Publications by authors named "Eric B Larson"

384 Publications

Application of deep learning to understand resilience to Alzheimer's disease pathology.

Brain Pathol 2021 May 19:e12974. Epub 2021 May 19.

Department of Ophthalmology, University of Washington, Seattle, WA, USA.

People who have Alzheimer's disease neuropathologic change (ADNC) typically associated with dementia but not the associated cognitive decline can be considered to be "resilient" to the effects of ADNC. We have previously reported lower neocortical levels of hyperphosphorylated tau (pTau) and less limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) in the resilient participants compared to those with dementia and similar ADNC as determined by current NIA-AA recommendations using traditional semi-quantitative assessments of amyloid β and pathological tau burden. To better understand differences between AD-dementia and resilient participants, we developed and applied a deep learning approach to analyze the neuropathology of 14 brain donors from the Adult Changes in Thought study, including seven stringently defined resilient participants and seven age-matched AD-dementia controls. We created two novel, fully automated deep learning algorithms to quantify the level of phosphorylated TDP-43 (pTDP-43) and pTau in whole slide imaging. The models performed better than traditional techniques for quantifying pTDP-43 and pTau. The second model was able to segment lesions staining for pTau into neurofibrillary tangles (NFTs) and tau neurites (neuronal processes positive for pTau). Both groups had similar quantities of pTau localizing to neurites, but the pTau burden associated with NFTs in the resilient group was significantly lower compared to the group with dementia. These results validate use of deep learning approaches to quantify clinically relevant microscopic characteristics from neuropathology workups. These results also suggest that the burden of NFTs is more strongly associated with cognitive impairment than the more diffuse neuritic tau commonly seen with tangle pathology and suggest that additional factors may underlie resilience mechanisms defined by traditional means.
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http://dx.doi.org/10.1111/bpa.12974DOI Listing
May 2021

Incident Dementia, Glycated Hemoglobin (HbA1c) Levels and Potentially Preventable Hospitalizations in People Age 65 and Older with Diabetes.

J Gerontol A Biol Sci Med Sci 2021 Apr 29. Epub 2021 Apr 29.

Kaiser Permanente Washington Health Research Institute, Seattle, USA.

Background: To determine whether incident dementia and HbA1c levels are associated with increased rates of potentially preventable hospitalizations (PPH) in persons with diabetes.

Methods: 565 adults age 65+ ever treated for diabetes were from ACT study. PPH were from principal discharge diagnoses and included diabetes PPH (dPPH), respiratory PPH (rPPH), urinovolemic PPH (uPPH), cardiovascular, and other PPH. Poisson generalized estimating equations estimated rate ratios (RR) and 95% confidence intervals (CI) for the associations between dementia or HbA1c measures and rate of PPH.

Results: 562 individuals contributed 3602 dementia-free years, and 132 individuals contributed 511 dementia follow-up years. 128 (23%) dementia-free individuals had 210 PPH admissions and a crude rate of 58 per 1000 person-years while 55 (42%) individuals with dementia had 93 PPH admissions, a rate of 182 per 1000 person-years. The adjusted RR (95% CI) comparing rates between dementia and dementia-free groups were 2.27 (1.60, 3.21) for overall PPH; 5.90 (2.70, 12.88) for dPPH; 5.17 (2.49, 10.73) for uPPH, and 2.01 (1.06, 3.83) for rPPH. Compared with HbA1c of 7-8% and adjusted for dementia, the RR (95% CI) for overall PPH was 1.43 (1.00, 2.06) for >8% and 1.18 (0.85, 1.65) for <7% HbA1c. The uPPH RR was also increased, comparing >8% and <7% HbA1c levels.

Conclusion: Incident dementia is associated with higher rates of PPH among people with diabetes, especially PPHs due to diabetes, UTI, and dehydration. Potential evidence suggested that HbA1c levels of >8% vs. lower levels are associated with higher rates of overall, UTI and dehydration-related PPHs.
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http://dx.doi.org/10.1093/gerona/glab119DOI Listing
April 2021

Modeling semi-competing risks data as a longitudinal bivariate process.

Biometrics 2021 Apr 28. Epub 2021 Apr 28.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

As individuals age, death is a competing risk for Alzheimer's disease (AD) but the reverse is not the case. As such, studies of AD can be placed within the semi-competing risks framework. Central to semi-competing risks, and in contrast to standard competing risks , is that one can learn about the dependence structure between the two events. To-date, however, most methods for semi-competing risks treat dependence as a nuisance and not a potential source of new clinical knowledge. We propose a novel regression-based framework that views the two time-to-event outcomes through the lens of a longitudinal bivariate process on a partition of the time scales of the two events. A key innovation of the framework is that dependence is represented in two distinct forms, local and global dependence, both of which have intuitive clinical interpretations. Estimation and inference are performed via penalized maximum likelihood, and can accommodate right censoring, left truncation, and time-varying covariates. An important consequence of the partitioning of the time scale is that an ambiguity regarding the specific form of the likelihood contribution may arise; a strategy for sensitivity analyses regarding this issue is described. The framework is then used to investigate the role of gender and having ≥1 apolipoprotein E (APOE) ε4 allele on the joint risk of AD and death using data from the Adult Changes in Thought study.
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http://dx.doi.org/10.1111/biom.13480DOI Listing
April 2021

Theoretical impact of the AT(N) framework on dementia using a community autopsy sample.

