Publications by authors named "Paul K Crane"

259 Publications

Association of Lifetime TBI and Military Employment with Late-Life ADL Functioning: A Population-Based Prospective Cohort Study.

Arch Phys Med Rehabil 2021 Jul 17. Epub 2021 Jul 17.

Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai; Department of Neurology, Icahn School of Medicine at Mount Sinai.

Objective: To determine associations of traumatic brain injury (TBI) and military employment with activities of daily living (ADL) in late life.

Setting: Community-based integrated healthcare delivery system.

Participants: Male (n=2066) and female (n=2887), aged 65+ and dementia-free.

Design: Population-based prospective cohort study with biennial follow-up and censoring at time of dementia diagnosis.

Main Outcome Measures: ADL difficulties at baseline and accumulation during follow-up.

Results: TBI with loss of consciousness (LOC) before age 40 was associated with slightly higher ADL difficulty at baseline for females (RR=1.44, 95% CI: 1.08-1.93, p=0.01). For males, TBI with LOC at any age was associated with greater ADL difficulty at baseline (age <40: RR=1.58, 95% CI: 1.20 - 2.08, p = 0.001; age 40+: RR=2.14, 95% CI: 1.24 - 3.68, p = 0.006). TBI with LOC was not associated with the rate of accumulation of ADL difficulties over time in males or females. There was no evidence of an association between military employment and either outcome, nor of an interaction between military employment and TBI with LOC. Findings were consistent across a variety of sensitivity analyses.

Conclusion: Further investigation into factors underlying greater late-life functional impairment among TBI survivors is warranted.
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http://dx.doi.org/10.1016/j.apmr.2021.06.018DOI Listing
July 2021

Differential trajectories of hypometabolism across cognitively-defined Alzheimer's disease subgroups.

Neuroimage Clin 2021 Jun 12;31:102725. Epub 2021 Jun 12.

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

Disentangling biologically distinct subgroups of Alzheimer's disease (AD) may facilitate a deeper understanding of the neurobiology underlying clinical heterogeneity. We employed longitudinal [F]FDG-PET standardized uptake value ratios (SUVRs) to map hypometabolism across cognitively-defined AD subgroups. Participants were 384 amyloid-positive individuals with an AD dementia diagnosis from ADNI who had a total of 1028 FDG-scans (mean time between first and last scan: 1.6 ± 1.8 years). These participants were categorized into subgroups on the basis of substantial impairment at time of dementia diagnosis in a specific cognitive domain relative to the average across domains. This approach resulted in groups of AD-Memory (n = 135), AD-Executive (n = 8), AD-Language (n = 22), AD-Visuospatial (n = 44), AD-Multiple Domains (n = 15) and AD-No Domains (for whom no domain showed substantial relative impairment; n = 160). Voxelwise contrasts against controls revealed that all AD-subgroups showed progressive hypometabolism compared to controls across temporoparietal regions at time of AD diagnosis. Voxelwise and regions-of-interest (ROI)-based linear mixed model analyses revealed there were also subgroup-specific hypometabolism patterns and trajectories. The AD-Memory group had more pronounced hypometabolism compared to all other groups in the medial temporal lobe and posterior cingulate, and faster decline in metabolism in the medial temporal lobe compared to AD-Visuospatial. The AD-Language group had pronounced lateral temporal hypometabolism compared to all other groups, and the pattern of metabolism was also more asymmetrical (left < right) than all other groups. The AD-Visuospatial group had faster decline in metabolism in parietal regions compared to all other groups, as well as faster decline in the precuneus compared to AD-Memory and AD-No Domains. Taken together, in addition to a common pattern, cognitively-defined subgroups of people with AD dementia show subgroup-specific hypometabolism patterns, as well as differences in trajectories of metabolism over time. These findings provide support to the notion that cognitively-defined subgroups are biologically distinct.
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http://dx.doi.org/10.1016/j.nicl.2021.102725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238088PMC
June 2021

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

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

Department of Medicine and Surgery, Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.

Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.

Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.

Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.
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http://dx.doi.org/10.1002/alz.12365DOI 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

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

Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups.

Neuroimage Clin 2021 3;30:102660. Epub 2021 Apr 3.

