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POSSIBILITIES FOR MID-LIFE INTERVENTION TO PREVENT ALZHEIMER'S DEMENTIA: A CONCEPTUAL FRAMEWORK
P284
Featured Research Sessions: F5-03: Does Late-Onset AD Begin in Mid-Life?
could be used as a prognostic marker of transition towards cognitive decline. By assessing a panel of peripheral biomarkers longitudinally, we will be able to implement prevention and treatment strategies to be initiated early in the disease process, thereby delaying the cognitive decline. F5-02-04
BLOOD-BASED BIOMARKERS OF NEUROPSYCHIATRIC SYMPTOMS IN ALZHEIMER’S: INFLAMMATION, VASCULAR RISKS, GENDER, AND APOE-E4 STATUS
James Richard Hall1, April Wiechmann2, Leigh Johnson3, Melissa Edwards4, Robert Barber3, Sid E. O’Bryant5, 1University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, United States; 2University of North Texas Health Science Center, Ft. Worth, Texas, United States; 3University of North Texas Health Science Center, Fort Worth, Texas, United States; 4University of North Texas, Ft. Worth, Texas, United States; 5University of North Texas Health Science Center, Lubbock, Texas, United States. Contact e-mail: [email protected] Background: Neuropsychiatric symptoms (NPS) in AD are common, difficult to treat, a primary source of caregiver stress and the single largest risk for nursing home placement. The identification of blood-based biomarkers would allow determination of those at higher risk and open new avenues for treatment. Methods: Data were analyzed on 220 AD participants from the TARCC cohort. Blood-based markers of cardiovascular risk, inflammation and microvascular pathology were assayed using Rules Based Medicine (RBM) multiplexed immunoassay human Multi-Analyte Profile (humanMAP). NPS were assessed using NPI-Q. Results: Linear regression modeling of a mixed gender sample revealed IL15, VCAM and triglycerides significantly and negatively related to total NPS symptoms and Total Cholesterol (TC) and Homocysteine were positively. TC was a positive marker for total NPS and symptoms of hyperactivity, psychosis, affect and apathy among men only. IL-15 and IL-1ra were negatively associated with NPS and homocysteine positively associated for females. TC was strongly related to NPS in males regardless of APOEε4status. TC accounted for 36% of the variance for APOE4 carriers and 32% among non-APOE4 carriers in (NPI-Q) total scores. IL15 was found to be negatively related to NPS for female APOEε4 carriers. For female non-carriers IL18 was a negative predictor of NPS. Compared to high TC females, high TC males were 2.66 times more likely to have multiple NPS, 2.78 times more likely to have hyperactive symptoms; 2.34 times more likely to have affective symptoms and 2.58 times more likely to have apathy. High TC males were 4 times more likely to have symptoms of psychosis compared to low TC males. Conclusions: Data suggest that cholesterol is a primary factor in the occurrence of NPS in male AD patients and dysregulation of inflammatory processes and oxidative stress primary for females. TC is strongly related to NPS in males regardless of APOEε4 status. TC 200 is a risk factor NPS in AD especially for males. Findings have implications for treatment of NPS in AD cases and may need to vary based on gender and APOE4 status. THURSDAY, JULY 17, 2014 FEATURED RESEARCH SESSIONS F5-03 DOES LATE-ONSET AD BEGIN IN MID-LIFE? F5-03-01
THE IMPORTANCE OF RISK FACTOR MODIFICATION OVER THE LIFECOURSE
Kristine Yaffe, University of California, San Francisco, San Francisco, California, United States. Contact e-mail: [email protected] Background: The pathophysiology of Alzheimer’s Disease (AD) probably develops over decades, but the majority of epidemiological studies have focused on risk factor exposure from mid or later life. In addition, the timing and duration of effective AD prevention strategies remains unclear. A small but growing body of evidence suggests that risk factors earlier in the lifecourse may also contribute to an increased risk of cognitive aging. Methods: We present data from the Coronary Artery Risk Development in Young Adults Study (CARDIA), a biracial cohort of 3,499 adults (18-30 years old at enrollment). Risk factors including demographics, comorbidities, and lifestyle behaviors were evaluated over 25 years. At Year 25, cognitive function was assessed
using the Digit Symbol Substitution Test (DSST), Stroop Interference Score, and Rey Auditory Verbal Learning Test (RAVLT). We also review findings from a study designed to determine the effect of midlife risk factor modification on projected prevalence of AD. Results: Results from CARDIA suggest that early adult risk factors could contribute to midlife cognitive aging. Over 25 years, elevated levels of blood pressure, fasting blood glucose, and cholesterol were associated with worse cognitive performance on RAVLT, DSST, and Stroop in midlife (p<0.05 for all). Relationships were similar for other modifiable risk factors in early adulthood, including those defined by existing guidelines for healthy behaviors such as physical activity, nutrition and the American Heart Association’s recommendations for ideal cardiovascular health. Epidemiological data also support a relationship between risk of AD and several potentially modifiable risk factors in mid and late life including diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. As a group, these risk factors could account for up to 50% of AD cases worldwide, and reduction of these risk factors could have a significant impact on AD prevalence. Conclusions: While there is robust evidence for modifiable risk factors and AD risk among older adults, recent findings also indicate that cognitive aging may begin even in midlife. Interventions that target risk factor exposure earlier in the lifecourse could play an important role in AD prevention. F5-03-02