Alzheimers Dement 2021 Apr 26. Epub 2021 Apr 26.

Department of Medicine, University of Washington, Seattle, Washington, USA.

The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) profiles using autopsy-based neuropathology correlates, and considered cost implications for clinical trials for secondary prevention of dementia based on AT(N) profiles. We used Consortium to Establish a Registry for Alzheimer's Disease (moderate/frequent) to approximate A+, Braak stage (IV-VI) for T+, and temporal pole lateral ventricular dilation for (N)+. Outcomes included dementia prevalence at death and incidence in the last 5 years of life. A+T+(N)+ was the most common profile (31%). Dementia prevalence ranged from 14% (A-T-[N]-) to 79% (A+T+[N]+). Between 8% (A+T-[N]-) and 68% (A+T+[N]-) of decedents developed incident dementia in the last 5 years of life. Clinical trials would incur substantial expense to characterize AT(N). Many people with biomarker-defined preclinical Alzheimer's disease will never develop clinical dementia during life, highlighting resilience to clinical expression of AD neuropathologic changes and the need for improved tools for prediction beyond current AT(N) biomarkers.
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http://dx.doi.org/10.1002/alz.12348DOI Listing
April 2021

Medical records-based chronic kidney disease phenotype for clinical care and "big data" observational and genetic studies.

NPJ Digit Med 2021 Apr 13;4(1):70. Epub 2021 Apr 13.

Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.

Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.
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http://dx.doi.org/10.1038/s41746-021-00428-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044136PMC
April 2021

In older adults, adding fall-risk screening with targeted interventions to mailed advice did not reduce fractures.

Authors:
Eric B Larson

Ann Intern Med 2021 04 6;174(4):JC46. Epub 2021 Apr 6.

Kaiser Permanente WA Health Research Institute, Seattle, Washington, USA (E.B.L.).

Source Citation: Lamb SE, Bruce J, Hossain A, et al. N Engl J Med. 2020;383:1848-59. 33211928.
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http://dx.doi.org/10.7326/ACPJ202104200-046DOI Listing
April 2021

The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample.

Front Neurol 2021 16;12:624696. Epub 2021 Mar 16.

Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States.

The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) β in brains from ACT participants with ( = 107) and without ( = 425) history of remote TBI with loss of consciousness (w/LOC). Further neuropathological assessments included immunohistochemistry for α-synuclein and phospho-TDP-43 pathology and astro- (GFAP) and micro- (Iba1) gliosis, mass spectrometry analysis of free radical injury, and gene expression evaluation (RNA sequencing) in a smaller sub-cohort of matched samples (49 cases with TBI and 49 non-exposed matched controls). Out of 532 cases, only 3 (0.6%-none with TBI w/LOC history) showed evidence of the neuropathologic signature of chronic traumatic encephalopathy (CTE). Across the entire cohort, the levels of pTau and Aβ showed expected differences for brain region (higher levels in temporal cortex), neuropathological diagnosis (higher in participants with Alzheimer's disease), and genotype (higher in participants with one or more ε4 allele). However, no differences in PHF-tau or Aβ were identified by Histelide with respect to the history of TBI w/LOC. In a subset of TBI cases with more carefully matched control samples and more extensive analysis, those with TBI w/LOC history had higher levels of hippocampal pTau but no significant differences in Aβ, α-synuclein, pTDP-43, GFAP, Iba1, or free radical injury. RNA-sequencing also did not reveal significant gene expression associated with any measure of TBI exposure. Combined, these findings suggest long term neuropathological changes associated with TBI w/LOC may be subtle, involve non-traditional pathways of neurotoxicity and neurodegeneration, and/or differ from those in autopsy cohorts specifically selected for neurotrauma exposure.
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http://dx.doi.org/10.3389/fneur.2021.624696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008107PMC
March 2021

Associations between physical function and device-based measures of physical activity and sedentary behavior patterns in older adults: moving beyond moderate-to-vigorous intensity physical activity.

BMC Geriatr 2021 03 31;21(1):216. Epub 2021 Mar 31.

Kaiser Permanente Washington Health Research Institute, 1730 Minor Ave, Suite 1600, Seattle, WA, 98101, USA.

Background: Research supports that moderate-to-vigorous intensity physical activity (MVPA) is key to prolonged health and function. Among older adults, substantial changes to MVPA may be infeasible, thus a growing literature suggests a shift in focus to whole-day activity patterns.

