@article {8401, title = {Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study.}, journal = {Alzheimer Dis Assoc Disord}, volume = {30}, year = {2016}, month = {2016 Jan-Mar}, pages = {15-20}, publisher = {30}, abstract = {

BACKGROUND: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result.

METHODS: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer{\textquoteright}s Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including β-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation.

RESULTS: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95\% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95\% CI, 1.02, 1.34). In the Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant.

CONCLUSIONS: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall.

}, keywords = {Alzheimer disease, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Humans, Insulin, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-4156}, doi = {10.1097/WAD.0000000000000128}, url = {http://europepmc.org/abstract/MED/26650880}, author = {Stefan Walter and Jessica R Marden and Laura D Kubzansky and Elizabeth R Mayeda and Paul K Crane and Chang, Shun-Chiao and Marilyn C Cornelis and David Rehkopf and Mukherjee, Shubhabrata and M. Maria Glymour} } @article {6483, title = {Do Physical Activity, Smoking, Drinking, or Depression Modify Transitions from Cognitive Impairment to Functional Disability?}, journal = {Journal of Alzheimer{\textquoteright}s Disease}, volume = {44}, year = {2015}, pages = {1171-1180}, chapter = {1171}, abstract = {Background: Individual-level modifiers can delay onset of limitations in basic activities of daily living (ADLs) among cognitively impaired individuals. We assessed whether these modifiers also delayed onset of limitations in instrumental ADLs (IADLs) among individuals at elevated dementia risk. Objectives: To determine whether modifiable individual-level factors delay incident IADL limitations among adults stratified by dementia risk. Methods: Health and Retirement Study participants aged 65 without activity limitations in 1998 or 2000 (n = 5,219) were interviewed biennially through 2010. Dementia probability, categorized in quartiles, was used to predict incident IADL limitations with Poisson regression. We estimated relative (risk ratio) and absolute (number of limitations) effects from models including dementia, individual-level modifiers (physical inactivity, smoking, no alcohol consumption, and depression) and interaction terms between dementia and individual-level modifiers. Results: Dementia probability quartile predicted incident IADL limitations (relative risk for highest versus lowest quartile = 0.44; 95 CI: 0.28 0.70). Most modifiers did not significantly increase risk of IADL limitations among the cognitively impaired. Physical inactivity (RR = 1.60; 95 CI: 1.16, 2.19) increased the risk of IADL limitations among the cognitively impaired. The interaction between physical inactivity and low dementia probability was statistically significant (p = 0.009) indicating that physical inactivity had significantly larger effects on incident IADLs among cognitively normal than among those with high dementia probability. Conclusion: Physical activity may protect against IADL limitations while smoking, alcohol consumption, and depression do not afford substantial protection among the cognitively impaired. Results highlight the need for extra support for IADLs among individuals with cognitive losses.}, keywords = {Disabilities, Health Conditions and Status, Healthcare}, doi = {10.3233/JAD-141866}, url = {http://dx.doi.org/10.3233/JAD-141866}, author = {Pamela M. Rist and Jessica R Marden and Benjamin D Capistrant and Bei Wu and M. Maria Glymour} } @article {6475, title = {Dementia and dependence: Do Modifiable Risk Factors Delay Disability?}, journal = {Neurology}, volume = {82}, year = {2014}, month = {04/2014}, pages = {1543-1550}, chapter = {1543}, abstract = {Objective: To identify modifying factors that preserve functional independence among individuals at high dementia risk. Methods: Health and Retirement Study participants aged 65 years or older without baseline activities of daily living (ADL) limitations (n = 4,922) were interviewed biennially for up to 12 years. Dementia probability, estimated from direct and proxy cognitive assessments, was categorized as low (i.e., normal cognitive function), mild, moderate, or high risk (i.e., very impaired) and used to predict incident ADL limitations (censoring after limitation onset). We assessed multiplicative and additive interactions of dementia category with modifiers (previously self-reported physical activity, smoking, alcohol consumption, depression, and income) in predicting incident limitations. Results: Smoking, not drinking, and income predicted incident ADL limitations and had larger absolute effects on ADL onset among individuals with high dementia probability than among cognitively normal individuals. Smoking increased the 2-year risk of ADL limitations onset from 9.9 to 14.9 among the lowest dementia probability category and from 32.6 to 42.7 among the highest dementia probability category. Not drinking increased the 2-year risk of ADL limitations onset by 2.1 percentage points among the lowest dementia probability category and 13.2 percentage points among the highest dementia probability category. Low income increased the 2-year risk of ADL limitations onset by 0.4 among the lowest dementia probability category and 12.9 among the highest dementia probability category. Conclusions: Smoking, not drinking, and low income predict incident dependence even in the context of cognitive impairment. Regardless of cognitive status, reducing these risk factors may improve functional outcomes and delay institutionalization.}, keywords = {Health Conditions and Status, Income}, doi = {10.1212/WNL.0000000000000357}, author = {Pamela M. Rist and Benjamin D Capistrant and Bei Wu and Jessica R Marden and M. Maria Glymour} }