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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.
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Enfermedad de Alzheimer/terapia , Disfunción Cognitiva/prevención & control , Educación en Salud , Cooperación del Paciente , Síntomas Prodrómicos , Conducta de Reducción del Riesgo , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares , Cognición , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
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.
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Enfermedad de Alzheimer/prevención & control , Medicina de Precisión , Conducta de Reducción del Riesgo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Cognición , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión/métodosRESUMEN
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.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/terapia , HumanosRESUMEN
BACKGROUND AND PURPOSE: The purpose of this study was to determine if postmortem intracranial arteries from donors with HIV without stroke have thinner media layers compared with patients without HIV and without stroke. METHODS: Cross-sectional cuts from intracranial arteries were stained with van Gieson and hematoxylin and eosin. Arteries were examined for thickness of each arterial layer. Univariable and multivariable models were used for statistical analyses with probability values <0.05 considered significant. RESULTS: A total of 18 brains were analyzed, 5 with HIV and 13 without. Fifty-five arteries were collected, 15 from HIV brains and 40 from unaffected controls. In univariable analysis, in arteries from HIV-infected brains, the media to wall thickness ratio was smaller than in donors without HIV (0.496 versus 0.563, P=0.017). In multivariable analysis, HIV infection was the only independent predictor of smaller media ratios compared with the same-aged control subjects (P=0.049) but not with aged control subjects (P=0.081). CONCLUSIONS: In patients with HIV without clinical stroke, the media arterial layer is thinner than in patients without HIV. This suggests that a thinner media layer might be a preclinical stage in the development of HIV-related vasculopathy.
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Arterias Cerebrales/patología , Infecciones por VIH/patología , Accidente Cerebrovascular/patología , Túnica Media/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.
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Lagunas en las Evidencias , Estado Nutricional , Humanos , Estados Unidos , Medicina de Precisión/métodos , Dieta , National Institutes of Health (U.S.) , NutrigenómicaRESUMEN
The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer's disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer's disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood-brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer's risk reduction.
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Enfermedad de Alzheimer/prevención & control , Dieta/métodos , Predisposición Genética a la Enfermedad/prevención & control , Terapia Nutricional/métodos , Medicina de Precisión/métodos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Astrocitos/metabolismo , Barrera Hematoencefálica/metabolismo , Femenino , Variación Genética , Humanos , Resistencia a la Insulina/fisiología , Masculino , Microglía/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: Research suggests optimizing sleep, exercise and work-life balance may improve resident physician burnout. Wearable biosensors may allow residents to detect and correct poor sleep and exercise habits before burnout develops. Our objectives were to evaluate the feasibility of a wearable biosensor to characterize exercise/sleep in neurology residents and examine its relationship to self-reported, validated survey measures. We also assessed the device's impact on well-being and barriers to use. METHODS: This prospective cohort study evaluated the WHOOP Strap 2.0 in neurology residents. Participants completed regular online surveys, including self-reported hours of sleep/exercise, and validated sleep/exercise scales at 3-month intervals. Autonomic, exercise, and sleep measures were obtained from WHOOP. Changes were evaluated over time via linear regression. Survey and WHOOP metrics were compared using Pearson correlations. RESULTS: Sixteen (72.7%) of 22 eligible participants enrolled. Eleven (68.8%) met the minimum usage requirement (6+ months) and were classified as 'consecutive wearers.' Significant increases were found in sleep duration and exercise intensity. Moderate-to-low correlations were found between survey responses and WHOOP measures. Most (73%) participants reported a positive impact on well-being. Barriers to use included 'Forgetting to wear' (20%) and 'not motivational' (23.3%). CONCLUSION: Wearable biosensors may be a feasible tool to evaluate sleep/exercise in residents.
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Técnicas Biosensibles , Internado y Residencia , Neurología , Dispositivos Electrónicos Vestibles , Estudios de Factibilidad , Humanos , Estudios Prospectivos , SueñoRESUMEN
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.
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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.
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Enfermedad de Alzheimer/prevención & control , Educación a Distancia/métodos , Educación en Salud/métodos , Promoción de la Salud/métodos , Estudiantes/psicología , Adolescente , Adulto , Personajes , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Internet , Masculino , Conducta de Reducción del Riesgo , Adulto JovenRESUMEN
OBJECTIVE: To investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (ß-amyloid load via 11C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI). METHODS: We examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences. RESULTS: Groups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB ß-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group (p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease. CONCLUSION: Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.