Department of Neurology & Alzheimer Center, Amsterdam University Medical Center - Location VU University Medical Center, Amsterdam, The Netherlands; Lund University, Clinical Memory Research Unit, Lund, Sweden. Electronic address:

The clinical presentation of Alzheimer's disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences.
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http://dx.doi.org/10.1016/j.nicl.2021.102660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186562PMC
July 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

Somatic symptoms have negligible impact on Patient Health Questionnaire-9 depression scale scores in neurological patients.

Eur J Neurol 2021 Jun 26;28(6):1812-1819. Epub 2021 Mar 26.

Division of General Internal Medicine, University of Washington, Seattle, Washington, USA.

Background And Purpose: There is concern that the Patient Health Questionnaire-9 (PHQ-9) depression scale may be impacted by the presence of somatic symptoms (differential item functioning [DIF]) in patients with neurological conditions. We evaluated the PHQ-9 for the presence and impact of DIF in large clinical samples of neurological patients.

Methods: We conducted a cross-sectional study of patients seen at the Cleveland Clinic Cerebrovascular, Headache, Movement Disorder, and Neuromuscular clinics who completed the PHQ-9 and patient-reported disease severity measures as part of standard care between 29 July 2008 and 21 February 2013. We evaluated PHQ-9 items for DIF with respect to disease-specific severity for each condition. Salient DIF impact was characterized as a difference between DIF-adjusted and unadjusted PHQ-9 scores.

Results: Included in the study were 2112 patients with stroke, 8221 with migraine, 440 with amyotrophic lateral sclerosis (ALS), and 5022 with Parkinson disease (PD). Several PHQ-9 items demonstrated DIF with respect to disease-specific severity, although salient DIF was present in very few patients (stroke, n = 0; migraine, n = 1; ALS, n = 13; PD, n = 1).

Conclusions: PHQ-9 items function consistently across disease severity, with salient levels of DIF impact found only for a very small proportion of people. These results suggest that the PHQ-9 provides a consistent measure of depression severity among people with neurological conditions associated with somatic symptoms that overlap with depression.
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http://dx.doi.org/10.1111/ene.14822DOI Listing
June 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

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

Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn's disease.

Hum Genet 2021 Jun 16;140(6):865-877. Epub 2021 Jan 16.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA.

To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn's Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10 and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10, with the effect independent of CD diagnosis). A pathway analysis of the variants overlapping between PRS-height and PRS-CD detected significant enrichment of genes from the inflammatory, immune-mediated and growth factor regulation pathways. This finding supports the clinical observation of growth failure in patients with childhood-onset CD and demonstrates the value of using individual-level data from dbGaP in searching for shared genetic determinants. This information can help provide a refined insight into disease pathogenesis and may have major implications for novel therapies and drug repurposing.
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http://dx.doi.org/10.1007/s00439-020-02250-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102349PMC
June 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

Development and validation of language and visuospatial composite scores in ADNI.

Alzheimers Dement (N Y) 2020 5;6(1):e12072. Epub 2020 Dec 5.

Department of Medicine University of Washington Seattle Washington USA.

Introduction: Composite scores may be useful to summarize overall language or visuospatial functioning in studies of older adults.

Methods: We used item response theory to derive composite measures for language (ADNI-Lan) and visuospatial functioning (ADNI-VS) from the cognitive battery administered in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We evaluated the scores among groups of people with normal cognition, mild cognitive impairment (MCI), and Alzheimer's disease (AD) in terms of responsiveness to change, association with imaging findings, and ability to differentiate between MCI participants who progressed to AD dementia and those who did not progress.

Results: ADNI-Lan and ADNI-VS were able to detect change over time and predict conversion from MCI to AD. They were associated with most of the pre-specified magnetic resonance imaging measures. ADNI-Lan had strong associations with a cerebrospinal fluid biomarker pattern.

Discussion: ADNI-Lan and ADNI-VS may be useful composites for language and visuospatial functioning in ADNI.
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http://dx.doi.org/10.1002/trc2.12072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718716PMC
December 2020

You say tomato, I say radish: can brief cognitive assessments in the US Health Retirement Study be harmonized with its International Partner Studies?

