@article {702, title = {Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study.}, journal = {JAMA}, volume = {288}, year = {2002}, month = {2002 Sep 25}, pages = {1475-83}, abstract = {

CONTEXT: Mild cognitive impairment (MCI) may be a precursor to dementia, at least in some cases. Dementia and MCI are associated with neuropsychiatric symptoms in clinical samples. Only 2 population-based studies exist of the prevalence of these symptoms in dementia, and none exist for MCI.

OBJECTIVE: To estimate the prevalence of neuropsychiatric symptoms in dementia and MCI in a population-based study.

DESIGN: Cross-sectional study derived from the Cardiovascular Health Study, a longitudinal cohort study.

SETTING AND PARTICIPANTS: A total of 3608 participants were cognitively evaluated using data collected longitudinally over 10 years and additional data collected in 1999-2000 in 4 US counties. Dementia and MCI were classified using clinical criteria and adjudicated by committee review by expert neurologists and psychiatrists. A total of 824 individuals completed the Neuropsychiatric Inventory (NPI); 362 were classified as having dementia, 320 as having MCI; and 142 did not meet criteria for MCI or dementia.

MAIN OUTCOME MEASURE: Prevalence of neuropsychiatric symptoms, based on ratings on the NPI in the previous month and from the onset of cognitive symptoms.

RESULTS: Of the 682 individuals with dementia or MCI, 43\% of MCI participants (n = 138) exhibited neuropsychiatric symptoms in the previous month (29\% rated as clinically significant) with depression (20\%), apathy (15\%), and irritability (15\%) being most common. Among the dementia participants, 75\% (n = 270) had exhibited a neuropsychiatric symptom in the past month (62\% were clinically significant); 55\% (n = 199) reported 2 or more and 44\% (n = 159) 3 or more disturbances in the past month. In participants with dementia, the most frequent disturbances were apathy (36\%), depression (32\%), and agitation/aggression (30\%). Eighty percent of dementia participants (n = 233) and 50\% of MCI participants (n = 139) exhibited at least 1 NPI symptom from the onset of cognitive symptoms. There were no differences in prevalence of neuropsychiatric symptoms between participants with Alzheimer-type dementia and those with other dementias, with the exception of aberrant motor behavior, which was more frequent in Alzheimer-type dementia (5.4\% vs 1\%; P =.02).

CONCLUSIONS: Neuropsychiatric symptoms occur in the majority of persons with dementia over the course of the disease. These are the first population-based estimates for neuropsychiatric symptoms in MCI, indicating a high prevalence associated with this condition as well. These symptoms have serious adverse consequences and should be inquired about and treated as necessary. Study of neuropsychiatric symptoms in the context of dementia may improve our understanding of brain-behavior relationships.

}, keywords = {Aged, Aggression, Anxiety, Behavioral Symptoms, Cognition Disorders, Comorbidity, Cross-Sectional Studies, Delusions, Dementia, Depression, Feeding and Eating Disorders, Female, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Prevalence, Sleep Wake Disorders}, issn = {0098-7484}, doi = {10.1001/jama.288.12.1475}, author = {Lyketsos, Constantine G and Lopez, Oscar and Jones, Beverly and Fitzpatrick, Annette L and Breitner, John and DeKosky, Steven} } @article {852, title = {Dementia and Alzheimer{\textquoteright}s disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Jul}, pages = {1101-7}, abstract = {

OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer{\textquoteright}s disease (AD).

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded.

MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders.

RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95\% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95\% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease.

CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Dementia, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Peripheral Vascular Diseases, Risk Factors}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53360.x}, author = {Newman, Anne B and Fitzpatrick, Annette L and Lopez, Oscar and Jackson, Sharon and Lyketsos, Constantine and Jagust, William and Ives, Diane and DeKosky, Steven T and Kuller, Lewis H} } @article {900, title = {Factors associated with geographic variations in stroke incidence among older populations in four US communities.}, journal = {Stroke}, volume = {37}, year = {2006}, month = {2006 Aug}, pages = {1980-5}, abstract = {

BACKGROUND AND PURPOSE: In the Cardiovascular Health Study (CHS), we previously observed lower stroke incidence in Allegheny County, PA compared with the other 3 study sites. The purpose of this study was to study possible reasons for the lower stroke incidence in Allegheny County.