Methods: With data from 795 older adults aged 65-100 in the Adult Changes in Thought Activity Monitoring study, we used linear regression to estimate associations between ActiGraph and activPAL measured activity patterns - including light intensity physical activity, steps, standing, and sedentary behaviors - and physical function as measured by a short Performance-based Physical Function (sPPF) score (range 0-12), a composite score based on three standardized physical performance tasks: gait speed, timed chair stands, and grip strength. We examined whether relationships persisted when controlling for MVPA or differed across age, gender, or quartiles of MVPA.

Results: In models unadjusted for MVPA, a 1-standard deviation (SD) increment of daily sitting (1.9 h more), mean sitting bout duration (8 min longer average), or time spent in sedentary activity (1.6 h more) was associated with ~ 0.3-0.4 points lower mean sPPF score (all p < 0.05). A 1-SD increment in daily steps (~ 3500 more steps) was associated with ~ 0.5 points higher mean sPPF score (95% CI: 0.22 to 0.73). MVPA adjustment attenuated all relationships. The association between physical function and steps was strongest among adults aged 75+; associations of worse function with greater sedentary behavior were more pronounced in participants with the lowest levels of MVPA.

Conclusions: We found associations between function and activity metrics other than MVPA in key subgroups, findings that support research on broader activity patterns and may offer ideas regarding practical intervention opportunities for improving function in older adults.
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http://dx.doi.org/10.1186/s12877-021-02163-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011072PMC
March 2021

Associations Between Retinal Artery/Vein Occlusions and Risk of Vascular Dementia.

J Alzheimers Dis 2021 ;81(1):245-253

Department of Medicine, University of Washington, Seattle, WA, USA.

Background: Vascular disease is a risk factor for Alzheimer's disease (AD) and related dementia in older adults. Retinal artery/vein occlusion (RAVO) is an ophthalmic complication of systemic vascular pathology. Whether there are associations between RAVO and dementia risk is unknown.

Objective: To determine whether RAVOs are associated with an increased risk of developing vascular dementia or AD.

Methods: Data from Adult Changes in Thought (ACT) study participants were analyzed. This prospective, population-based cohort study followed older adults (age ≥65 years) who were dementia-free at enrollment for development of vascular dementia or AD based on research criteria. RAVO diagnoses were extracted from electronic medical records. Cox-regression survival analyses were stratified by APOEɛ4 genotype and adjusted for demographic and clinical factors.

Results: On review of 41,216 person-years (4,743 participants), 266 (5.6%) experienced RAVO. APOEɛ4 carriers who developed RAVO had greater than four-fold higher risk for developing vascular dementia (Hazard Ratio [HR] 4.54, 95% Confidence Interval [CI] 1.86, 11.10, p = 0.001). When including other cerebrovascular disease (history of carotid endarterectomy or transient ischemic attack) in the model, the risk was three-fold higher (HR 3.06, 95% CI 1.23, 7.62). No other conditions evaluated in the secondary analyses were found to confound this relationship. There was no effect in non-APOEɛ4 carriers (HR 1.03, 95% CI 0.37, 2.80). There were no significant associations between RAVO and AD in either APOE group.

Conclusion: Older dementia-free patients who present with RAVO and carry the APOEɛ4 allele appear to be at higher risk for vascular dementia.
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http://dx.doi.org/10.3233/JAD-201492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168611PMC
January 2021

Trends in Use of Low-Value Care in Traditional Fee-for-Service Medicare and Medicare Advantage.

JAMA Netw Open 2021 03 1;4(3):e211762. Epub 2021 Mar 1.

Kaiser Permanente Washington Health Research Institute, Seattle.

Importance: Decreasing use of low-value care is a major goal for Medicare given the potential to decrease costs and harms. Compared with traditional fee-for-service Medicare (TM), Medicare Advantage (MA) is more strongly financially incentivized to decrease use of low-value care.

Objectives: To compare use of low-value care among individuals enrolled in TM and those enrolled in MA overall and to examine trends in use of low-value care in both programs from 2006 to 2015.

Design, Setting, And Participants: This cross-sectional study analyzed individuals enrolled in TM and MA using data from the 2006 to 2015 Medical Expenditure Panel Survey. To account for differences in characteristics between individuals enrolled in TM and those enrolled in MA, a propensity score-based approach was used. Data were analyzed from August 2020 through January 2021.

Exposures: Being enrolled in MA or TM.

Main Outcomes And Measures: Binary measures of use were collected for 13 low-value services in 4 categories (ie, [1] cancer screening: cervical, colorectal, and prostate cancer screening in older adults; [2] antibiotic use: antibiotic for acute upper respiratory infection and antibiotic for influenza; [3] medication: anxiolytic, sedative, or hypnotic in an adult older than 65 years; benzodiazepine for depression; opioid for headache; opioid for back pain; and nonsteroidal anti-inflammatory drug [NSAID] for hypertension, heart failure, or chronic kidney disease; and [4] imaging: magnetic resonance imaging [MRI] or computed tomography [CT] for back pain, radiograph for back pain, and MRI or CT for headache) and 4 low-value composites corresponding to the categories (ie, cancer screening composite, antibiotic use composite, medication composite, and imaging composite).