J Gerontol B Psychol Sci Soc Sci 2020 Nov 29. Epub 2020 Nov 29.

Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI, USA.

Objectives: To characterize the extent to which brief cognitive assessments administered in the population-representative US Health and Retirement Study (HRS) and its International Partner Studies can be considered to be measuring a single, unidimensional latent cognitive function construct.

Method: Cognitive function assessments were administered in face-to-face interviews in 12 studies in 26 countries (N=155,690), including the US HRS and selected International Partner Studies. We used the time point of first cognitive assessment for each study to minimize differential practice effects across studies, and documented cognitive test item coverage across studies. Using confirmatory factor analysis models, we estimated single factor general cognitive function models, and bifactor models representing memory-specific and non-memory-specific cognitive domains for each study. We evaluated model fits and factor loadings across studies.

Results: Despite relatively sparse and inconsistent cognitive item coverage across studies, all studies had some cognitive test items in common with other studies. In all studies, the bifactor models with a memory-specific domain fit better than single factor general cognitive function models. The data fit the models at reasonable thresholds for single factor models in six of the 12 studies, and for the bifactor models in all 12 of the 12 studies.

Discussion: The cognitive assessments in the US HRS and its International Partner Studies reflect comparable underlying cognitive constructs. We discuss the assumptions underlying our methods, present alternatives, and future directions for cross-national harmonization of cognitive aging data.
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http://dx.doi.org/10.1093/geronb/gbaa205DOI Listing
November 2020

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

Genetic architecture of cardiometabolic risks in people living with HIV.

BMC Med 2020 10 28;18(1):288. Epub 2020 Oct 28.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, United States of America.

Background: Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown.

Methods: We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH.

Results: We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI.

Conclusions: Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.
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http://dx.doi.org/10.1186/s12916-020-01762-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592520PMC
October 2020

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

JAMA Neurol 2021 01;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

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

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

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

Association of Demographic and Early-Life Socioeconomic Factors by Birth Cohort With Dementia Incidence Among US Adults Born Between 1893 and 1949.

JAMA Netw Open 2020 07 1;3(7):e2011094. Epub 2020 Jul 1.

Kaiser Permanente Washington Health Research Institute, Seattle.

Importance: Early-life factors may be important for later dementia risk. The association between a more advantaged early-life environment, as reflected through an individual's height and socioeconomic status indicators, and decreases in dementia incidence by birth cohort is unknown.

Objectives: To examine the association of birth cohort and early-life environment with dementia incidence among participants in the Adult Changes in Thought study from 1994 to 2015.

Design, Setting, And Participants: This prospective cohort study included 4277 participants from the Adult Changes in Thought study, an ongoing longitudinal population-based study of incident dementia in a random sample of adults 65 years and older who were born between 1893 and 1949 and are members of Kaiser Permanente Washington in the Seattle region. Participants in the present analysis were followed up from 1994 to 2015. At enrollment, all participants were dementia-free and completed a baseline evaluation. Subsequent study visits were held every 2 years until a diagnosis of dementia, death, or withdrawal from the study. Participants were categorized by birth period (defined by historically meaningful events) into 5 cohorts: pre-World War I (1893-1913), World War I and Spanish influenza (1914-1920), pre-Great Depression (1921-1928), Great Depression (1929-1939), and World War II and postwar (1940-1949). Participants' height, educational level, childhood financial stability, and childhood household density were examined as indicators of early-life environment, and later-life vascular risk factors for dementia were assessed. Cox proportional hazards regression models, adjusted for competing survival risk, were used to analyze data. Data were analyzed from June 1, 2018, to April 29, 2020.