METHODS: CHS participants 65 years or older who were stroke-free at baseline (n=5639) were followed between 1989 to 1990 and 2000 for the development of stroke. Risk factors at baseline and their subsequent control were compared among both groups. Site-specific hazard ratios for stroke incidence were calculated using Cox regression models.

RESULTS: The unadjusted hazard ratio for total stroke incidence in Forsyth County, NC; Sacramento County, CA; and Washington County, MD combined compared with Allegheny County, PA was 1.74 (95\% CI: 1.42, 2.14). After adjustment for age and other traditional risk factors, there was modest reduction of the excess hazard in non-Allegheny sites compared with Allegheny County (hazard ratio=1.52, 95\% CI: 1.17, 1.98). Between baseline and the seventh-year visits, control of hypertension, diabetes, lipids, smoking, atrial fibrillation and transient ischemic attack were similar across sites. White matter grade > or = 3 on the baseline brain MRI was less common in Allegheny County (25.8\% versus 36.3\%, respectively; P<0.001) and accounted for 25\% of the excess hazard in non-Allegheny sites compared with Allegheny County.

CONCLUSIONS: Site differences in stroke risk factors at baseline and subsequent control only partially explain site differences in stroke incidence. White matter grade as a possible integrated measure of exposure and control of risk factors may help in explaining geographic variations in stroke incidence.

}, keywords = {Aged, Brain, California, Female, Humans, Incidence, Magnetic Resonance Imaging, Male, Maryland, North Carolina, Pennsylvania, Proportional Hazards Models, Risk Assessment, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000231454.77745.d9}, author = {El-Saed, Aiman and Kuller, Lewis H and Newman, Anne B and Lopez, Oscar and Costantino, Joseph and McTigue, Kathleen and Cushman, Mary and Kronmal, Richard} } @article {901, title = {Geographic variations in stroke incidence and mortality among older populations in four US communities.}, journal = {Stroke}, volume = {37}, year = {2006}, month = {2006 Aug}, pages = {1975-9}, abstract = {

BACKGROUND AND PURPOSE: Stroke is a leading cause of death and disability in the US. There is limited data on geographic variations in stroke incidence among older US populations who experience the majority of stroke burden. The purpose of this study was to compare stroke incidence and mortality rates in 4 US communities.

METHODS: Participants in the Cardiovascular Health Study (CHS) who had no history of stroke at baseline (n=5639) were followed for 10 or 7 years in predominantly white (n=5002) and black (n=637) participants, respectively. Incident stroke was validated by a stroke adjudication committee after ascertainment at annual visits, interim telephone contacts, and review of Medicare hospitalization data.

RESULTS: The 2000 US population age and sex standardized total stroke incidence rate for all CHS participants was 17.7 per 1000 person-years (95\% CI: 15.9, 19.5). The rate was significantly lower in Allegheny County, Pennsylvania 9.6/1000 person-years (95\% CI: 7.7, 11.5) than Forsyth County, North Carolina 19.2/1000 person-years (95\% CI: 15.6, 22.8), Sacramento County, California 20.7/1000 person-years (95\% CI: 16.9, 24.5), and Washington County, Maryland 19.8/1000 person-years (95\% CI: 16.1, 23.5). The lower stroke incidence rate in Allegheny County was consistent in gender, race, and age groups. Though not statistically significant, stroke mortality was also lower in Allegheny County than other 3 sites. The 1-month case fatality rate was similar in the 4 sites for all strokes, and by stroke types.

CONCLUSIONS: Understanding geographic variations in stroke incidence may be an important step in improving preventive practices of stroke.

