- Email: [email protected]
ASSESSING PREVENTION STRATEGIES FOR ALZHEIMER’S DEMENTIA: A NEW APPROACH
Podium Presentations: Wednesday, July 19, 2017
Hsa21 sequences, other than APP, cause cysteine cathepsin deficits that result in failure to activate these proteases in DS. We successfully modelled these enzymatic changes in a novel AD-DS mouse model system, and found that they occur independently of gross-enlargement of the endo-lysosomes. Using our AD-DS mouse model, we show that trisomy of Hsa21 sequences, other than APP, also alter the metabolism of APP/Ab. These changes decrease the soluble Ab38/42 ratio and are associated with an increase in Ab aggregation and deposition, and result in exacerbation of APP/Ab-associated hyper-activity and specific deficits in two tests of short-term memory. We also show that the trisomy-associated changes in APP/Ab metabolism we observe occur independently of alterations in a-, b- or g-secretase activity or changes in the rate of extracellular Ab-clearance in vivo. Conclusions: We propose that trisomy Hsa21-associated cathepsin deficits are a novel AD-DS pathomechanism that alter APP/Ab processing and may contribute to the development of AD in people who have DS. WEDNESDAY, JULY 19, 2017 FEATURED RESEARCH SESSION F4-03 ASSESSING THE EFFECTIVENESS OF INTERVENTIONS TO PREVENT, DELAY, OR SLOW ALZHEIMER’S DISEASE, MILD COGNITIVE IMPAIRMENT, OR AGE-RELATED COGNITIVE DECLINE
F4-03-01
ASSESSING PREVENTION STRATEGIES FOR ALZHEIMER’S DEMENTIA: A NEW APPROACH
Melinda Kelley, National Institute on Aging, Bethesda, MD, USA. Contact e-mail: [email protected] Background: For the past several years, there has been increased interest across both governmental and non-governmental agencies around the world, in whether the field of Alzheimer’s disease research currently provides sufficient evidence regarding strategies the public can take to prevent this condition. The U.S. National Institutes of Health (NIH) had not formally explored this literature since 2010, when the agency held a State-of-the-Science Conference entitled Preventing Alzheimer’s Disease and Cognitive Decline. After considering an Agency for Healthcare Research and Quality (AHRQ)-conducted systematic review of the literature and several additional sources of input, an independent panel found that “firm conclusions cannot be drawn about the association of modifiable risk factors with cognitive decline or Alzheimer’s disease” and that “there is insufficient evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease.” Methods: The National Institute on Aging (NIA) believed that the development of new evidence in this field warranted revisiting the literature, and that novel models might be explored that could enhance the rigor and independence of the evidence review process, and ensure the involvement of experts in a wide range of key scientific and clinical disciplines. Ultimately, the NIA established two separate contracts to conduct this review: one with the Minnesota Evidence-based Practice Center (EPC; via AHRQ), and the second with the National Academies of Science, Engineering, and Medicine. The NIA tasked these groups with exploring the state of the science regarding interventions for delaying or slowing age-related cognitive decline and preventing, delaying, or slowing mild cognitive impairment and clinical Alzheimer’s-type dementia. Results: The Minnesota EPC conducted a systematic review that informed the deliberations of a National Academies committee, which took the evidence review and considered it in light of ongoing research, evidence external to the interven-
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tion literature, and the need to provide the public with the most up-todate information possible. Conclusions: This two-pronged, coordinated approach offers rigorous, complementary information that can inform future public health messaging and research decisions, and the model itself can be used in the future to address similarly complex questions that bridge research and public health. F4-03-02
BEHAVIORAL INTERVENTIONS TO PREVENT, DELAY, OR SLOW ALZHEIMER’S DISEASE, MILD COGNITIVE IMPAIRMENT, OR AGERELATED COGNITIVE DECLINE
Mary Butler, University of Minnesota, Minneapolis, MN, USA. Contact e-mail: [email protected] Background: Assess evidence for behavioral interventions aimed at
