Individualized clinical management of patients at risk for Alzheimer's dementia.

INTRODUCTION: Multidomain intervention for Alzheimer's disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS: Patients were prescribed individually tailored interventions (education/pharmacologic/nonpharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical AD was classified as Prevention. Mild cognitive impairment due to AD/mild-AD was classified as Early Treatment. Change from baseline to 18 months on the modified Alzheimer's Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk scales, and serum biomarkers were secondary outcomes. RESULTS: One hundred seventy-four were assigned interventions (age 25-86). Higher-compliance Prevention improved more than both historical cohorts (P = .0012, P < .0001). Lower-compliance Prevention also improved more than both historical cohorts (P = .0088, P < .0055). Higher-compliance Early Treatment improved more than lower compliance (P = .0007). Higher-compliance Early Treatment improved more than historical cohorts (P < .0001, P = .0428). Lower-compliance Early Treatment did not differ (P = .9820, P = .1115). Similar effects occurred for CogAging. AD/cardiovascular risk scales and serum biomarkers improved. DISCUSSION: Individualized multidomain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD dementia.

The clinical practice of risk reduction for Alzheimer's disease: A precision medicine approach.

Like virtually all age-related chronic diseases, late-onset Alzheimer's disease (AD) develops over an extended preclinical period and is associated with modifiable lifestyle and environmental factors. We hypothesize that multimodal interventions that address many risk factors simultaneously and are individually tailored to patients may help reduce AD risk. We describe a novel clinical methodology used to evaluate and treat patients at two Alzheimer's Prevention Clinics. The framework applies evidence-based principles of clinical precision medicine to tailor individualized recommendations, follow patients longitudinally to continually refine the interventions, and evaluate N-of-1 effectiveness (trial registered at ClinicalTrials.gov NCT03687710). Prior preliminary results suggest that the clinical practice of AD risk reduction is feasible, with measurable improvements in cognition and biomarkers of AD risk. We propose using these early findings as a foundation to evaluate the comparative effectiveness of personalized risk management within an international network of clinician researchers in a cohort study possibly leading to a randomized controlled trial.

Education Research: Online Alzheimer education for high school and college students: A randomized controlled trial.

OBJECTIVE: Alzheimer disease (AD) risk factors are present throughout the lifespan. This randomized controlled trial evaluated the effectiveness of various online education strategies concerning AD risk reduction and brain health in younger populations. METHOD: High school and college students were recruited via social media (Facebook and Instagram) to join AlzU.org, an evidence-based education portal, and were randomized to 1 of 4 courses: highly interactive webinar lessons narrated by actor Seth Rogen (celebrity webinar) or a physician (doctor webinar), minimally interactive video lessons with Seth Rogen (celebrity video), or minimally interactive video lessons (control). Surveys were administered at baseline and postcourse. The primary outcome was change in knowledge of AD risk reduction assessed by pre vs post lesson quiz scores. Secondary outcomes included change in awareness of AD research, hopefulness about AD, interest in pursuing health care, willingness to volunteer, and likelihood of recommending AlzU.org. RESULT: A total of 721 participants joined. A total of 281 (38.9%) completed the course. Among college students, quiz score improvements were greater in celebrity webinar and celebrity video vs doctor webinar and control. Among high school students, no differences were found in quiz scores. In both groups, celebrity webinar, celebrity video, and doctor webinar resulted in greater improvements in awareness that nutrition and exercise may reduce AD risk vs controls. Among college students, celebrity webinar and celebrity video group participants felt more hopeful about the future of AD and more likely to recommend AlzU.org vs doctor webinar and control participants. Among college students, celebrity webinar, celebrity video, and doctor webinar participants were more willing to volunteer for AD causes and pursue health care careers vs controls. CONCLUSION: Online education involving a celebrity may be an effective strategy for educating college students about AD risk reduction strategies. Further studies are warranted in high school students.