}, keywords = {Aged, Aged, 80 and over, California, Female, Humans, Incidence, Male, Maryland, North Carolina, Pennsylvania, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000231453.98473.67}, author = {El-Saed, Aiman and Kuller, Lewis H and Newman, Anne B and Lopez, Oscar and Costantino, Joseph and McTigue, Kathleen and Cushman, Mary and Kronmal, Richard} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {5849, title = {Adiposity and cognitive decline in the cardiovascular health study.}, journal = {Neuroepidemiology}, volume = {40}, year = {2013}, month = {2013}, pages = {274-81}, abstract = {

BACKGROUND: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.

METHODS: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.

RESULTS: The final sample was comprised of 2,681 women (57.9\%) and 1,949 men (42.1\%) aged 73 {\textpm} 5.2 and 73.9 {\textpm} 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.

CONCLUSIONS: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions.

}, keywords = {Adiposity, Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cognition Disorders, Electric Impedance, Female, Humans, Male, Risk Factors, Waist Circumference, Waist-Hip Ratio}, issn = {1423-0208}, doi = {10.1159/000345136}, author = {Luchsinger, Jos{\'e} A and Biggs, Mary L and Kizer, Jorge R and Barzilay, Joshua and Fitzpatrick, Annette and Newman, Anne and Longstreth, William T and Lopez, Oscar and Siscovick, David and Kuller, Lewis} } @article {6285, title = {Bidirectional relationship between cognitive function and pneumonia.}, journal = {Am J Respir Crit Care Med}, volume = {188}, year = {2013}, month = {2013 Sep 01}, pages = {586-92}, abstract = {

RATIONALE: Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems.

OBJECTIVES: To determine bidirectional relationships between cognition and pneumonia.

METHODS: We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate.

MEASUREMENTS AND MAIN RESULTS: Of the 5,888 participants, 639 (10.9\%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1\%, 22.8\%, and 10.0\% vs. 76.0\%, 19.3\%, and 4.6\% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = -0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95\% confidence interval, 1.62-3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections.

CONCLUSIONS: A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.

}, keywords = {Aged, Cognition Disorders, Dementia, Female, Hospitalization, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Pneumonia, Proportional Hazards Models, Risk Factors}, issn = {1535-4970}, doi = {10.1164/rccm.201212-2154OC}, author = {Shah, Faraaz Ali and Pike, Francis and Alvarez, Karina and Angus, Derek and Newman, Anne B and Lopez, Oscar and Tate, Judith and Kapur, Vishesh and Wilsdon, Anthony and Krishnan, Jerry A and Hansel, Nadia and Au, David and Avdalovic, Mark and Fan, Vincent S and Barr, R Graham and Yende, Sachin} } @article {7185, title = {Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, volume = {53}, year = {2016}, month = {2016 Jun 18}, pages = {921-32}, abstract = {

Effective prevention of Alzheimer{\textquoteright}s disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer{\textquoteright}s Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17\% increase in AD risk (pooled HR = 1.17; 95\% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86{\texttimes}10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95\% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95\% CI =   [1.08-1.18]; pinteraction = 3.45{\texttimes}10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

}, issn = {1875-8908}, doi = {10.3233/JAD-150749}, author = {Chouraki, Vincent and Reitz, Christiane and Maury, Fleur and Bis, Joshua C and Bellenguez, C{\'e}line and Yu, Lei and Jakobsdottir, Johanna and Mukherjee, Shubhabrata and Adams, Hieab H and Choi, Seung Hoan and Larson, Eric B and Fitzpatrick, Annette and Uitterlinden, Andr{\'e} G and De Jager, Philip L and Hofman, Albert and Gudnason, Vilmundur and Vardarajan, Badri and Ibrahim-Verbaas, Carla and van der Lee, Sven J and Lopez, Oscar and Dartigues, Jean-Fran{\c c}ois and Berr, Claudine and Amouyel, Philippe and Bennett, David A and van Duijn, Cornelia and DeStefano, Anita L and Launer, Lenore J and Ikram, M Arfan and Crane, Paul K and Lambert, Jean-Charles and Mayeux, Richard and Seshadri, Sudha} } @article {8287, title = {Association of CD14 with incident dementia and markers of brain aging and injury.}, journal = {Neurology}, volume = {94}, year = {2020}, month = {2020 01 21}, pages = {e254-e266}, abstract = {

OBJECTIVE: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.