preventing or delaying onset of age-related cognitive decline, mild cognitive impairment (MCI), or clinical Alzheimer’s-type dementia (CATD). Methods: We searched Medline, PsycINFO, Embase, and Cochrane Central Register of Controlled Trials through September, 2016, supplemented with hand-searching. Two investigators screened abstracts and full-text articles of identified references. Eligible studies included randomized and nonrandomized controlled trials and quasiexperimental observational studies enrolling people with normal cognition and/or MCI. We extracted data, assessed risk of bias, summarized results for studies without high risk of bias, and evaluated strength of evidence for studies with sufficient sample size. Cognitive outcomes were grouped into domains to facilitate analysis. Results: We identified 170 eligible studies over 6 classes of interventions: cognitive training, physical activity, nutraceuticals, diet, multimodal interventions, and vitamins. We found no high-strength evidence for the effectiveness of any intervention to delay or prevent age-related cognitive decline, MCI, and/or CATD. Moderate-strength evidence shows cognitive training in adults with presumed normal cognition improves performance in the cognitive domain trained (memory, reasoning, or processing speed), but not transfer of benefits to other cognitive areas and little evidence for benefit beyond 2 years; evidence for effect on CATD is weak. Moderate-strength evidence showed no benefit for Vitamin E in women and B12 plus folic acid for executive/attention/processing speed. Physical activity interventions show no consistent benefit in preventing cognitive decline, but the proportion of results showing benefit were unlikely to be explained solely by chance, providing a signal of a possible relationship. A few other interventions showed at least one positive finding for a specific outcome, some reaching low strength of evidence, but these were more than offset by findings of no effect for other outcomes. We found no eligible studies for depression treatment or smoking cessation. Conclusions: Overall, evidence for is weak. Future research should address wide-spread methodological problems, including use of consistent cognitive outcome measures, longer follow-ups, and recognizing that attrition is a major problem in longer studies. More work is needed to understand the relationship between intermediate outcomes like cognitive test results and the onset of MCI and dementia. F4-03-03
PHARMACOLOGICAL INTERVENTIONS TO PREVENT OR DELAY ALZHEIMER’S DISEASE, MILD COGNITIVE IMPAIRMENT, OR AGE-RELATED COGNITIVE DECLINE
Howard Fink, Minneapolis VA Medical Center, Minneapolis, MN, USA. Contact e-mail: [email protected]
Hsa21 sequences, other than APP, cause cysteine cathepsin deficits that result in failure to activate these proteases in DS. We successfully modelled these enzymatic changes in a novel AD-DS mouse model system, and found that they occur independently of gross-enlargement of the endo-lysosomes. Using our AD-DS mouse model, we show that trisomy of Hsa21 sequences, other than APP, also alter the metabolism of APP/Ab. These changes decrease the soluble Ab38/42 ratio and are associated with an increase in Ab aggregation and deposition, and result in exacerbation of APP/Ab-associated hyper-activity and specific deficits in two tests of short-term memory. We also show that the trisomy-associated changes in APP/Ab metabolism we observe occur independently of alterations in a-, b- or g-secretase activity or changes in the rate of extracellular Ab-clearance in vivo. Conclusions: We propose that trisomy Hsa21-associated cathepsin deficits are a novel AD-DS pathomechanism that alter APP/Ab processing and may contribute to the development of AD in people who have DS. WEDNESDAY, JULY 19, 2017 FEATURED RESEARCH SESSION F4-03 ASSESSING THE EFFECTIVENESS OF INTERVENTIONS TO PREVENT, DELAY, OR SLOW ALZHEIMER’S DISEASE, MILD COGNITIVE IMPAIRMENT, OR AGE-RELATED COGNITIVE DECLINE
F4-03-01
ASSESSING PREVENTION STRATEGIES FOR ALZHEIMER’S DEMENTIA: A NEW APPROACH
Melinda Kelley, National Institute on Aging, Bethesda, MD, USA. Contact e-mail: [email protected] Background: For the past several years, there has been increased interest across both governmental and non-governmental agencies around the world, in whether the field of Alzheimer’s disease research currently provides sufficient evidence regarding strategies the public can take to prevent this condition. The U.S. National Institutes of Health (NIH) had not formally explored this literature since 2010, when the agency held a State-of-the-Science Conference entitled Preventing Alzheimer’s Disease and Cognitive Decline. After considering an Agency for Healthcare Research and Quality (AHRQ)-conducted systematic review of the literature and several additional sources of input, an independent panel found that “firm conclusions cannot be drawn about the association of modifiable