA and CC individuals aged 46-77 years with a parental history of AD were enrolled.
Measurements: Participants completed a Food Frequency questionnaire, cognitive function testing, which consisted of 8 neuropsychological tests, and cardiovascular risk factor assessments, including evaluation of microvascular and macrovascular function and ambulatory blood pressure monitoring.
Results: Results revealed a relationship between the Southern diet and worse cognitive performance among AAs. AAs who consumed pies, mashed potatoes, tea, and sugar drinks showed worse cognitive performance (p<0.05) compared with CCs. In addition, gravy (p=0.06) and cooking oil/fat (p=0.06) showed negative trends with cognitive performance in AAs. In both CC and AA adults, greater adherence to a Prudent dietary pattern was associated with better cognitive outcomes. Cardiovascular results show that participants are overall healthy. AAs and CCs did not differ on any vascular measure including BP, arterial stiffness and endothelial function.
Conclusion: Research shows that dietary factors can associate with cognitive outcomes. This preliminary cross-sectional study suggests that foods characteristic of the Southern and Prudent diets may have differential effects on cognitive function in middle-aged individuals at high risk for AD. Results suggest that diet could be a non-pharmaceutical tool to reduce cognitive decline in racially diverse populations. It is possible that the increased prevalence of AD in AA could be partially reduced via diet modification.
A.C. Nutaitis ; S.D. Tharwani ; M.C. Serra ; F.C. Goldstein ; L. Zhao ; S.S. Sher ; D.D. Verble ; W. Wharton (2018): Diet as a Risk Factor for Cognitive Decline in African Americans and Caucasians with a Parental History of Alzheimer’s Disease: A Cross-Sectional Pilot Study Dietary Patterns. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.44
INCREASED FUNCTIONAL CONNECTIVITY AFTER LISTENING TO FAVORED MUSIC IN ADULTS WITH ALZHEIMER DEMENTIA
J.B. King, K.G. Jones, E. Goldberg, M. Rollins, K. MacNamee, C. Moffit, S.R. Naidu, M.A. Ferguson, E. Garcia-Leavitt, J. Amaro, K.R. Breitenbach, J.M. Watson, R.K. Gurgel, J.S. Anderson, N.L. Foster
J Prev Alz Dis 2019;6(1):56-62Show summaryHide summary
Background: Personalized music programs have been proposed as an adjunct therapy for patients with Alzheimer disease related dementia, and multicenter trials have now demonstrated improvements in agitation, anxiety, and behavioral symptoms. Underlying neurophysiological mechanisms for these effects remain unclear.
Methods: We examined 17 individuals with a clinical diagnosis of Alzheimer disease related dementia using functional MRI following a training period in a personalized music listening program.
Results: We find that participants listening to preferred music show specific activation of the supplementary motor area, a region that has been associated with memory for familiar music that is typically spared in early Alzheimer disease. We also find widespread increases in functional connectivity in corticocortical and corticocerebellar networks following presentation of preferred musical stimuli, suggesting a transient effect on brain function.
Conclusions: Findings support a mechanism whereby attentional network activation in the brain’s salience network may lead to improvements in brain network synchronization.
J.B. King ; K.G. Jones ; E. Goldberg ; M. Rollins ; K. MacNamee ; C. Moffit ; S.R. Naidu ; M.A. Ferguson ; E. Garcia-Leavitt ; J. Amaro ; K.R. Breitenbach ; J.M. Watson ; R.K. Gurgel ; J.S. Anderson1 ; N.L. Foster (2018): Increased Functional Connectivity After Listening to Favored Music in Adults With Alzheimer Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.19
AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT
P. Novak, N. Zilka, M. Zilkova, B. Kovacech, R. Skrabana, M. Ondrus, L. Fialova, E. Kontsekova, M. Otto, M. Novak
J Prev Alz Dis 2019;6(1):63-69Show summaryHide summary
Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.
P. Novak ; N. Zilka ; M. Zilkova ; B. Kovacech ; R. Skrabana ; M. Ondrus ; L. Fialova ; E. Kontsekova ; M. Otto ; M. Novak (2018): AADvac1, an Active Immunotherapy for Alzheimer’s Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.45
BIFIDOBACTERIUM BREVE A1 SUPPLEMENTATION IMPROVED COGNITIVE DECLINE IN OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT: AN OPEN-LABEL, SINGLE-ARM STUDY
Y. Kobayashi, T. Kinoshita, A. Matsumoto, K. Yoshino, I. Saito, J.-Z. Xiao
J Prev Alz Dis 2019;6(1):70-75Show summaryHide summary
Objectives: We previously reported the therapeutic potential of Bifidobacterium breve A1 (B. breve A1) for preventing cognitive impairment in Alzheimer’s disease model mice, which suggested that supplementation of the probiotics could be an effective therapeutic strategy for managing cognitive function in mild cognitive impairment (MCI).
Design and settings: We conducted an open-label, single-arm study to examine the effects of 24-week supplementation of B. breve A1 on elderly with MCI in Aki Orthopedics Rehabilitation Clinic in Japan.
Participants: 27 participants were screened by their Mini Mental State Examination (MMSE) scores.
Measurements: Cognitive function was assessed using MMSE and Digit Symbol Substitution Test (DSST) at baseline and every 8 weeks. Mental condition and quality of life for gastrointestinal symptoms were measured using the Profile of Mood States 2nd Edition (POMS2), and the Gastrointestinal Symptom Rating Scale (GSRS).
Results: Of the 27 participants enrolled, 19 completed the study. MMSE scores were significantly increased during the intervention by mixed model Dunnett’s test and Wilcoxon signed-rank tests (+1.7, P < 0.01). POMS2 and GSRS scores were significantly improved during intervention when analyzed by Wilcoxon signed-rank tests.
Conclusion: The present study showed that oral supplementation of B. breve A1 in participants with MCI improved cognitive function, thus suggesting the potential of B. breve A1 for improving cognitive function and maintaining quality of life of the elderly. Further randomized, double-blind placebo-controlled studies are worth conducting to examine the beneficial effect of B. breve A1.
Y. Kobayashi ; T. Kinoshita ; A. Matsumoto ; K. Yoshino ; I. Saito ; J.-Z. Xiao (2018): Psychometric Evaluation of the Neuropsychological Test Battery in Individuals with Normal Cognition, Mild Cognitive Impairment, or Mild to Moderate Alzheimer’s Disease: Results from a Longitudinal Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.32