METHODS: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.

RESULTS: We studied 1,588 participants from the FHS (mean age 69 {\textpm} 6 years, 47\% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 {\textpm} 5 years, 41\% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12\% increase in the risk of incident dementia (95\% confidence interval 1.03-1.23; = 0.01) following adjustments for age, sex, ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.

CONCLUSION: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000008682}, author = {Pase, Matthew P and Himali, Jayandra J and Beiser, Alexa S and DeCarli, Charles and McGrath, Emer R and Satizabal, Claudia L and Aparicio, Hugo J and Adams, Hieab H H and Reiner, Alexander P and Longstreth, W T and Fornage, Myriam and Tracy, Russell P and Lopez, Oscar and Psaty, Bruce M and Levy, Daniel and Seshadri, Sudha and Bis, Joshua C} } @article {8824, title = {Examining the causal mediating role of brain pathology on the relationship between diabetes and cognitive impairment: the Cardiovascular Health Study.}, journal = {J R Stat Soc Ser A Stat Soc}, volume = {183}, year = {2020}, month = {2020 Oct}, pages = {1705-1726}, abstract = {

The paper examines whether leads to incident mild cognitive impairment and dementia through brain hypoperfusion and white matter disease. We performed inverse odds ratio weighted causal mediation analyses to decompose the effect of diabetes on cognitive impairment into direct and indirect effects, and we found that approximately a third of the total effect of diabetes is mediated through vascular-related brain pathology. Our findings lend support for a common aetiological hypothesis regarding incident cognitive impairment, which is that diabetes increases the risk of clinical cognitive impairment in part by impacting the vasculature of the brain.

}, issn = {0964-1998}, doi = {10.1111/rssa.12570}, author = {Andrews, Ryan M and Shpitser, Ilya and Lopez, Oscar and Longstreth, William T and Chaves, Paulo H M and Kuller, Lewis and Carlson, Michelle C} } @article {8706, title = {Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study.}, journal = {J Thromb Haemost}, year = {2021}, month = {2021 Mar 16}, abstract = {

BACKGROUND: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.

OBJECTIVE: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during >=8~years of follow-up in the Cardiovascular Health Study (CHS) of older adults.

METHODS: We included participants of an existing CHS cross-sectional substudy (n~=~400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.

RESULTS: Of 20 factors evaluated individually, only higher levels of plasmin-α -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP β~=~-0.65, 95\% confidence interval [CI]: -1.08 to -0.21; TFPI β~=~-0.55, 95\% CI: -0.90 to -0.19; FXc β~=~0.52, 95\% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.

CONCLUSIONS: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

}, issn = {1538-7836}, doi = {10.1111/jth.15300}, author = {Harrington, Laura B and Ehlert, Alexa N and Thacker, Evan L and Jenny, Nancy S and Lopez, Oscar and Cushman, Mary and Fitzpatrick, Annette and Mukamal, Kenneth J and Jensen, Majken K} } @article {9157, title = {Longitudinal Associations of Plasma TMAO and Related Metabolites with Cognitive Impairment and Dementia in Older Adults: The Cardiovascular Health Study.}, journal = {J Alzheimers Dis}, year = {2022}, month = {2022 Sep 02}, abstract = {

BACKGROUND: Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear.

OBJECTIVE: We examined prospective associations of TMAO, γ-butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS).

METHODS: TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models.

RESULTS: Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20-32\% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ-butyrobetaine was associated with \~{}25\% lower risk of the same cognitive outcomes per IQR.||Conclusion:These findings suggest that γ-butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life.

