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.

Development and validation of the Alzheimer's prevention beliefs measure in a multi-ethnic cohort-a behavioral theory approach.

Background: Understanding health beliefs and how they influence willingness will enable the development of targeted curricula that maximize public engagement in Alzheimer's disease (AD) risk reduction behaviors. Methods: Literature on behavioral theory and community input was used to develop and validate a health beliefs survey about AD risk reduction among 428 community-dwelling adults. Principal component analysis was performed to assess internal consistency. Linear regression was performed to identify key predictors of Willingness to engage in AD risk reduction behaviors. Results: The measure as well as the individual scales (Benefits, Barriers, Severity, Susceptibility and Social Norm) were found to be internally consistent. Overall, as Benefits and Barriers scores increased, Willingness scores also increased. Those without prior AD experience or family history had lower willingness scores. Finally, we observed an interaction between age and norms, suggesting that social factors related to AD prevention may differentially affect people of different ages. Conclusions: The Alzheimer Prevention Beliefs Measure provides assessment of several health belief factors related to AD prevention. Age, Family History, Logistical Barriers and total Benefits are significant determinants of willingness to engage in AD risk reduction behaviors, such as seeing a doctor or making a lifestyle change.

Early Life Epidemiology of Alzheimer's Disease--A Critical Review.

BACKGROUND: As adult brain structure is primarily established in early life, genetic and environmental exposures in infancy and childhood influence the risk for Alzheimer disease (AD). In this systematic review, we identified several early life risk factors and discussed the evidence and underlying mechanism for each. SUMMARY: Early risk factors for AD may alter brain anatomy, causing vulnerability to AD-related dementia later in life. In the perinatal period, both genes and learning disabilities have been associated with the development of distinct AD phenotypes. During early childhood, education and intellect, as well as body growth, may predispose to AD through alterations in cognitive and brain reserve, though the specific mediators of neural injury are disputed. Childhood socioeconomic status (SES) may predispose to AD by influencing adult SES and cognition. Association of these risk factors with underlying AD pathology (rather than just clinical diagnosis) has not been sufficiently examined. KEY MESSAGES: Factors that impede or alter brain growth during early life could render certain brain regions or networks selectively vulnerable to the onset, accumulation or spread of AD-related pathology during later life. Careful life-course epidemiology could provide clues as to why the brain systematically degenerates during AD.

Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia and is responsible for significant individual morbidity and mortality, and economic impact on the health care system. Neurodegeneration (including neuronal atrophy and/or loss) are attributed to extraneuronal toxic amyloid oligomers and proteins, intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau, region-specific diminished cerebral glucose metabolism, synaptic dysfunction, and mitochondrial dysfunction. Several of these pathologic changes may occur decades before symptom onset, leaving ample time for implementing prevention strategies that target the earliest stages of the disease. In recent years, a myriad of modifiable and nonmodifiable risk factors have been elucidated. We describe the latest criteria for the diagnosis of AD, including earliest diagnostic stage of preclinical AD, which has the highest potential for research, including diagnosis and disease modification. We discuss both FDA-approved pharmacologic treatments, as well as nonpharmacologic strategies for AD therapeutics, including prevention via evidence-based, low-risk interventions. Genotype is an important consideration in managing patients on the AD continuum, as presence of the APOE ε4 allele may influence response to treatment. We present the most current evidence relating to pharmacogenomics, nutrigenomics, and distinctive nutritional requirements targeted toward AD.

Detecting Non-cognitive Features of Prodromal Neurodegenerative Diseases.

BACKGROUND: Prodromal Neurodegenerative Disease (ND) due to tauopathies such as Alzheimer's Disease (AD) and Synucleinopathies (SN) such as Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB) present subtly. Although ND are considered cognitive disorders, in fact ND present with behavioral and even medical symptomatology years to decades prior to the onset of cognitive changes. Recognizing prodromal ND syndromes is a public health priority because ND is common, disabling and expensive. Diagnosing prodromal ND in real world clinical settings is challenging because ND of the same pathology can present with different symptoms in different people. Individual variability in nature and variability in nurture across the life course influence how ND pathology manifests clinically. The objective of this study was to describe how non-cognitive symptoms from behavioral, medical, neurological and psychiatric domains cluster in prodromal and early stages of ND. METHODS: This was an observational study of patients receiving routine clinical care for memory disorders. All patients receiving a standardized evaluation including complete neurological history and examination and standardized brief neuropsychological testing. A Principal Component Analysis (PCA) considering emotion, motor, sensory and sleep factors was performed on the entire sample of patients in order to identify co-occurring symptom clusters. All patients received a consensus diagnosis adjudicated by at least two dementia experts. Patients were grouped into Cognitively Normal, Detectable Cognitive Impairment, and Mild Cognitive Impairment categories due to AD and/or PD/LBD or NOS pathology. Symptom cluster scores were compared between clinical diagnostic groups. RESULTS: In this study 165 patients completed baseline neuropsychological testing and reported subjective measures of non-cognitive symptoms. Four syndrome specific symptom factors emerged and eight non-specific symptom factors. Symptoms of personality changes, paranoia, hallucinations, cravings, agitation, and changes in appetite grouped together into a cluster consistent with an "SN Non-motor Phenotype". Appetite, walking, balance, hearing, increased falls, and dandruff grouped together into a cluster consistent with an "SN Motor Phenotype". The Prodromal AD phenotype included symptoms of anxiety, irritability, apathy, sleep disturbance and social isolation. The fourth factor included symptoms of increased sweating, twitching, and tremor grouped into a cluster consistent with an Autonomic phenotype. CONCLUSION: Non-cognitive features can be reliably measured by self-report in busy clinical settings. Such measurement can be useful in distinguishing patients with different etiologies of ND. Better characterization of unique, prodromal, non-cognitive ND trajectories could improve public health efforts to modify the course of ND for all patients at risk.