risk factors with cognitive decline or Alzheimer’s disease” and that “there is insufficient evidence to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease.” Methods: The National Institute on Aging (NIA) believed that the development of new evidence in this field warranted revisiting the literature, and that novel models might be explored that could enhance the rigor and independence of the evidence review process, and ensure the involvement of experts in a wide range of key scientific and clinical disciplines. Ultimately, the NIA established two separate contracts to conduct this review: one with the Minnesota Evidence-based Practice Center (EPC; via AHRQ), and the second with the National Academies of Science, Engineering, and Medicine. The NIA tasked these groups with exploring the state of the science regarding interventions for delaying or slowing age-related cognitive decline and preventing, delaying, or slowing mild cognitive impairment and clinical Alzheimer’s-type dementia. Results: The Minnesota EPC conducted a systematic review that informed the deliberations of a National Academies committee, which took the evidence review and considered it in light of ongoing research, evidence external to the interven-
P1213
tion literature, and the need to provide the public with the most up-todate information possible. Conclusions: This two-pronged, coordinated approach offers rigorous, complementary information that can inform future public health messaging and research decisions, and the model itself can be used in the future to address similarly complex questions that bridge research and public health. F4-03-02
BEHAVIORAL INTERVENTIONS TO PREVENT, DELAY, OR SLOW ALZHEIMER’S DISEASE, MILD COGNITIVE IMPAIRMENT, OR AGERELATED COGNITIVE DECLINE
Mary Butler, University of Minnesota, Minneapolis, MN, USA. Contact e-mail: [email protected] Background: Assess evidence for behavioral interventions aimed at
preventing or delaying onset of age-related cognitive decline, mild cognitive impairment (MCI), or clinical Alzheimer’s-type dementia (CATD). Methods: We searched Medline, PsycINFO, Embase, and Cochrane Central Register of Controlled Trials through September, 2016, supplemented with hand-searching. Two investigators screened abstracts and full-text articles of identified references. Eligible studies included randomized and nonrandomized controlled trials and quasiexperimental observational studies enrolling people with normal cognition and/or MCI. We extracted data, assessed risk of bias, summarized results for studies without high risk of bias, and evaluated strength of evidence for studies with sufficient sample size. Cognitive outcomes were grouped into domains to facilitate analysis. Results: We identified 170 eligible studies over 6 classes of interventions: cognitive training, physical activity, nutraceuticals, diet, multimodal interventions, and vitamins. We found no high-strength evidence for the effectiveness of any intervention to delay or prevent age-related cognitive decline, MCI, and/or CATD. Moderate-strength evidence shows cognitive training in adults with presumed normal cognition improves performance in the cognitive domain trained (memory, reasoning, or processing speed), but not transfer of benefits to other cognitive areas and little evidence for benefit beyond 2 years; evidence for effect on CATD is weak. Moderate-strength evidence showed no benefit for Vitamin E in women and B12 plus folic acid for executive/attention/processing speed. Physical activity interventions show no consistent benefit in preventing cognitive decline, but the proportion of results showing benefit were unlikely to be explained solely by chance, providing a signal of a possible relationship. A few other interventions showed at least one positive finding for a specific outcome, some reaching low strength of evidence, but these were more than offset by findings of no effect for other outcomes. We found no eligible studies for depression treatment or smoking cessation. Conclusions: Overall, evidence for is weak. Future research should address wide-spread methodological problems, including use of consistent cognitive outcome measures, longer follow-ups, and recognizing that attrition is a major problem in longer studies. More work is needed to understand the relationship between intermediate outcomes like cognitive test results and the onset of MCI and dementia. F4-03-03
PHARMACOLOGICAL INTERVENTIONS TO PREVENT OR DELAY ALZHEIMER’S DISEASE, MILD COGNITIVE IMPAIRMENT, OR AGE-RELATED COGNITIVE DECLINE
Howard Fink, Minneapolis VA Medical Center, Minneapolis, MN, USA. Contact e-mail: [email protected]