Effectiveness of online education for recruitment to an Alzheimer's disease prevention clinical trial.

INTRODUCTION: Low awareness of Alzheimer's disease (AD) clinical trials is a recruitment barrier. To assess whether online education may affect screening rates for AD prevention clinical trials, we conducted an initial prospective cohort study (n = 10,450) and subsequent randomized study (n = 351) using an online digital tool: AlzU.org. METHODS: A total of 10,450 participants were enrolled in an initial cohort study and asked to complete a six-lesson course on AlzU.org, as well as a baseline and 6-month follow-up questionnaire. Participants were stratified into three groups based on lesson completion at 6 months: group 1 (zero to one lesson completed), group 2 (two to four lessons), and group 3 (five or more lessons). For the subsequent randomized-controlled trial (RCT), 351 new participants were enrolled in a six-lesson course (n = 180) versus a time-neutral control (n = 171). Screening and enrollment in the Anti-Amyloid Treatment in Asymptomatic AD (A4) clinical trial were reported via the 6-month questionnaire and are the primary outcomes. RESULTS: Cohort: 3.9% of group 1, 5% of group 2, and 8.4% of group 3 screened for the A4 trial. Significant differences were found among the groups (P < 0.001). Post hoc analyses showed differences in A4 screening rates between groups 1 and 3 (P < 0.001) and groups 2 and 3 (P = 0.0194). There were no differences in enrollment among the three groups. RCT: 2.78% of the intervention group screened for A4 compared to 0% of controls (P = 0.0611). DISCUSSION: Online education via the AlzU.org digital tool may serve as an effective strategy to supplement clinical trial recruitment.

Legal Objections to Use of Neurologic Criteria to Declare Death in the United States: 1968 to 2017.

BACKGROUND: There have been a number of prominent lawsuits challenging the use of neurologic criteria to declare death in the United States. METHODS: To put these lawsuits into perspective, we conducted a search of Nexis Uni to identify cases from the past 50 years that involved objections to the use of neurologic criteria to declare death in the United States. RESULTS: We identified lawsuits about 67 decedents (59 state and 8 federal) from 34 different regions which were filed for crime-related issues (n = 42), hospital-related issues (n = 20), insurance-related issues (n = 2), and other issues related to time of death (n = 3). The judicial opinions about the lawsuits addressed: (1) acceptance of the use of neurologic criteria to declare death (n = 55), (2) criteria to declare death (n = 3), (3) management of decedents after death by neurologic criteria (n = 13), (4) identification of the time of death (n = 4), and (5) rights of the dead (n = 3). The outcomes of these cases were heterogeneous. CONCLUSIONS: Since the incorporation of neurologic criteria into the medical practice of declaration of death, there have been a number of legal objections to its use. To avoid the rendering of variable opinions by the courts, there is a need for consistent legislative modification throughout the country to address (1) the specific criteria to use when declaring death by neurologic criteria, (2) management of religious objections to use of neurologic criteria to declare death, and (3) management after declaration of death by neurologic criteria.

Precision Medicine for Alzheimer's Disease Prevention.

Precision medicine is an approach to medical treatment and prevention that takes into account individual variability in genes, environment, and lifestyle and allows for personalization that is based on factors that may affect the response to treatment. Several genetic and epigenetic risk factors have been shown to increase susceptibility to late-onset Alzheimer's disease (AD). As such, it may be beneficial to integrate genetic risk factors into the AD prevention approach, which in the past has primarily been focused on universal risk-reduction strategies for the general population rather than individualized interventions in a targeted fashion. This review discusses examples of a "one-size-fits-all" versus clinical precision medicine AD prevention strategy, in which the precision medicine approach considers two genes that can be commercially sequenced for polymorphisms associated with AD, apolipoprotein E (APOE), and methylenetetrahydrofolate reductase (MTHFR). Comparing these two distinct approaches provides support for a clinical precision medicine prevention strategy, which may ultimately lead to more favorable patient outcomes as the interventions are targeted to address individualized risks.

Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer's Disease Prevention.

Alzheimer's disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease-modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms-dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity-involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases.

Using social media to disseminate education about Alzheimer's prevention & treatment: a pilot study on Alzheimer's universe (www.AlzU.org).

BACKGROUND: The use of social media may be a valuable tool for dissemination of patient education interventions. However, in Alzheimer's disease (AD), little data exists about the effectiveness, associated cost, or conditions for utilization. METHODS: Alzheimer's Universe (www.AlzU.org) is an online educational portal that provides evidence-based educational content for the public and a variety of activities related to optimizing AD management. The primary goal of our study was to assess the effectiveness of using the social media platform Facebook.com as a tool to recruit subjects to visit AlzU.org via targeted advertising and evaluate the associated costs. Secondary outcomes included AlzU.org join rates, lesson and activity completion rates, user demographics and attitudes about the education research platform. RESULTS: A total of $706 generated 4268 visits to AlzU.org via a series of page posts promoted with targeted advertising to individuals with previously expressed interest in 'Alzheimer's disease,' to those who had 'liked' the Alzheimer's Association page, and followers of www.facebook.com/AlzheimersDisease. Advertising used different promotional taglines in the Facebook Advertising manager tool using 'Cost Per Click' and the 'Optimized for Engagement' settings. Across all strategies combined, 503 visitors joined AlzU.org (11.8% join rate), 412 engaged with at least one lesson/activity (82%), and 100 completed all available lessons and activities (19.8%). Users were primarily women (79.8%) and the most common age group was 50's (43.3%, range 22-92). The majority joined AlzU.org to learn more about AD prevention or treatment (66.3% and 65.3%, respectively). Over 90% were satisfied with their experience. DISCUSSION: Subjects were quickly and cost-effectively recruited to AlzU.org. Completion rates of education content and activities were adequate, and subjects were highly satisfied with their experiences. Overall, targeted advertising on Facebook.com was an effective means of disseminating AD education online.

Increased Alzheimer's risk during the menopause transition: A 3-year longitudinal brain imaging study.

Two thirds of all persons with late-onset Alzheimer's disease (AD) are women. Identification of sex-based molecular mechanisms underpinning the female-based prevalence of AD would advance development of therapeutic targets during the prodromal AD phase when prevention or delay in progression is most likely to be effective. This 3-year brain imaging study examines the impact of the menopausal transition on Alzheimer's disease (AD) biomarker changes [brain ß-amyloid load via 11C-PiB PET, and neurodegeneration via 18F-FDG PET and structural MRI] and cognitive performance in midlife. Fifty-nine 40-60 year-old cognitively normal participants with clinical, neuropsychological, and brain imaging exams at least 2 years apart were examined. These included 41 women [15 premenopausal controls (PRE), 14 perimenopausal (PERI), and 12 postmenopausal women (MENO)] and 18 men. We used targeted minimum loss-based estimation to evaluate AD biomarker and cognitive changes. Older age was associated with baseline Aß and neurodegeneration markers, but not with rates of change in these biomarkers. APOE4 status influenced change in Aß load, but not neurodegenerative changes. Longitudinally, MENO and PERI groups showed declines in estrogen-dependent memory tests as compared to men (p < .04). Adjusting for age, APOE4 status, and vascular risk confounds, the MENO and PERI groups exhibited higher rates of CMRglc decline as compared to males (p ≤ .015). The MENO group exhibited the highest rate of hippocampal volume loss (p's ≤ .001), and higher rates of Aß deposition than males (p < .01). CMRglc decline exceeded Aß and atrophy changes in all female groups vs. men. These findings indicate emergence and progression of a female-specific hypometabolic AD-endophenotype during the menopausal transition. These findings suggest that the optimal window of opportunity for therapeutic intervention to prevent or delay progression of AD endophenotype in women is early in the endocrine aging process.