Results: Among 11 677 individuals enrolled in TM and 5164 individuals enrolled in MA, 9429 (56.0%) were women and the mean (SD) age was 74.5 (6.3) years. Of 13 low-value services and 4 low-value composites, statistically significant differences were found in 2 measures. For the low-value medication composite, 2054 of 11 636 eligible individuals enrolled in TM (adjusted mean, 17.6%; 95% CI, 16.8%-18.3%) received the care, and 981 of 5141 eligible individuals enrolled in MA (adjusted mean, 19.7%; 95% CI, 18.3%-21.2%) received the care, for a rate of use that was significantly higher among individuals enrolled in MA, by 2.2 percentage points (95% CI, 0.5-3.8 percentage points; P = .02). For the NSAID use for hypertension, heart failure, or kidney disease metric, 807 of 7832 individuals enrolled in TM (adjusted mean, 10.0%; 95% CI, 9.2%-10.8%) received the care, and 447 of 3566 individuals enrolled in MA (adjusted mean, 12.9%; 95% CI, 19.7%-27.1%) received the care, for a rate of use that was significantly higher among individuals enrolled in MA, by 2.9 percentage points (95% CI, 1.3-4.6 percentage points; P = .001). Overall, there were no decreases in use of low-value care in TM or MA over time.

Conclusions And Relevance: This cross-sectional study found that use of low-value care was similarly prevalent in MA and TM, suggesting that MA enrollment was not associated with decreased provision of low-value care compared with TM.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970337PMC
March 2021

Preferences of biobank participants for receiving actionable genomic test results: results of a recontacting study.

Genet Med 2021 Jun 18;23(6):1163-1166. Epub 2021 Feb 18.

Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA, USA.

Purpose: We sought to determine preferences of biobank participants whose samples were tested for clinically actionable variants but did not respond to an initial invitation to receive results.

Methods: We recontacted a subsample of participants in the Kaiser Permanente Washington/University of Washington site of the Electronic Medical Records and Genomics (eMERGE3) Network. The subsample had provided broad consent for their samples to be used for research but had not responded to one initial mailed invitation to receive their results. We sent a letter from the principal investigators with phone outreach. If no contact was made, we sent a certified letter stating our assumption that participant had actively refused. We collected reasons for declining.

Results: We recontacted 123 participants. Response rate was 70.7% (n = 87). Of these, 62 (71.3%) declined the offer of returned results and 25 (28.7%) consented. The most common reasons provided for refusal included not wanting to know (n = 22) and concerns about insurability (n = 28).

Conclusion: Efforts to recontact biobank participants can yield high response. Though active refusal upon recontact was common, our data do not support assuming initial nonresponse to be refusal. Future research can work toward best practices for reconsenting, especially when clinically actionable results are possible.
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http://dx.doi.org/10.1038/s41436-021-01111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194390PMC
June 2021

The FamilyTalk randomized controlled trial: patient-reported outcomes in clinical genetic sequencing for colorectal cancer.

Cancer Causes Control 2021 May 16;32(5):483-492. Epub 2021 Feb 16.

Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA, USA.

As genetics gains favor in clinical oncology, it is important to address patient concerns around confidentiality, privacy, and security of genetic information that might otherwise limit its utilization. We designed a randomized controlled trial to assess the social impact of an online educational tool (FamilyTalk) to increase family communication about colorectal cancer (CRC) risk and screening. Of 208 randomized participants, 149 (71.6%) returned six-month surveys. Overall, there was no difference in CRC screening between the study arms. Privacy and confidentiality concerns about medical and genetic information, reactions to genetic test results, and lifestyle changes did not differ between arms. Participants with pathogenic or likely pathogenic (P/LP) and variant of uncertain significance (VUS) results were more likely than those with negative results to report that the results accurately predicted their disease risks (OR 5.37, p = 0.02 and OR 3.13, p = 0.02, respectively). This trial demonstrated no evidence that FamilyTalk impacted patient-reported outcomes. Low power, due to the limited number of participants with P/LP results in the overall sample, as well as the short follow-up period, could have contributed to the null findings.
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http://dx.doi.org/10.1007/s10552-021-01398-1DOI Listing
May 2021

Glucose-Dementia Association Is Consistent Over Blood Pressure/Antihypertensive Groups.

J Alzheimers Dis 2021 ;80(1):79-90

Department of Medicine, University of Washington, Seattle, WA, USA.

Background: Higher glucose levels are associated with dementia risk in people with and without diabetes. However, little is known about how this association might vary by hypertension status and antihypertensive treatment. Most studies on modifiable dementia risk factors consider each factor in isolation.

Objective: To test the hypothesis that hypertension and antihypertensive treatments may modify associations between glucose levels and dementia.