Utility of the NIH Toolbox for assessment of prodromal Alzheimer's disease and dementia.

INTRODUCTION: The NIH Toolbox Cognition Battery (NIHTB-CB) is a computer-based protocol not yet validated for clinical assessment. METHODS: We administered the NIHTB-CB and traditional neuropsychological tests to 247 Memory Disorders and Alzheimer's Prevention Clinic patients with subjective cognitive decline, mild cognitive impairment, mild dementia due to Alzheimer's disease, and normal cognition. Principal component analysis, partial correlations, and univariate general linear model tests were performed to assess construct validity. Discriminant function analyses compared classification accuracy. RESULTS: Principal component analysis identified three conceptually coherent factors: memory (MEMNIH), executive function (EFNIH), and crystallized intelligence (CINIH). These factors were strongly associated with corresponding traditional tests and differed across diagnostic groups as expected. Both NIHTB and traditional batteries yielded strong overall discriminative ability (>80%). DISCUSSION: The NIHTB-CB is a valid method to assess neurocognitive domains pertinent to aging and dementia and has utility for applications in a memory clinic setting.

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.

Detection of neurodevelopmental diversity in memory clinics-Validation of a self-report measure.

BACKGROUND: Neurodevelopmental learning and attentional disorders (NLAD) such as dyslexia, dyscalculia and attention deficit hyperactivity disorder (ADHD) affect at least 6% of the adult population or more. They are associated with atypical cognitive patterns in early and adult life. The cognitive patterns of affected individuals in late life have never been described. One main challenge is detecting individuals in clinical settings during which mild cognitive changes could be confounding the clinical presentation. This is a critical research gap because these conditions interact, across the life course, with an individual's risk for dementia. Also, learning disabilities which present in childhood pose persistent cognitive differences in areas involving executive function, reading and math. Clinicians lack tools to detect undiagnosed neurodevelopmental in adults with memory disorders. The majority of patients presenting at memory clinics today come from a generation during which NLAD were not yet clinically recognized. In this study, we hypothesized that a self-report scale can detect NLAD in a memory clinic population. METHODS: We developed a self-report, retrospective childhood cognitive questionnaire including key attributes adapted from prior validated measures. 233 participants were included in the primary analysis. RESULTS: Confirmatory Factor Analysis resulted in a best-fit model with six labelled factors (Math, Language, Attention, Working Memory, Sequential Processing, and Executive Function) and 15 total question items. The model demonstrated unidimensionality, reliability, convergent validity, discriminant validity, and predictive validity. Using 1.5 standard deviations as the cut-off, subjects were categorized into: Normal (n = 169), Language (n = 10), Math (n = 12), Attention (n = 10) or Other/Mixed (n = 32). CONCLUSION: A self-report measure can be a useful tool to elicit childhood cognitive susceptibilities in various domains that could represent NLAD among patients in a memory clinic setting, even in the presence of mild cognitive impairment.

Nutritional interventions for Alzheimer's prevention: a clinical precision medicine approach.

Alzheimer's disease (AD) is a major source of morbidity and mortality, with the disease burden expected to rise as the population ages. No disease-modifying agent is currently available, but recent research suggests that nutritional and lifestyle modifications can delay or prevent the onset of AD. However, preventive nutritional interventions are not universally applicable and depend on the clinical profile of the individual patient. This article reviews existing nutritional modalities for AD prevention that act through improvement of insulin resistance, correction of dyslipidemia, and reduction of oxidative stress, and discusses how they may be modified on the basis of individual biomarkers, genetics, and behavior. In addition, we report preliminary results of clinical application of these personalized interventions at the first AD prevention clinic in the United States. The use of these personalized interventions represents an important application of precision medicine techniques for the prevention of AD that can be adopted by clinicians across disciplines.

Economic evaluation of medical technologies.

