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.

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.

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.