Methods: Analyses of data generated from a research study and clinical care of participants from a prospective cohort of dementia-free older adults, including glucose measures, diabetes and antihypertensive treatments, and blood pressure data. We defined groups based on blood pressure (hypertensive versus not, ≥140/90 mmHg versus <140/90 mmHg) and antihypertensive treatment intensity (0, 1, or ≥2 classes of antihypertensives). We used Bayesian joint models to jointly model longitudinal exposure and time to event data.

Results: A total of 3,056 participants without diabetes treatment and 480 with diabetes treatment were included (mean age at baseline, 75.1 years; mean 7.5 years of follow-up). Higher glucose levels were associated with greater dementia risk among people without and with treated diabetes. Hazard ratios for dementia were similar across all blood pressure/antihypertensive treatment groups (omnibus p = 0.82 for people without and p = 0.59 for people with treated diabetes).

Conclusion: Hypertension and antihypertensive treatments do not appear to affect the association between glucose and dementia risk in this population-based longitudinal cohort study of community-dwelling older adults. Future studies are needed to examine this question in midlife and by specific antihypertensive treatments.
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http://dx.doi.org/10.3233/JAD-201138DOI Listing
January 2021

Antihypertensive Medication Classes and the Risk of Dementia: A Systematic Review and Network Meta-Analysis.

J Am Med Dir Assoc 2021 Jan 16. Epub 2021 Jan 16.

Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, the Netherlands; Department of Neurology, Amsterdam University Medical Center, location AMC, Amsterdam, the Netherlands.

Objectives: To systematically review and synthesize the evidence on differential associations between antihypertensive medication (AHM) classes and the risk of incident dementia.

Design: Systematic review and random effects frequentist network meta-analysis. Embase, MEDLINE, and the Cochrane library were searched from origin to December 2019.

Setting And Participants: Randomized controlled trials (RCTs) and prospective cohort studies that compared associations of different AHM classes with incident all-cause dementia and/or Alzheimer's disease over at least 1 year of follow-up.

Measures: All cause dementia and/or Alzheimer's disease.

Results: Fifteen observational studies and 7 RCTs were included. Data on AHM classes were available for 649,790 participants and dementia occurred in 19,600 (3.02%). Network meta-analysis showed that in observational studies, treatment with either calcium channel blockers (CCBs) or angiotensin II receptor blockers (ARBs) was associated with lower dementia risks than treatment with other antihypertensives: CCBs vs angiotensin converting enzyme inhibitors (ACE inhibitors) (HR=0.84, 95% CI 0.74-0.95), beta blockers (HR=0.83, 95% CI 0.73-0.95) and diuretics (HR=0.89, 95% CI 0.78-1.01) and ARBs vs ACE inhibitors (HR=0.88, 95% CI 0.81-0.97), beta blockers (HR=0.87, 95% CI 0.77-0.99), and diuretics (HR=0.93, 95% CI 0.83-1.05). There were insufficient RCTs to create a robust network based on randomized data alone.

Conclusions And Implications: Recommending CCBs or ARBs as preferred first-line antihypertensive treatment may significantly reduce the risk of dementia. If corroborated in a randomized setting, these findings reflect a low-cost and scalable opportunity to reduce dementia incidence worldwide.
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http://dx.doi.org/10.1016/j.jamda.2020.12.019DOI Listing
January 2021

Fine Particulate Matter and Markers of Alzheimer's Disease Neuropathology at Autopsy in a Community-Based Cohort.

J Alzheimers Dis 2021 ;79(4):1761-1773

Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, WA, USA.

Background: Evidence links fine particulate matter (PM2.5) to Alzheimer's disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy.

Objective: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score).

Methods: We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score.

Results: 10-year average (SD) PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3. Average age (SD) at death was 89 (7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19)). There was no association with Braak stage (OR: 0.99 (0.64, 1.47)).

Conclusion: We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding.
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http://dx.doi.org/10.3233/JAD-201005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061707PMC
January 2021

Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort.

BMC Med Genomics 2021 Jan 6;14(1):11. Epub 2021 Jan 6.

Division of Medical Genetics, School of Medicine, University of Washington Medical Center, 1705 NE Pacific St, Box 357720, Seattle, WA, 98195, USA.

Background: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample.

Methods: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry.

Results: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP.

Conclusions: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
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http://dx.doi.org/10.1186/s12920-020-00854-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789246PMC
January 2021

Association of remote traumatic brain injury and military employment with late-life trajectories of depressive symptom severity.

J Affect Disord 2021 02 5;281:376-383. Epub 2020 Dec 5.

Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai; Department of Neurology, Icahn School of Medicine at Mount Sinai. Electronic address:

Background: Traumatic brain injury (TBI) and military service are common lifetime exposures among current older adults that may affect late-life mental health. The objective of the present study was to evaluate the association between TBI with loss of consciousness (LOC) and military employment and late-life depressive symptom severity trajectory.

Methods: 1445 males and 2096 females adults at least 65 years old without dementia or recent TBI were enrolled and followed biennially for up to 10 years in the Adult Changes in Thought study from Kaiser Permanente Washington in Seattle, Washington.