}, issn = {1875-8908}, doi = {10.3233/JAD-220477}, author = {de Oliveira Otto, Marcia C and Li, Xinmin S and Wang, Zeneng and Siscovick, David and Newman, Anne B and Lai, Heidi Tsz Mung and Nemet, Ina and Lee, Yujin and Wang, Meng and Fretts, Amanda and Lemaitre, Rozenn N and Tang, W H Wilson and Lopez, Oscar and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9035, title = {New insights into the genetic etiology of Alzheimer{\textquoteright}s disease and related dementias.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 Apr}, pages = {412-436}, abstract = {

Characterization of the genetic landscape of Alzheimer{\textquoteright}s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/{\textquoteright}proxy{\textquoteright} AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

}, keywords = {Alzheimer Disease, Cognitive Dysfunction, Genome-Wide Association Study, Humans, tau Proteins}, issn = {1546-1718}, doi = {10.1038/s41588-022-01024-z}, author = {Bellenguez, C{\'e}line and K{\"u}{\c c}{\"u}kali, Fahri and Jansen, Iris E and Kleineidam, Luca and Moreno-Grau, Sonia and Amin, Najaf and Naj, Adam C and Campos-Martin, Rafael and Grenier-Boley, Benjamin and Andrade, Victor and Holmans, Peter A and Boland, Anne and Damotte, Vincent and van der Lee, Sven J and Costa, Marcos R and Kuulasmaa, Teemu and Yang, Qiong and de Rojas, Itziar and Bis, Joshua C and Yaqub, Amber and Prokic, Ivana and Chapuis, Julien and Ahmad, Shahzad and Giedraitis, Vilmantas and Aarsland, Dag and Garcia-Gonzalez, Pablo and Abdelnour, Carla and Alarc{\'o}n-Mart{\'\i}n, Emilio and Alcolea, Daniel and Alegret, Montserrat and Alvarez, Ignacio and Alvarez, Victoria and Armstrong, Nicola J and Tsolaki, Anthoula and Antunez, Carmen and Appollonio, Ildebrando and Arcaro, Marina and Archetti, Silvana and Pastor, Alfonso Arias and Arosio, Beatrice and Athanasiu, Lavinia and Bailly, Henri and Banaj, Nerisa and Baquero, Miquel and Barral, Sandra and Beiser, Alexa and Pastor, Ana Bel{\'e}n and Below, Jennifer E and Benchek, Penelope and Benussi, Luisa and Berr, Claudine and Besse, C{\'e}line and Bessi, Valentina and Binetti, Giuliano and Bizarro, Alessandra and Blesa, Rafael and Boada, Merce and Boerwinkle, Eric and Borroni, Barbara and Boschi, Silvia and Boss{\`u}, Paola and Br{\r a}then, Geir and Bressler, Jan and Bresner, Catherine and Brodaty, Henry and Brookes, Keeley J and Brusco, Luis Ignacio and Buiza-Rueda, Dolores and B{\^u}rger, Katharina and Burholt, Vanessa and Bush, William S and Calero, Miguel and Cantwell, Laura B and Chene, Genevi{\`e}ve and Chung, Jaeyoon and Cuccaro, Michael L and Carracedo, Angel and Cecchetti, Roberta and Cervera-Carles, Laura and Charbonnier, Camille and Chen, Hung-Hsin and Chillotti, Caterina and Ciccone, Simona and Claassen, Jurgen A H R and Clark, Christopher and Conti, Elisa and Corma-G{\'o}mez, Ana{\"\i}s and Costantini, Emanuele and Custodero, Carlo and Daian, Delphine and Dalmasso, Maria Carolina and Daniele, Antonio and Dardiotis, Efthimios and Dartigues, Jean-Fran{\c c}ois and de Deyn, Peter Paul and de Paiva Lopes, Katia and de Witte, Lot D and Debette, Stephanie and Deckert, J{\"u}rgen and Del Ser, Teodoro and Denning, Nicola and DeStefano, Anita and Dichgans, Martin and Diehl-Schmid, Janine and Diez-Fairen, Monica and Rossi, Paolo Dionigi and Djurovic, Srdjan