Innovation in medical science is progressing at a rapid pace. As a result, new medical technologies that offer to improve upon or completely replace existing alternatives are continually appearing. These technologies--which include pharmaceuticals, devices, equipment, supplies, medical and surgical procedures, and administrative and support systems--are changing the way medicine can be practiced and delivered, forcing healthcare providers and policymakers to consistently evaluate and adapt to new treatment options. Meanwhile, society is becoming more demanding of new medical technologies. Emerging medical technology, however, has been viewed as a significant factor in increasing the cost of healthcare. The abundance of new medical alternatives, combined with scarcity of resources, has led to priority setting, rationing and the need for more technology management and assessment. Economic evaluation of medical technologies is a system of analysis used to formally compare the costs and consequences of alternative healthcare interventions. EEMT can be used by many healthcare entities, including national policymakers, manufacturers, payers and providers, as a tool to aid in resource allocation decisions. This paper discusses the four current popular methodologies for EEMT (cost-minimization, cost-benefit, cost-effectiveness and cost-utility), and describes the industry environment that has shaped their development.

Medical technology management: bridging the gap between theory and practice.

New medical technologies that offer to improve upon or completely replace existing ones are continuously appearing. These technologies are forcing healthcare policymakers to consistently evaluate new treatment options. However, emerging medical technology has been viewed as a significant factor in increasing the cost of healthcare. The abundance of new medical alternatives, combined with scarcity of resources, has led to priority setting, rationing, and the need for further technology management and assessment. Economic evaluation of medical technologies is a system of analysis within the framework of health technology assessment to formally compare the costs and consequences of alternative healthcare interventions. EEMT can be used by many healthcare entities, including national policymakers, manufacturers, payers and providers, as a tool to aid in resource allocation decisions. In this paper we discuss the historical evolution and potential of EEMT, the practical limitations hindering more extensive implementation of these types of studies, current efforts at improvement, and the ethical issues influencing ongoing development. The Medical Technologies Administration in Israel's Ministry of Health is given as an example of an entity that has succeeded in practically implementing EEMT to optimize healthcare resource allocation.

Childhood Learning Disabilities and Atypical Dementia: A Retrospective Chart Review.

OBJECTIVE: To further our understanding of the association between self-reported childhood learning disabilities (LDs) and atypical dementia phenotypes (Atypical Dementia), including logopenic primary progressive aphasia (L-PPA), Posterior Cortical Atrophy (PCA), and Dysexecutive-type Alzheimer's Disease (AD). METHODS: This retrospective case series analysis of 678 comprehensive neuropsychological assessments compared rates of self-reported LD between dementia patients diagnosed with Typical AD and those diagnosed with Atypical Dementia. 105 cases with neuroimaging or CSF data available and at least one neurology follow-up were identified as having been diagnosed by the neuropsychologist with any form of neurodegenerative dementia. These cases were subject to a consensus diagnostic process among three dementia experts using validated clinical criteria for AD and PPA. LD was considered Probable if two or more statements consistent with prior LD were documented within the Social & Developmental History of the initial neuropsychological evaluation. RESULTS: 85 subjects (Typical AD n=68, Atypical AD n=17) were included in the final analysis. In logistic regression models adjusted for age, gender, handedness, education and symptom duration, patients with Probable LD, compared to patients without Probable LD, were significantly more likely to be diagnosed with Atypical Dementia vs. Typical AD (OR 13.1, 95% CI 1.3-128.4). All three of the L-PPA cases reporting a childhood LD endorsed childhood difficulty with language. By contrast, both PCA cases reporting Probable childhood LD endorsed difficulty with attention and/or math. CONCLUSIONS: In people who develop dementia, childhood LD may predispose to atypical phenotypes. Future studies are required to confirm whether atypical neurodevelopment predisposes to regional-specific neuropathology in AD and other dementias.

Hippocampal laminar distribution of tau relates to Alzheimer's disease and age of onset.

BACKGROUND: Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. OBJECTIVE: To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. METHODS: 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. RESULTS: High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI -6.7 to -0.7, p < 0.01), after adjustment for demographics and symptom duration. CONCLUSIONS: Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course.

Perspective: the case for subspecialty clinical learning in early medical education-moving from case-based to patient-based learning.

The subspecialty departments are greatly underutilized for teaching during the first two years of medical school. While second-year students are spending most of their time behind closed doors in the laboratory, lectures, and small groups, the clinical environment is teeming with actual patients whose cases are often directly analogous to the material being learned. Moreover, even in today's environment of increased emphasis on quality of medical care and medical education reform, many U.S. medical students still lack essential exposure to common technologies, tests, and procedures performed within several subspecialties. To remedy this situation, the authors propose that educators develop a system of subspecialty clinical learning for first- and/or second-year students correlated to the classroom study of the pathophysiology of the various organ systems. For example, the second-year cardiology course could be augmented with self-directed, patient-centered learning assignments in the cardiac unit, the pathology lab, the echo lab, and other areas. The authors explain the several advantages of comprehensive subspecialty clinical learning (e.g., it will help prepare physicians to practice distributed care, aid development of competencies within the behavioral and social sciences, foster students' professional development, and encourage creative approaches to issues of health care quality). The authors acknowledge the multiple difficulties of implementing such an approach, and present evidence supporting their argument that with the appropriate vision and leadership, such a living curriculum is important and achievable.