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Enfermedad de Alzheimer/epidemiología , Imagen Multimodal , Neuroimagen , Adulto , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Compuestos de Anilina , Apolipoproteínas E/genética , Femenino , Fluorodesoxiglucosa F18 , Hormonas/sangre , Humanos , Estilo de Vida , Imagen por Resonancia Magnética , Masculino , Menopausia/psicología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Radiofármacos , Factores de Riesgo , Factores Sexuales , TiazolesRESUMEN
INTRODUCTION: Glucose hypometabolism and insulin resistance increase risk for and accelerate progression in Parkinson's disease and neurocognitive disorders. We conducted a proof of concept trial to determine whether ketogenesis, a metabolic adaptation induced by dietary carbohydrate restriction, can improve cognitive performance in Parkinson's disease patients with mild cognitive impairment. METHODS: We enrolled patients with mild cognitive impairment associated with Parkinson's disease in an eight-week nutritional intervention with random assignment to either high-carbohydrate consumption typical of the Western dietary pattern (nâ¯=â¯7) or to a low-carbohydrate, ketogenic regimen (nâ¯=â¯7). We assessed changes in cognitive performance as well as motor function, anthropometrics, and metabolic parameters. RESULTS: Relative to the high-carbohydrate group, the low-carbohydrate group demonstrated improvements in lexical access (pâ¯=â¯0.02, Cohen's f effect sizeâ¯=â¯0.76) and memory (pâ¯=â¯0.01, fâ¯=â¯0.87) and as well as a trend for reduced interference in memory (pâ¯=â¯0.06, fâ¯=â¯0.60). The low-carbohydrate group also exhibited reduced body weight (pâ¯<â¯0.0001, fâ¯=â¯1.89) and increased circulation of beta-hydroxybutyrate (pâ¯=â¯0.01, fâ¯=â¯0.90). Change in body weight was strongly associated with memory performance (pâ¯=â¯0.001). Motor function was not affected by the intervention. CONCLUSION: Nutritional ketosis enhanced cognitive performance in Parkinson's disease-associated mild cognitive impairment in this pilot study. This metabolic intervention and its mechanisms deserve further investigation in the context of neurodegeneration.
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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.
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Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/psicología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Diagnóstico Precoz , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/psicología , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/psicología , Fenotipo , Síntomas Prodrómicos , Estudios RetrospectivosRESUMEN
Research indicates that after advanced age, the major risk factor for late-onset Alzheimer's disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the "estrogen hypothesis." This posits that sex hormones, 17ß-estradiol in particular, exert a neuroprotective effect by shielding females' brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17ß-estradiol during the menopause transition (MT) as key underlying mechanisms.
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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.
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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.
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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.
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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.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/etiología , Menopausia/psicología , Anciano , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/análisis , Apolipoproteína E4/análisis , Biomarcadores , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Memoria , Menopausia/fisiología , Persona de Mediana Edad , Neuroimagen/métodos , Pruebas Neuropsicológicas , Tomografía de Emisión de PositronesRESUMEN
OBJECTIVE: To investigate the associations between lifestyle and vascular risk factors and changes in Alzheimer's disease (AD) biomarkers (beta-amyloid load via 11C-PiB PET, glucose metabolism via 18F-FDG PET and neurodegeneration via structural MRI) and global cognition in middle-aged asymptomatic participants at risk for AD. DESIGN: Prospective, longitudinal. SETTING: The study was conducted at New York University Langone/Weill Cornell Medical Centres in New York City. PARTICIPANTS: Seventy cognitively normal participants from multiple community sources, aged 30-60 years with lifestyle measures (diet, intellectual activity and physical activity), vascular risk measures and two imaging biomarkers visits over at least 2 years, were included in the study. OUTCOME MEASURES: We examined MRI-based cortical thickness, fluoro-deoxy-glucose (FDG) glucose metabolism and PiB beta-amyloid in AD-vulnerable regions. A global cognitive z-score served as our summary cognition measure. We used regression change models to investigate the associations of clinical, lifestyle and vascular risk measures with changes in AD biomarkers and global cognition. RESULTS: Diet influenced changes in glucose metabolism, but not amyloid or cortical thickness changes. With and without accounting for demographic measures, vascular risk and baseline FDG measures, lower adherence to a Mediterranean-style diet was associated with faster rates of FDG decline in the posterior cingulate cortex (p≤0.05) and marginally in the frontal cortex (p=0.07). None of the other lifestyle variables or vascular measures showed associations with AD biomarker changes. Higher baseline plasma homocysteine was associated with faster rates of decline in global cognition, with and without accounting for lifestyle and biomarker measures (p=0.048). None of the lifestyle variables were associated with cognition. CONCLUSIONS: Diet influenced brain glucose metabolism in middle-aged participants, while plasma homocysteine explained variability in cognitive performance. These findings suggest that these modifiable risk factors affect AD risk through different pathways and support further investigation of risk reduction strategies in midlife.
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Enfermedad de Alzheimer/etiología , Enfermedades Vasculares/complicaciones , Adulto , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Biomarcadores/análisis , Biomarcadores/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica , Dieta/efectos adversos , Glucosa/metabolismo , Homocisteína/sangre , Humanos , Estilo de Vida , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Ciudad de Nueva York , Tomografía de Emisión de Positrones , Estudios Prospectivos , Factores de Riesgo , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patologíaRESUMEN
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.
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OBJECTIVE: To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN: Cross-sectional, observational. SETTING: Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS: We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS: Adherence to a Mediterranean-style diet (MeDi) and insulin sensitivity were both positively associated with MRI-based cortical thickness (diet: ßs≥0.26, insulin sensitivity ßs≥0.58, P≤0.008). After accounting for vascular risk, EC in turn explained variance in memory (P≤0.001). None of the other lifestyle and vascular risk variables were associated with brain thickness. In addition, the path associations between intellectual enrichment and better cognition were significant (ßs≥0.25 P≤0.001), as were those between overweight and lower cognition (ßs≥-0.22, P≤0.01). CONCLUSIONS: In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.