Ahead of print articles
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
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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
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
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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
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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
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
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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
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)
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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
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
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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
PIMAVANSERIN IN ALZHEIMER’S DISEASE PSYCHOSIS: EFFICACY IN PATIENTS WITH MORE PRONOUNCED PSYCHOTIC SYMPTOMS
C. Ballard, J.M. Youakim, B. Coate, S. Stankovic
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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
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
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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
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. Gurge, J.S. Anderson, N.L. Foster
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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
JPAD Volume 5, N°04 - 2018
WHAT WE LEARN FROM THE CTAD 2018 (CLINICAL TRIALS ALZHEIMER’S DISEASE)
B. Vellas, P. Aisen, M. Weiner, J. Touchon
J Prev Alz Dis 2018;5(4):214-215Show summaryHide summary
B. Vellas ; P. Aisen ; M. Weiner ; J. Touchon (2018): What We Learn from the CTAD 2018 (Clinical Trials Alzheimer’s Disease). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.38
ASSESSMENT OF INSTRUMENTAL ACTIVITIES OF DAILY LIVING IN OLDER ADULTS WITH SUBJECTIVE COGNITIVE DECLINE USING THE VIRTUAL REALITY FUNCTIONAL CAPACITY ASSESSMENT TOOL (VRFCAT)
A.S. Atkins, A. Khan, D. Ulshen, A. Vaughan, D. Balentin, H. Dickerson, L.E. Liharska, B. Plassman, K. Welsh-Bohmer, R. S.E. Keefe
J Prev Alz Dis 2018;5(4):216-224Show summaryHide summary
Background: Continuing advances in the understanding of Alzheimer’s disease progression have inspired development of disease-modifying therapeutics intended for use in preclinical populations. However, identification of clinically meaningful cognitive and functional outcomes for individuals who are, by definition, asymptomatic remains a significant challenge. Clinical trials for prevention and early intervention require measures with increased sensitivity to subtle deficits in instrumental activities of daily living (IADL) that comprise the first functional declines in prodromal disease. Validation of potential endpoints is required to ensure measure sensitivity and reliability in the populations of interest.
Objectives: The present research validates use of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for performance-based assessment of IADL functioning in older adults (age 55+) with subjective cognitive decline.
Design: Cross-sectional validation study.
Setting: All participants were evaluated on-site at NeuroCog Trials, Durham, NC, USA.
Participants: Participants included 245 healthy younger adults ages 20-54 (131 female), 247 healthy older adults ages 55-91 (151 female) and 61 older adults with subjective cognitive
decline (SCD) ages 56-97 (45 female).
Measures: Virtual Reality Functional Capacity Assessment Tool; Brief Assessment of Cognition App; Alzheimer’s Disease Cooperative Study Prevention Instrument Project – Mail-In Cognitive Function Screening Instrument; Alzheimer’s Disease Cooperative Study Instrumental Activities of Daily Living – Prevention Instrument, University of California, San Diego Performance-Based Skills Assessment – Validation of Intermediate Measures; Montreal Cognitive Assessment; Trail Making Test- Part B.
Results: Participants with SCD performed significantly worse than age-matched normative controls on all VRFCAT endpoints, including total completion time, errors and forced progressions (p≤0001 for all, after Bonferonni correction). Consistent with prior findings, both groups performed significantly worse than healthy younger adults (age 20-54). Participants with SCD also performed significantly worse than controls on objective cognitive measures. VRFCAT performance was strongly correlated with cognitive performance. In the SCD group, VRFCAT performance was strongly correlated with cognitive performance across nearly all tests with significant correlation coefficients ranging from 0.3 to 0.7; VRFCAT summary measures all had correlations greater than r=0.5 with MoCA performance and BAC App Verbal Memory (p<0.01 for all).
Conclusions: Findings suggest the VRFCAT provides a sensitive tool for evaluation of IADL functioning in individuals with subjective cognitive decline. Strong correlations with cognition across groups suggest the VRFCAT may be uniquely suited for clinical trials in preclinical AD, as well as longitudinal investigations of the relationship between cognition and function.
A.S. Atkins ; A. Khan ; D. Ulshen ; A. Vaughan ; D. Balentin ; H. Dickerson ; L.E. Liharska ; B. Plassman ; K. Welsh-Bohmer ; R. S.E. Keefe (2018): Assessment of Instrumental Activities of Daily Living in Older Adults with Subjective Cognitive Decline Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.28
FEMALE SEX AND ALZHEIMER’S RISK: THE MENOPAUSE CONNECTION
O. Scheyer, A. Rahman, H. Hristov, C. Berkowitz, R.S. Isaacson, R. Diaz Brinton, L. Mosconi
J Prev Alz Dis 2018;5(4):225-230Show summaryHide summary
Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer’s disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.
O. Scheyer ; A. Rahman ; H. Hristov ; C. Berkowitz ; R.S. Isaacson ; R. Diaz Brinton ; L. Mosconi (2018): Female Sex and Alzheimer’s Risk: The Menopause Connection. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.34
GEOGRAPHIC CLUSTERS OF ALZHEIMER’S DISEASE MORTALITY RATES IN THE USA: 2008-2012
R.W. Amin, E.M. Yacko, R.P. Guttmann
J Prev Alz Dis 2018;5(4):231-235Show summaryHide summary
Importance: The results identified geographic clusters of high and low Alzheimer’s disease (AD)-related mortality across the contiguous United States. These clusters identify specific geographic groupings of counties that allow researchers to narrow the focus to identify some of the biopsychosocial variables contributing to increased or decreased AD mortality.