Results: Using group-based trajectory modeling, we documented four distinct depressive symptom severity trajectories that followed a similar course in males and females (Minimal, Decreasing, Increasing, and Persistent). In multinomial regression analyses, TBI with LOC in males was associated with greater likelihood of Persistent versus Minimal depressive symptom severity compared to individuals without TBI (OR = 1.51, 95% CI: 1.01, 2.27; p=0.046). Males reporting past military employment had greater likelihood of Decreasing versus Minimal depressive symptom severity compared to individuals without past military employment (OR = 1.54, 95% CI: 1.03, 2.31; p=0.035). There was no association between TBI or military employment and depression trajectories in females, and no evidence of effect modification by age or between exposures.

Limitations: Lifetime history of TBI was ascertained retrospectively and may be subject to recall bias. Also, past military employment does not presuppose combat exposure.

Conclusions: Remote TBI and past military employment are relevant to late-life trajectories of depressive symptom severity in dementia-free older males.
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http://dx.doi.org/10.1016/j.jad.2020.12.003DOI Listing
February 2021

Association of Angiotensin II-Stimulating Antihypertensive Use and Dementia Risk: Post Hoc Analysis of the PreDIVA Trial.

Neurology 2021 01 5;96(1):e67-e80. Epub 2020 Nov 5.

From the Departments of Neurology (J.W.v.D., W.A.v.G., E.R.) and General Practice (E.P.M.v.C.), Amsterdam UMC, University of Amsterdam; Department of Neurology (J.W.v.D., E.R.), Donders Institute for Brain, Behaviour and Cognition, Radboud University Medical Centre, Nijmegen, the Netherlands; Schools of Pharmacy (Z.A.M., S.L.G., D.B.) and Medicine (P.K.C.), University of Washington; and Kaiser Permanente Washington Health Research Institute (E.B.L.), Seattle.

Objective: To assess whether angiotensin II-stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers, and angiotensin I receptor blockers) convey a lower risk of incident dementia compared to angiotensin II-inhibiting antihypertensives (angiotensin-converting enzyme inhibitors, β-blockers, and nondihydropyridine calcium channel blockers), in accordance with the "angiotensin hypothesis."

Methods: We performed Cox regression analyses of incident dementia (or mortality as competing risk) during 6-8 years of follow-up in a population sample of 1,909 community-dwelling individuals (54% women) without dementia, aged 70-78 (mean 74.5 ± 2.5) years.

Results: After a median of 6.7 years of follow-up, dementia status was available for 1,870 (98%) and mortality for 1,904 (>99%) participants. Dementia incidence was 5.6% (27/480) in angiotensin II-stimulating, 8.2% (59/721) in angiotensin II-inhibiting, and 6.9% (46/669) in both antihypertensive type users. Adjusted for dementia risk factors including blood pressure and medical history, angiotensin II-stimulating antihypertensive users had a 45% lower incident dementia rate (hazard ratio [HR], 0.55; 95% CI, 0.34-0.89) without excess mortality (HR, 0.86; 95% CI, 0.64-1.16), and individuals using both types had a nonsignificant 20% lower dementia rate (HR, 0.80; 95% CI,0.53-1.20) without excess mortality (HR, 0.97; 95% CI, 0.76-1.24), compared to angiotensin II-inhibiting antihypertensive users. Results were consistent for subgroups based on diabetes and stroke history, but may be specific for individuals without a history of cardiovascular disease.

Conclusions: Users of angiotensin II-stimulating antihypertensives had lower dementia rates compared to angiotensin II-inhibiting antihypertensive users, supporting the angiotensin hypothesis. Confounding by indication must be examined further, although subanalyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.
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http://dx.doi.org/10.1212/WNL.0000000000010996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884979PMC
January 2021

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 Jan;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.

Genet Epidemiol 2021 Feb 22;45(1):4-15. Epub 2020 Sep 22.

Division of Medical Genetics, School of Medicine, University of Washington, Seattle, Washington, USA.

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.
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http://dx.doi.org/10.1002/gepi.22360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891640PMC
February 2021

Differences in Health Care Utilization, Process of Diabetes Care, Care Satisfaction, and Health Status in Patients With Diabetes in Medicare Advantage Versus Traditional Medicare.

Med Care 2020 11;58(11):1004-1012

Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objective: The objective of this study was to determine differences in health care utilization, process of diabetes care, care satisfaction, and health status for Medicare Advantage (MA) and traditional Medicare (TM) beneficiaries with and without diabetes.

Methods: Using the 2010-2016 Medicare Current Beneficiary Survey, we identified MA and TM beneficiaries with and without diabetes. To address the endogenous plan choice between MA and TM, we used an instrumental variable approach. Using marginal effects, we estimated differences in the outcomes between MA and TM beneficiaries with and without diabetes.