Main Outcomes And Measures: Participants completed the Cognitive Abilities Screening Instrument every 2 years to assess global cognition. Those with scores indicative of cognitive impairment completed an evaluation for dementia, with dementia diagnoses determined during consensus conferences using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

Results: Among 4277 participants, the mean (SD) age was 74.5 (6.4) years, and 2519 participants (58.9%) were women. The median follow-up was 8 years (interquartile range, 4-12 years), with 730 participants developing dementia over 24 378 person-years. The age-specific dementia incidence was lower for those born in 1929 and later compared with those born earlier. Compared with participants born in the pre-Great Depression years (1921-1928), the age- and sex-adjusted hazard ratio was 0.67 (95% CI, 0.53-0.85) for those born in the Great Depression period (1929-1939) and 0.62 (95% CI, 0.29-1.31) for those born in the World War II and postwar period (1940-1949). Although indicators of a more advantaged early-life environment and higher educational level (college or higher) were associated with a lower incidence of dementia, these variables did not explain the association between birth cohort and dementia incidence, which remained when vascular risk factors were included and were similar by sex.

Conclusions And Relevance: Age-specific dementia incidence was lower in participants born after the mid-1920s compared with those born earlier. In this population, the decrease in dementia incidence may reflect societal-level changes or individual differences over the life course rather than early-life environment, as reflected through recalled childhood socioeconomic status and measured height, educational level, and later-life vascular risk.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.11094DOI Listing
July 2020

Lower practice effects as a marker of cognitive performance and dementia risk: A literature review.

Alzheimers Dement (Amst) 2020 9;12(1):e12055. Epub 2020 Jul 9.

Brooklyn College and The Graduate Center of The City University of New York Brooklyn New York USA.

Background: Practice effects (PEs) are improvements in performance after repeated exposure to test materials, and typically viewed as a source of bias in repeated cognitive assessments. We aimed to determine whether characterizing PEs could also provide a useful marker of early cognitive decline.

Methods: We conducted a systematic review of the literature, searching PsycInfo (Ebsco) and PubMed databases for articles studying PEs in aging and dementia populations. Articles published between 1920 and 2019 were included.

Result: We identified 259 articles, of which 27 studied PEs as markers of cognitive performance. These studies consistently showed that smaller, less-robust PEs were associated with current diagnostic status and/or future cognitive decline. In addition, lower PEs were associated with Alzheimer's disease risk factors and neurodegeneration biomarkers.

Conclusion: PEs provide a potentially useful marker of cognitive decline, and could prove valuable as part of a cost-effective strategy to select individuals who are at-risk for dementia for future interventions.
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http://dx.doi.org/10.1002/dad2.12055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346865PMC
July 2020

β-amyloid and tau drive early Alzheimer's disease decline while glucose hypometabolism drives late decline.

Commun Biol 2020 07 6;3(1):352. Epub 2020 Jul 6.

Sanders-Brown Center on Aging, University of Kentucky, 307 Sanders-Brown Building, 800 S. Limestone Street, Lexington, KY, 40506-0230, USA.

Clinical trials focusing on therapeutic candidates that modify β-amyloid (Aβ) have repeatedly failed to treat Alzheimer's disease (AD), suggesting that Aβ may not be the optimal target for treating AD. The evaluation of Aβ, tau, and neurodegenerative (A/T/N) biomarkers has been proposed for classifying AD. However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally throughout the progression of AD. Here, using the random forest machine learning method to analyze participants in the Alzheimer's Disease Neuroimaging Initiative dataset, we show that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ and tau better predicting early dementia status, and biomarkers of neurodegeneration, especially glucose hypometabolism, better predicting later dementia status. Our results suggest that AD treatments may also need to be disease stage-oriented with Aβ and tau as targets in early AD and glucose metabolism as a target in later AD.
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http://dx.doi.org/10.1038/s42003-020-1079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338410PMC
July 2020

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

Alzheimers Dement 2020 08 23;16(8):1134-1145. Epub 2020 Jun 23.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD.

Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes.

Results: Suggestive associations (P < 1.0 × 10 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10 ), chromosome 7 (rs60465337,P = 4.06 × 10 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10 ) and 4 (rs1304013, P = 7.73 × 10 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified.

Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.
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http://dx.doi.org/10.1002/alz.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924136PMC
August 2020

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology.

PLoS Genet 2020 06 3;16(6):e1008775. Epub 2020 Jun 3.

The Jackson Laboratory, Bar Harbor, Maine, United States of America.

Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10-8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.
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http://dx.doi.org/10.1371/journal.pgen.1008775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295244PMC
June 2020
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