and Duron, Emmanuelle and D{\"u}zel, Emrah and Dufouil, Carole and Eiriksdottir, Gudny and Engelborghs, Sebastiaan and Escott-Price, Valentina and Espinosa, Ana and Ewers, Michael and Faber, Kelley M and Fabrizio, Tagliavini and Nielsen, Sune Fallgaard and Fardo, David W and Farotti, Lucia and Fenoglio, Chiara and Fern{\'a}ndez-Fuertes, Marta and Ferrari, Raffaele and Ferreira, Catarina B and Ferri, Evelyn and Fin, Bertrand and Fischer, Peter and Fladby, Tormod and Flie{\ss}bach, Klaus and Fongang, Bernard and Fornage, Myriam and Fortea, Juan and Foroud, Tatiana M and Fostinelli, Silvia and Fox, Nick C and Franco-Mac{\'\i}as, Emlio and Bullido, Mar{\'\i}a J and Frank-Garc{\'\i}a, Ana and Froelich, Lutz and Fulton-Howard, Brian and Galimberti, Daniela and Garc{\'\i}a-Alberca, Jose Maria and Garcia-Gonzalez, Pablo and Garcia-Madrona, Sebastian and Garcia-Ribas, Guillermo and Ghidoni, Roberta and Giegling, Ina and Giorgio, Giaccone and Goate, Alison M and Goldhardt, Oliver and Gomez-Fonseca, Duber and Gonz{\'a}lez-Perez, Antonio and Graff, Caroline and Grande, Giulia and Green, Emma and Grimmer, Timo and Gr{\"u}nblatt, Edna and Grunin, Michelle and Gudnason, Vilmundur and Guetta-Baranes, Tamar and Haapasalo, Annakaisa and Hadjigeorgiou, Georgios and Haines, Jonathan L and Hamilton-Nelson, Kara L and Hampel, Harald and Hanon, Olivier and Hardy, John and Hartmann, Annette M and Hausner, Lucrezia and Harwood, Janet and Heilmann-Heimbach, Stefanie and Helisalmi, Seppo and Heneka, Michael T and Hernandez, Isabel and Herrmann, Martin J and Hoffmann, Per and Holmes, Clive and Holstege, Henne and Vilas, Raquel Huerto and Hulsman, Marc and Humphrey, Jack and Biessels, Geert Jan and Jian, Xueqiu and Johansson, Charlotte and Jun, Gyungah R and Kastumata, Yuriko and Kauwe, John and Kehoe, Patrick G and Kilander, Lena and St{\r a}hlbom, Anne Kinhult and Kivipelto, Miia and Koivisto, Anne and Kornhuber, Johannes and Kosmidis, Mary H and Kukull, Walter A and Kuksa, Pavel P and Kunkle, Brian W and Kuzma, Amanda B and Lage, Carmen and Laukka, Erika J and Launer, Lenore and Lauria, Alessandra and Lee, Chien-Yueh and Lehtisalo, Jenni and Lerch, Ondrej and Lleo, Alberto and Longstreth, William and Lopez, Oscar and de Munain, Adolfo Lopez and Love, Seth and L{\"o}wemark, Malin and Luckcuck, Lauren and Lunetta, Kathryn L and Ma, Yiyi and Mac{\'\i}as, Juan and MacLeod, Catherine A and Maier, Wolfgang and Mangialasche, Francesca and Spallazzi, Marco and Marqui{\'e}, Marta and Marshall, Rachel and Martin, Eden R and Montes, Angel Mart{\'\i}n and Rodr{\'\i}guez, Carmen Mart{\'\i}nez and Masullo, Carlo and Mayeux, Richard and Mead, Simon and Mecocci, Patrizia and Medina, Miguel and Meggy, Alun and Mehrabian, Shima and Mendoza, Silvia and Men{\'e}ndez-Gonz{\'a}lez, Manuel and Mir, Pablo and Moebus, Susanne and Mol, Merel and Molina-Porcel, Laura and Montrreal, Laura and Morelli, Laura and Moreno, Fermin and Morgan, Kevin and Mosley, Thomas and N{\"o}then, Markus M and Muchnik, Carolina and Mukherjee, Shubhabrata and Nacmias, Benedetta and Ngandu, Tiia and Nicolas, Ga{\"e}l and Nordestgaard, B{\o}rge G and Olaso, Robert and Orellana, Adelina and Orsini, Michela and Ortega, Gemma and Padovani, Alessandro and Paolo, Caffarra and Papenberg, Goran and Parnetti, Lucilla and Pasquier, Florence and