Results: Our instrumental variable analysis showed that compared with TM beneficiaries with diabetes, MA beneficiaries with diabetes had less annual health care utilization, including -22.4 medical provider visits [95% confidence interval (CI): -23.6 to -21.1] and -3.4 outpatient hospital visits (95% CI: -3.8 to -3.0). A significant difference between MA and TM beneficiaries without diabetes was only observed in medical provider visits and the difference was greater among beneficiaries with diabetes than beneficiaries without diabetes (-12.5 medical provider visits; 95% CI: -15.9 to -9.2). While we did not detect significant differences in 5 measures of the process of diabetes care between MA and TM beneficiaries with diabetes, there were inconsistent results in the other 3 measures. There were no or marginal differences in care satisfaction and health status between MA and TM beneficiaries with and without diabetes.

Conclusions: MA enrollment was associated with lower health care utilization without compromising care satisfaction and health status, particularly for beneficiaries with diabetes. MA may have a more efficient care delivery system for beneficiaries with diabetes.
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http://dx.doi.org/10.1097/MLR.0000000000001390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572707PMC
November 2020

Dementia Is Associated With Earlier Mortality for Men and Women in the United States.

Gerontol Geriatr Med 2020 Jan-Dec;6:2333721420945922. Epub 2020 Aug 19.

National Bureau of Economic Research, Cambridge, MA, USA.

Sociodemographic trends in the United States may influence future dementia-associated mortality, yet there is little evidence about their potential impact. Our study objective was to estimate the effect of dementia on survival in adults stratified by sex, education, and marital status. Using survey data from the Health and Retirement Study (HRS) linked to Medicare claims from 1991 to 2012, we identified a retrospective cohort of adults with at least one International Classification of Diseases-ninth revision-Clinical Modification (ICD-9-CM) dementia diagnosis code ( = 3,714). For each case, we randomly selected up to five comparators, matching on sex, birth year, education, and HRS entry year ( = 9,531), and assigned comparators the diagnosis date of their matched case. Participants were followed for up to 60 months following diagnosis. We estimated a survival function for the entire study population and then within successive strata defined by sex, education, and marital status. On average, dementia cases were 80.5 years old at diagnosis. Most were female, had less than college-level education, and approximately 40% were married at diagnosis. In multivariate analyses, dementia diagnosis was associated with earlier mortality for women (predicted median survival of 54.5 months vs. 62.5 months; dementia coefficient = -0.13; 95% confidence interval [CI] = [-0.22, -0.04]; = .003), but even more so among men (predicted median survival of 35.5 months vs. 54.5 months; dementia coefficient = -0.42; 95% CI = [-0.52, -0.31]; < .001). We found substantial heterogeneity in the relationship between dementia and survival, associated with both education and marital status. Both sex and level of education moderate the relationship between dementia diagnosis and length of survival.
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http://dx.doi.org/10.1177/2333721420945922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444147PMC
August 2020

Engaging Patients to Design the Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT) Intervention: Findings from a Web-Based Survey.

J Alzheimers Dis Rep 2020 Jul 23;4(1):255-260. Epub 2020 Jul 23.

Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.

We administered a web-based survey to a convenience sample of 561 patients in a large health system to assess patient attitudes toward dementia prevention in the context of designing a multi-domain Alzheimer's risk reduction intervention. The majority of respondents reported being very concerned about Alzheimer's disease, wanted to know their personal risk factors, and were highly motivated to make healthy lifestyle changes to lower dementia risk. The areas they were most interested in targeting to reduce dementia risk included physical activity, cognitive stimulation, nutrition, and sleep. These results provided strong support for our conceptual framework to target higher-risk patients with a personalized risk reduction strategy.
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http://dx.doi.org/10.3233/ADR-200210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458551PMC
July 2020

Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Brain 2020 08;143(8):2561-2575

Department of Neurology, Columbia University, New York, NY, USA.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.
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http://dx.doi.org/10.1093/brain/awaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447518PMC
August 2020

Health Care Costs of Alzheimer's and Related Dementias Within a Medicare Managed Care Provider.

Med Care 2020 09;58(9):833-841

Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia, PA.

Background: Although one third of Medicare beneficiaries are enrolled in Medicare Advantage (MA) plans, there is limited information about the cost of treating Alzheimer disease and related dementias (ADRD) in these settings.

Objective: The objective of this study was to estimate direct health care costs attributable to ADRD among older adults within a large MA plan.

Research Design: A retrospective cohort design was used to estimate direct total, outpatient, inpatient, ambulatory pharmacy, and nursing home costs for 3 years before and after an incident ADRD diagnosis for 927 individuals diagnosed with ADRD relative to a sex-matched and birth year-matched set of 2945 controls.

Subject: Adults 65 years of age and older enrolled in the Kaiser Permanente Washington MA plan and the Adult Changes in Thought (ACT) Study, a prospective longitudinal cohort study of ADRD and brain aging.

Measures: Data on monthly health service use obtained from health system electronic medical records for the period 1992-2012.

