Publications by authors named "Oscar L Lopez"

302 Publications

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer's Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study.

J Alzheimers Dis 2021 ;82(1):293-305

Computer Science, State University of New York at Binghamton, Binghamton, NY, USA.

Background: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Objective: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD.

Methods: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed.

Results: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections).

Conclusion: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.
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http://dx.doi.org/10.3233/JAD-210199DOI Listing
January 2021

Association Between the APOEɛ2/ɛ4 Genotype and Alzheimer's Disease and Mild Cognitive Impairment Among African Americans.

J Alzheimers Dis 2021 ;81(3):943-948

University of Pittsburgh, School of Nursing, Pittsburgh, PA, USA.

We examined the association between APOEɛ2/ɛ4 with incident Alzheimer's disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer's Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ3/ɛ3 carriers, ɛ2/ɛ4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOEɛ2/ɛ4 genotype is not associated with the incidence of AD and MCI among African Americans.
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http://dx.doi.org/10.3233/JAD-201613DOI Listing
January 2021

Case-cohort study of plasma phospholipid fatty acid profiles, cognitive function, and risk of dementia: a secondary analysis in the Ginkgo Evaluation of Memory Study.

Am J Clin Nutr 2021 Jul;114(1):154-162

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function.

Objectives: We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk.

Methods: We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics.

Results: Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n-6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: -0.12, -0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n-3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n-3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex.

Conclusions: Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention.
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http://dx.doi.org/10.1093/ajcn/nqab087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277434PMC
July 2021

Direct comparison of the tau PET tracers [F]flortaucipir and [F]MK-6240 in human subjects.

J Nucl Med 2021 Apr 16. Epub 2021 Apr 16.

University of Pittsburgh, United States.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compares two frequently used tau PET tracers, [F]flortaucipir (FTP) and [F]MK-6240, in the same subjects. [F]flortaucipir and [F]MK-6240 scans were collected within two months in 15 elderly subjects varying in terms of clinical diagnosis and cognition. FreeSurfer v5.3 was applied to 3T MR images to segment Braak pathologic regions (I-VI) for PET analyses. Off-target binding was assessed in choroid plexus, meninges, and striatum. SUVR outcomes were determined over 80-100 min ([F]flortaucipir) or 70-90 min ([F]MK-6240) normalized to cerebellar grey matter. Blinded visual interpretation of images was performed by five raters for both medial temporal lobe (MTL) and neocortex (NEO) and an overall (majority) rating determined. Overall visual ratings showed complete concordance between radiotracers for both MTL and NEO. SUVR outcomes were highly correlated (r2>0.92; << 0.001) for all Braak regions except Braak II. The dynamic range of SUVR values in target regions was approximately two-fold higher for [F]MK-6240 compared to [F]flortaucipir. Cerebellar SUV values were similar for [F]MK-6240 and [F]flortaucipir, suggesting that differences in SUVR values are driven by specific signal. Apparent off-target binding in striatum and choroid plexus was often observed with [F]flortaucipir, and most often in meninges with [F]MK-6240. Both [F]MK-6240 and [F]flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in AD and perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. [F]MK-6240 showed greater dynamic range in SUVR estimates, which may be an advantage for detecting very early signal or in longitudinal studies designed to detect small interval changes.
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http://dx.doi.org/10.2967/jnumed.120.254961DOI Listing
April 2021

Dataset of why inclusion matters for Alzheimer's disease biomarker discovery in plasma.

Data Brief 2021 Apr 1;35:106923. Epub 2021 Mar 1.

Department of Chemistry, Vanderbilt University, 5423 Stevenson Center, Nashville, TN 37235, United States.

Here we present a plasma proteomics dataset that was generated to understand the importance of self-reported race for biomarker discovery in Alzheimer's disease. This dataset is related to the article "Why inclusion matters for Alzheimer's disease biomarker discovery in plasma" [1]. Plasma samples were obtained from clinically diagnosed Alzheimer's disease and cognitively normal adults of African American/Black and non-Hispanic White racial and ethnic backgrounds. Plasma was immunodepleted, digested, and isobarically tagged with commercial reagents. Tagged peptides were fractionated using high pH fractionation and resulting fractions analysed by liquid chromatography - mass spectrometry (LC-MS/MS & MS) analysis on an Orbitrap Fusion Lumos mass spectrometer. The resulting data was processed using Proteome Discoverer to produce a list of identified proteins with corresponding tandem mass tag (TMT) intensity information.
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http://dx.doi.org/10.1016/j.dib.2021.106923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988280PMC
April 2021

Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-β in cognitively unimpaired older adults.