Pastor, Pau and Peloso, Gina and P{\'e}rez-Cord{\'o}n, Alba and P{\'e}rez-Tur, Jordi and Pericard, Pierre and Peters, Oliver and Pijnenburg, Yolande A L and Pineda, Juan A and Pi{\~n}ol-Ripoll, Gerard and Pisanu, Claudia and Polak, Thomas and Popp, Julius and Posthuma, Danielle and Priller, Josef and Puerta, Raquel and Quenez, Olivier and Quintela, In{\'e}s and Thomassen, Jesper Qvist and R{\'a}bano, Alberto and Rainero, Innocenzo and Rajabli, Farid and Ramakers, Inez and Real, Luis M and Reinders, Marcel J T and Reitz, Christiane and Reyes-Dumeyer, Dolly and Ridge, Perry and Riedel-Heller, Steffi and Riederer, Peter and Roberto, Natalia and Rodriguez-Rodriguez, Eloy and Rongve, Arvid and Allende, Irene Rosas and Rosende-Roca, Mait{\'e}e and Royo, Jose Luis and Rubino, Elisa and Rujescu, Dan and S{\'a}ez, Mar{\'\i}a Eugenia and Sakka, Paraskevi and Saltvedt, Ingvild and Sanabria, {\'A}ngela and S{\'a}nchez-Arjona, Mar{\'\i}a Bernal and Sanchez-Garcia, Florentino and Juan, Pascual S{\'a}nchez and S{\'a}nchez-Valle, Raquel and Sando, Sigrid B and Sarnowski, Chloe and Satizabal, Claudia L and Scamosci, Michela and Scarmeas, Nikolaos and Scarpini, Elio and Scheltens, Philip and Scherbaum, Norbert and Scherer, Martin and Schmid, Matthias and Schneider, Anja and Schott, Jonathan M and Selb{\ae}k, Geir and Seripa, Davide and Serrano, Manuel and Sha, Jin and Shadrin, Alexey A and Skrobot, Olivia and Slifer, Susan and Snijders, Gijsje J L and Soininen, Hilkka and Solfrizzi, Vincenzo and Solomon, Alina and Song, Yeunjoo and Sorbi, Sandro and Sotolongo-Grau, Oscar and Spalletta, Gianfranco and Spottke, Annika and Squassina, Alessio and Stordal, Eystein and Tartan, Juan Pablo and Tarraga, Lluis and Tes{\'\i}, Niccolo and Thalamuthu, Anbupalam and Thomas, Tegos and Tosto, Giuseppe and Traykov, Latchezar and Tremolizzo, Lucio and Tybj{\ae}rg-Hansen, Anne and Uitterlinden, Andre and Ullgren, Abbe and Ulstein, Ingun and Valero, Sergi and Valladares, Otto and Broeckhoven, Christine Van and Vance, Jeffery and Vardarajan, Badri N and van der Lugt, Aad and Dongen, Jasper Van and van Rooij, Jeroen and van Swieten, John and Vandenberghe, Rik and Verhey, Frans and Vidal, Jean-S{\'e}bastien and Vogelgsang, Jonathan and Vyhnalek, Martin and Wagner, Michael and Wallon, David and Wang, Li-San and Wang, Ruiqi and Weinhold, Leonie and Wiltfang, Jens and Windle, Gill and Woods, Bob and Yannakoulia, Mary and Zare, Habil and Zhao, Yi and Zhang, Xiaoling and Zhu, Congcong and Zulaica, Miren and Farrer, Lindsay A and Psaty, Bruce M and Ghanbari, Mohsen and Raj, Towfique and Sachdev, Perminder and Mather, Karen and Jessen, Frank and Ikram, M Arfan and de Mendon{\c c}a, Alexandre and Hort, Jakub and Tsolaki, Magda and Pericak-Vance, Margaret A and Amouyel, Philippe and Williams, Julie and Frikke-Schmidt, Ruth and Clarimon, Jordi and Deleuze, Jean-Francois and Rossi, Giacomina and Seshadri, Sudha and Andreassen, Ole A and Ingelsson, Martin and Hiltunen, Mikko and Sleegers, Kristel and Schellenberg, Gerard D and van Duijn, Cornelia M and Sims, Rebecca and van der Flier, Wiesje M and Ruiz, Agustin and Ramirez, Alfredo and Lambert, Jean-Charles} } @article {9477, title = {Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.}, journal = {J Alzheimers Dis}, year = {2023}, month = {2023 Aug 23}, abstract = {