POSSIBILITIES FOR MID-LIFE INTERVENTION TO PREVENT ALZHEIMER’S DEMENTIA: A CONCEPTUAL FRAMEWORK
Craig William Ritchie, Imperial College London, London, United Kingdom. Contact e-mail: [email protected] Background: Recent proposals and accumulating evidence suggest that the genesis of the neurodegenerative diseases that lead to dementia in late life have their genesis several decades earlier. Cohort studies, like the PREVENT programme are establishing detailed risk factor and phenotypic evidence for the interplay between risk factors and expression of neurodegenerative disease in multiple biomarker modalities in a mid-life, asymptomatic population. Methods: The main aim of developing this evidence is to inform the design of prevention studies that would be applied in mid-life. Intervention studies and thereafter prevention programmes will be informed by accurate stratification of an individual’s risk for dementia. These risk models can be developed from the interplay between proposed risk factors (such as depression, diabetes, ApoE status, lifestyle etc.) and expression of disease at baseline (e.g. amyloid deposition, CSF/Blood Biomarkers and MRI changes). Over time as cognitive and other symptoms emerge and disease manifestations progress, risk models can be refined. Results: An individual’s risk indexfor dementia can then be used to determine their access to a variety of trials. Those considered at the highest risk of dementia defined by multiple risks, early manifestations of disease and early symptoms may be considered for pharmacological, potentially disease modifying trials whereas those with lower risk indices could access prevention programmes which target riskfactor modification. Conclusions: The establishment and aggregation of such cohorts at a national and international level in readiness for secondary prevention studies in mid-life and early old age is ongoing with the dual benefit of developing a trial ready, risk stratified population and creating high quality natural history data for disease and symptom development in a younger population pool than is currently available. This conceptual framework and early evidence that informs its development will be presented as will models for proof of concept early intervention trials. F5-03-03
DOES LATE-LIFE AD BEGIN ALREADY IN MIDLIFE? EVIDENCE FROM LONG TERM POPULATION STUDIES
Ingmar Skoog, University of Gothenburg, M€olndal, Sweden. Contact e-mail: [email protected] Background: There is evidence from neuropathological and neurochemical studies that AD changes are present decades before the clinical onset of the disease. Several longitudinal population studies report that midlife high blood pressure and higher BMI are related to late onset AD. Methods: Analyses derived from longitudinal studies. Results: Blood pressure and BMI starts
Featured Research Sessions: F5-03: Does Late-Onset AD Begin in Mid-Life?
could be used as a prognostic marker of transition towards cognitive decline. By assessing a panel of peripheral biomarkers longitudinally, we will be able to implement prevention and treatment strategies to be initiated early in the disease process, thereby delaying the cognitive decline. F5-02-04
BLOOD-BASED BIOMARKERS OF NEUROPSYCHIATRIC SYMPTOMS IN ALZHEIMER’S: INFLAMMATION, VASCULAR RISKS, GENDER, AND APOE-E4 STATUS
James Richard Hall1, April Wiechmann2, Leigh Johnson3, Melissa Edwards4, Robert Barber3, Sid E. O’Bryant5, 1University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, United States; 2University of North Texas Health Science Center, Ft. Worth, Texas, United States; 3University of North Texas Health Science Center, Fort Worth, Texas, United States; 4University of North Texas, Ft. Worth, Texas, United States; 5University of North Texas Health Science Center, Lubbock, Texas, United States. Contact e-mail: [email protected] Background: Neuropsychiatric symptoms (NPS) in AD are common, difficult to treat, a primary source of caregiver stress and the single largest risk for nursing home placement. The identification of blood-based biomarkers would allow determination of those at higher risk and open new avenues for treatment. Methods: Data were analyzed on 220 AD participants from the TARCC cohort. Blood-based markers of cardiovascular risk, inflammation and microvascular pathology were assayed using Rules Based Medicine (RBM) multiplexed immunoassay human Multi-Analyte Profile (humanMAP). NPS were assessed using NPI-Q. Results: Linear regression modeling of a mixed gender sample revealed IL15, VCAM and triglycerides significantly and negatively related to total NPS symptoms and Total Cholesterol (TC) and Homocysteine were positively. TC was a positive marker for total NPS and symptoms of hyperactivity, psychosis, affect and apathy among men only. IL-15 and IL-1ra were negatively associated with NPS and homocysteine positively associated for females. TC was strongly related to NPS in males regardless of APOEε4status. TC accounted for 36% of the variance for APOE4 carriers and 32% among non-APOE4 carriers in (NPI-Q) total scores. IL15 was found to be negatively related to NPS for female APOEε4 carriers. For female non-carriers IL18 was a negative predictor of NPS. Compared to high TC females, high TC males were 2.66 times more likely to have multiple NPS, 2.78 times more likely to have hyperactive symptoms; 2.34 times more likely to have affective symptoms and 2.58 times more likely to have apathy. High TC males were 4 times more likely to have symptoms of psychosis compared to low TC males. Conclusions: Data suggest that cholesterol is a primary factor in the occurrence of NPS in male AD patients and dysregulation of inflammatory processes and oxidative stress primary for females. TC is strongly related to NPS in males regardless of APOEε4 status. TC 200 is a risk factor NPS in AD especially for males. Findings have implications for treatment of NPS in AD cases and may need to vary based on gender and APOE4 status. THURSDAY, JULY 17, 2014 FEATURED RESEARCH SESSIONS F5-03 DOES LATE-ONSET AD BEGIN IN MID-LIFE? F5-03-01