Results: Total monthly health care costs for individuals with ADRD are statistically greater (P<0.05) than controls beginning in the third month before diagnosis and remain significantly greater through the eighth month following diagnosis. Greater total health costs are driven by significantly (P<0.05) greater nursing home costs among individuals diagnosed with ADRD beginning in the third month prediagnosis. Although total costs were no longer significantly greater at 8 months following diagnosis, nursing home costs remained higher for the people with dementia through the 3 years postdiagnosis we analyzed.

Conclusion: Greater total health care costs among individuals with ADRD are primarily driven by nursing home costs.
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http://dx.doi.org/10.1097/MLR.0000000000001380DOI Listing
September 2020

Device-assessed physical activity and sedentary behavior in a community-based cohort of older adults.

BMC Public Health 2020 Aug 18;20(1):1256. Epub 2020 Aug 18.

University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.

Background: Few studies characterize older adult physical activity and sitting patterns using accurate accelerometer and concurrent posture measures. In this descriptive paper, we report accelerometer data collection protocols, consent rates, and physical behavior measures from a population-based cohort study (Adult Changes in Thought, ACT).

Methods: The ACT study holds enrollment steady at approximately 2000 members of Kaiser Permanente Washington aged 65+ without dementia undergoing detailed biennial assessments. In 2016 the ACT-Activity Monitor (ACT-AM) sub-study was initiated to obtain data from wearing activPAL and ActiGraph devices for 7 days following regular biennial visits. We describe the methods protocol of ACT-AM and present characteristics of people who did and did not consent to wear devices. We compute inverse probability of response weights and incorporate these weights in linear regression models to estimate means and 95% confidence intervals (CI) of device-based pattern metrics, adjusted for wear time and demographic factors, and weighted to account for potential selection bias due to device-wear consent.

Results: Among 1885 eligible ACT participants, 56% agreed to wear both devices (mean age 77 years, 56% female, 89% non-Hispanic white, 91% with post-secondary education). On average, those who agreed to wear devices were younger and healthier. Estimated mean (95% CI) activPAL-derived sitting, standing, and stepping times were 10.2 h/day (603-618 min/day), 3.9 h/day (226-239 min/day), and 1.4 h/day (79-84 min/day), respectively. Estimated mean ActiGraph derived sedentary (Vector Magnitude [VM] < =18 counts/15 s), light intensity (VM 19-518 counts/15 s), and moderate-to-vigorous intensity (VM > 518 counts/15 s) physical activity durations were 9.5 h/day (565-577 min/day), 4.5 h/day (267-276 min/day), and 1.0 h/day (59-64 min/day). Participants who were older, had chronic conditions, and were unable to walk a half-mile had higher sedentary time and less physical activity.

Conclusions: Our recruitment rate demonstrates the feasibility of cohort participants to wear two devices that measure sedentary time and physical activity. Data indicate high levels of sitting time in older adults but also high levels of physical activity using cut-points developed for older adults. These data will help researchers test hypotheses related to physical behavior and health in older adults in the future.
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http://dx.doi.org/10.1186/s12889-020-09330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436994PMC
August 2020

Glucose control and cognitive and physical function in adults 80+ years of age with diabetes.

Alzheimers Dement (N Y) 2020 13;6(1):e12058. Epub 2020 Aug 13.

Kaiser Permanente Washington Health Research Institute Seattle USA.

Introduction: We modeled associations between glycated hemoglobin (HbA1c) levels (<7%, 7% to 8%, and >8%) and cognitive and physical function among adults 80+ years of age with diabetes and determined whether associations differ by frailty, multimorbidity, and disability.

Methods: A total of 316, adults with diabetes, 80+ years of age, were from the Adult Changes in Thought Study. Cognitive Abilities Screening Instrument Item Response Theory (CASI-IRT) measured cognition. Short performance-based physical function (sPPF) and gait speed measured physical function. Glycosylated hemoglobin (HbA1c) levels were from clinical measurements. Analyses estimated associations between average HbA1c levels (<7%, 7% to 8%, and >8%) and functional outcomes using linear regressions estimated with generalized estimating equations.

Results: sPPF scores did not differ significantly by HbA1c levels. Gait speed did, but only for non-frail individuals; those with HbA1c >8% were slower (-0.10 m/s [95% CI, -0.16 to -0.04]) compared to those with HbA1c 7% to 8%. The association between HbA1c and CASI-IRT varied with age (interaction  = 0.04). At age 80, for example, relative to people with HbA1c levels of 7% to 8%, CASI-IRT scores were, on average, 0.18 points lower (95% CI, -0.35 to -0.02) for people with HbA1c <7% and 0.22 points lower (95% CI, -0.40 to -0.05) for people with HbA1c >8%. At older ages, these estimated differences were attenuated. Estimated associations were not modified by multimorbidity or disability.

Discussion: Moderate HbA1c levels of 7% to 8% were associated with better cognition in early but not late octogenarians with diabetes. Furthermore, HbA1c >8% was associated with slower gait speed among those without frailty. These results add to an evidence base for determining glucose targets for very old adults with diabetes.
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http://dx.doi.org/10.1002/trc2.12058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424264PMC
August 2020