BACKGROUND: Comprising nearly 35\% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.

OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged>=65 years in the Cardiovascular Health Study.

METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.

RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95\% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95\% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.

CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

}, issn = {1875-8908}, doi = {10.3233/JAD-230083}, author = {de Oliveira Otto, Marcia C and Wu, Jason H Y and Thacker, Evan L and Lai, Heidi Tsz Mung and Lemaitre, Rozenn N and Padhye, Nikhil and Song, Xiaoling and King, Irena B and Lopez, Oscar and Siscovick, David S and Mozaffarian, Dariush} } @article {9505, title = {Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 13}, abstract = {

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.

DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.

MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.

RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95\%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95\%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95\%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.

CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer{\textquoteright}s disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

}, doi = {10.1101/2023.08.08.23293761}, author = {Sargurupremraj, Muralidharan and Soumar{\'e}, A{\"\i}cha and Bis, Joshua C and Surakka, Ida and J{\"u}rgenson, Tuuli and Joly, Pierre and Knol, Maria J and Wang, Ruiqi and Yang, Qiong and Satizabal, Claudia L and Gudjonsson, Alexander and Mishra, Aniket and Bouteloup, Vincent and Phuah, Chia-Ling and van Duijn, Cornelia M and Cruchaga, Carlos and Dufouil, Carole and Chene, Genevi{\`e}ve and Lopez, Oscar and Psaty, Bruce M and Tzourio, Christophe and Amouyel, Philippe and Adams, Hieab H and Jacqmin-Gadda, H{\'e}l{\`e}ne and Ikram, Mohammad Arfan and Gudnason, Vilmundur and Milani, Lili and Winsvold, Bendik S and Hveem, Kristian and Matthews, Paul M and Longstreth, W T and Seshadri, Sudha and Launer, Lenore J and Debette, Stephanie} } @article {9417, title = {Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Jul 03}, pages = {e2325152}, abstract = {

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5\%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9\% to 28.9\%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1\% increase, 0.08; 95\% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95\% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] >=5) was associated with poorer global cognition (pooled β, -0.06; 95\% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95\% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.25152}, author = {Pase, Matthew P and Harrison, Stephanie and Misialek, Jeffrey R and Kline, Christopher E and Cavuoto, Marina and Baril, Andree-Ann and Yiallourou, Stephanie and Bisson, Alycia and Himali, Dibya and Leng, Yue and Yang, Qiong and Seshadri, Sudha and Beiser, Alexa and Gottesman, Rebecca F and Redline, Susan and Lopez, Oscar and Lutsey, Pamela L and Yaffe, Kristine and Stone, Katie L and Purcell, Shaun M and Himali, Jayandra J} } @article {9613, title = {Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study.}, journal = {Thromb Res}, volume = {235}, year = {2024}, month = {2024 Mar}, pages = {148-154}, abstract = {

INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk.

METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n~=~3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer{\textquoteright}s disease, and mixed dementia.

RESULTS: At baseline, participants had a median age of 73~years. Over 5.4~years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95~\% confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar.

CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

}, keywords = {Aged, Anticoagulants, Antithrombin III, Antithrombins, Dementia, Factor VIIa, Fibrinogen, Hemostatics, Humans, Prospective Studies, Thrombin}, issn = {1879-2472}, doi = {10.1016/j.thromres.2024.01.024}, author = {Harrington, Laura B and Ehlert, Alexa N and Thacker, Evan L and Jenny, Nancy S and Lopez, Oscar and Cushman, Mary and Olson, Nels C and Fitzpatrick, Annette and Mukamal, Kenneth J and Jensen, Majken K} }