THE IMPORTANCE OF RISK FACTOR MODIFICATION OVER THE LIFECOURSE
Kristine Yaffe, University of California, San Francisco, San Francisco, California, United States. Contact e-mail: [email protected] Background: The pathophysiology of Alzheimer’s Disease (AD) probably develops over decades, but the majority of epidemiological studies have focused on risk factor exposure from mid or later life. In addition, the timing and duration of effective AD prevention strategies remains unclear. A small but growing body of evidence suggests that risk factors earlier in the lifecourse may also contribute to an increased risk of cognitive aging. Methods: We present data from the Coronary Artery Risk Development in Young Adults Study (CARDIA), a biracial cohort of 3,499 adults (18-30 years old at enrollment). Risk factors including demographics, comorbidities, and lifestyle behaviors were evaluated over 25 years. At Year 25, cognitive function was assessed
using the Digit Symbol Substitution Test (DSST), Stroop Interference Score, and Rey Auditory Verbal Learning Test (RAVLT). We also review findings from a study designed to determine the effect of midlife risk factor modification on projected prevalence of AD. Results: Results from CARDIA suggest that early adult risk factors could contribute to midlife cognitive aging. Over 25 years, elevated levels of blood pressure, fasting blood glucose, and cholesterol were associated with worse cognitive performance on RAVLT, DSST, and Stroop in midlife (p<0.05 for all). Relationships were similar for other modifiable risk factors in early adulthood, including those defined by existing guidelines for healthy behaviors such as physical activity, nutrition and the American Heart Association’s recommendations for ideal cardiovascular health. Epidemiological data also support a relationship between risk of AD and several potentially modifiable risk factors in mid and late life including diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. As a group, these risk factors could account for up to 50% of AD cases worldwide, and reduction of these risk factors could have a significant impact on AD prevalence. Conclusions: While there is robust evidence for modifiable risk factors and AD risk among older adults, recent findings also indicate that cognitive aging may begin even in midlife. Interventions that target risk factor exposure earlier in the lifecourse could play an important role in AD prevention. F5-03-02
POSSIBILITIES FOR MID-LIFE INTERVENTION TO PREVENT ALZHEIMER’S DEMENTIA: A CONCEPTUAL FRAMEWORK
Craig William Ritchie, Imperial College London, London, United Kingdom. Contact e-mail: [email protected] Background: Recent proposals and accumulating evidence suggest that the genesis of the neurodegenerative diseases that lead to dementia in late life have their genesis several decades earlier. Cohort studies, like the PREVENT programme are establishing detailed risk factor and phenotypic evidence for the interplay between risk factors and expression of neurodegenerative disease in multiple biomarker modalities in a mid-life, asymptomatic population. Methods: The main aim of developing this evidence is to inform the design of prevention studies that would be applied in mid-life. Intervention studies and thereafter prevention programmes will be informed by accurate stratification of an individual’s risk for dementia. These risk models can be developed from the interplay between proposed risk factors (such as depression, diabetes, ApoE status, lifestyle etc.) and expression of disease at baseline (e.g. amyloid deposition, CSF/Blood Biomarkers and MRI changes). Over time as cognitive and other symptoms emerge and disease manifestations progress, risk models can be refined. Results: An individual’s risk indexfor dementia can then be used to determine their access to a variety of trials. Those considered at the highest risk of dementia defined by multiple risks, early manifestations of disease and early symptoms may be considered for pharmacological, potentially disease modifying trials whereas those with lower risk indices could access prevention programmes which target riskfactor modification. Conclusions: The establishment and aggregation of such cohorts at a national and international level in readiness for secondary prevention studies in mid-life and early old age is ongoing with the dual benefit of developing a trial ready, risk stratified population and creating high quality natural history data for disease and symptom development in a younger population pool than is currently available. This conceptual framework and early evidence that informs its development will be presented as will models for proof of concept early intervention trials. F5-03-03
DOES LATE-LIFE AD BEGIN ALREADY IN MIDLIFE? EVIDENCE FROM LONG TERM POPULATION STUDIES
Ingmar Skoog, University of Gothenburg, M€olndal, Sweden. Contact e-mail: [email protected] Background: There is evidence from neuropathological and neurochemical studies that AD changes are present decades before the clinical onset of the disease. Several longitudinal population studies report that midlife high blood pressure and higher BMI are related to late onset AD. Methods: Analyses derived from longitudinal studies. Results: Blood pressure and BMI starts