Objectives: To determine the extent to which geographic clusters exist where AD mortality significantly differs from the national average. Such knowledge could further future research in a more focused study of variables that are contributing to these differences.
Design: Age adjusted AD mortality rates were analyzed with a spatial cluster analysis using the disease surveillance software SatScanTM.
Results: Three large clusters had elevated age-adjusted AD mortality of at least 60% above the national average. These clusters were in Washington State, Iowa, and North and South Dakota. Below average AD mortality was observed in several areas including New York City, and parts of Arizona, California, Arkansas and Texas.
Conclusion and Relevance: This study demonstrates the use of disease surveillance methodology in identifying geographic patterns of unusually high or low AD mortality rates in the USA. Such results provide supporting evidence of appropriate locations to test interventions with the goal to reduce AD mortality.
R.W. Amin ; E.M. Yacko ; R.P. Guttmann (2018): Geographic Clusters of Alzheimer’s Disease Mortality Rates in the USA: 2008-2012. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.36
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
J.E. Harrison, D.M. Rentz, H.R. Brashear, H.M. Arrighi, M.T. Ropacki, E. Liu
J Prev Alz Dis 2018;5(4):236-244Show summaryHide summary
Background: The Neuropsychological Test Battery (NTB) is a combination of widely used clinical neuropsychological tests measuring memory and executive function and was designed to overcome some of the limitations of the traditionally used Alzheimer’s disease Assessment Scale – Cognitive subscale (ADAS-Cog). A previously reported account indicated high levels of NTB reliability in patients with mild-to-moderate Alzheimer’s disease (AD) and mild cognitive impairment (MCI).
Objectives: We examined capacity of the Neuropsychological Test Battery (NTB) and its component subtests to measure cognitive change over time. Correlations with other cognitive and functional assessments were also determined.
Design, Settings, Participants: This was a multicentre, prospective, non-interventional, longitudinal cohort study involving patients with mild-to-moderate AD (n=196), MCI (n=70), or cognitively normal control participants (NC, n=75).
Intervention: The NTB, as well as other Clinical Outcome Assessments including, ADAS-Cog, other cognitive measures, functional/behavioral questionnaires, health outcome questionnaires, and resource utilization tools were administered.
Results: Mean change from baseline for the NTB composite score and the six individual NTB subtests showed greater reductions in performance over time in the AD and MCI groups, compared with NC group. The ADAS-Cog was found to be more sensitive to change than the NTB in all three populations.
Conclusions: The NTB showed high correlation with the ADAS-Cog and appears to be a sensitive and reliable assessment tool for measuring cognitive decline in patients with mild-to-moderate AD. However, the ADAS-Cog was found to be more sensitive to change over time in both the AD and MCI populations.
J.E. Harrison ; D.M. Rentz ; H.R. Brashear ; H.M. Arrighi ; M.T. Ropacki ; E. Liu (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.2018.31
CLINICAL APPLICATION OF APOE IN ALZHEIMER’S PREVENTION: A PRECISION MEDICINE APPROACH
C.L. Berkowitz, L. Mosconi, A. Rahman, O. Scheyer, H. Hristov, R.S. Isaacson
J Prev Alz Dis 2018;5(4):245-252Show summaryHide summary
Population-attributable risk models estimate that up to one-third of Alzheimer’s disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.
C.L. Berkowitz ; L. Mosconi ; A. Rahman ; O. Scheyer ; H. Hristov ; R.S. Isaacson (2018): Clinical Application of APOE in Alzheimer’s Prevention: A Precision Medicine Approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.35
PIMAVANSERIN: POTENTIAL TREATMENT FOR DEMENTIA-RELATED PSYCHOSIS
J. Cummings, C. Ballard, P. Tariot, R. Owen, E. Foff, J. Youakim, J. Norton, S.Stankovic
J Prev Alz Dis 2018;5(4):253-258Show summaryHide summary
Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson’s disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer’s disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS <12. The results of these studies in cognitively impaired patients with PDP provided the scientific foundation for an ongoing study of pimavanserin for treating patients with dementia-related psychosis associated with the most common neurodegenerative disorders. The study uses a relapse-prevention design with the endpoint of time-to-relapse of psychosis to evaluate the long-term efficacy and safety of pimavanserin as a potential treatment for hallucinations and delusions of dementia-related psychosis.
J. Cummings ; C. Ballard ; P. Tariot ; R. Owen ; E. Foff ; J. Youakim ; J. Norton ; S. Stankovic (2018): Pimavanserin: Potential Treatment For Dementia-Related Psychosis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.29
Letter to the Editor
LETTER TO THE EDITOR: PREVENTING DEMENTIA THROUGH COMMUNITY INVOLVEMENT AND ALTRUISTIC BEHAVIORS
J Prev Alz Dis 2018;5(4):259-260Show summaryHide summary
Y. Maki (2018): Preventing Dementia through Community Involvement and Altruistic Behaviors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.37
Clinical Trials and Aging: 11th Conference Clinical Trials on Alzheimer’s Disease, October 24-27, 2018, Barcelona, Spain