Brain Behav Immun 2021 07 15;95:178-189. Epub 2021 Mar 15.

Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

Introduction: Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults.

Methods: A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations.

Results: At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions.

Discussion: In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.
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http://dx.doi.org/10.1016/j.bbi.2021.03.015DOI Listing
July 2021

ENGAGE and EMERGE: Truth and consequences?

Alzheimers Dement 2021 04 3;17(4):692-695. Epub 2021 Mar 3.

Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

The potential benefit of the anti-amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti-amyloid drug therapies. The two trials of 18-month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high-dose EMERGE trial initially also showed no benefit but with longer follow-up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti-amyloid drugs is very substantial as well as the brain amyloid-AD-dementia hypothesis.
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http://dx.doi.org/10.1002/alz.12286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248059PMC
April 2021

Dementia in Latin America: Paving the way toward a regional action plan.

Alzheimers Dement 2021 02 20;17(2):295-313. Epub 2020 Nov 20.

Hospital Geral de Fortaleza, University of Fortaleza, Brazil.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.
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http://dx.doi.org/10.1002/alz.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984223PMC
February 2021

Why Inclusion Matters for Alzheimer's Disease Biomarker Discovery in Plasma.

J Alzheimers Dis 2021 ;79(3):1327-1344

Department of Chemistry, Vanderbilt University, Nashville, TN, USA.

Background: African American/Black adults have a disproportionate incidence of Alzheimer's disease (AD) and are underrepresented in biomarker discovery efforts.

Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults.

Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N = 113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates.

Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86%for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47%for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD.

Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers.
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http://dx.doi.org/10.3233/JAD-201318DOI Listing
January 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Associations of equol-producing status with white matter lesion and amyloid-β deposition in cognitively normal elderly Japanese.

Alzheimers Dement (N Y) 2020 22;6(1):e12089. Epub 2020 Oct 22.

Department of Epidemiology Graduate School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA.

Introduction: Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aβ) deposition.

Methods: From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using C-Pittsburgh compound-B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers.

Results: The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aβ positive, and 51% were equol producers. Equol-producing status (non-producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend  < .01). Equol-producing status was not associated with Aβ status.

Discussion: A randomized-controlled trial of equol targeting WML volume is warranted.
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http://dx.doi.org/10.1002/trc2.12089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580022PMC
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

Differential Effects of an AIDS Defining Illness and Chronic HIV Infection on Gray Matter Volume.

Clin Infect Dis 2020 Oct 14. Epub 2020 Oct 14.

University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh PA.

Background: Age, HIV infection, illicit drug use, and CNS opportunistic infections all can affect brain structure, with the striatum being particularly sensitive to HIV effects. Nevertheless, the impact of non-CNS AIDS defining illness (ADI) on brain structure has been less investigated. We examined ADI and HIV effects on brain volume.

Methods: In a cross-sectional study, including 95 virally-suppressed seropositive and 84 demographically-matched, seronegative participants, we examined serostatus and ADI effects. Cortical and subcortical GMV ROIs were estimated with computational neuroanatomy techniques applied to high resolution, T1-weighted MRI data. Linear regression was used to model HIV serostatus and ADI effects on global and regional GMV, adjusting for age, sex, CD4 nadir, drug use and total intracranial volume.

Results: While HIV serostatus was associated with lower striatal volume (B = -0.59; 95% CI = [-1.08 - -0.10]), co-occurring ADI was independently associated with lower striatal volume (B=-0.73; 95% CI =[-1.36 - -0.09]). ADI was also associated with lower global (B = -19.35; 95% CI = [-32.42 - -6.29]) and regional GMV.

Conclusions: While HIV infection is associated with a localized effect on striatal structure, having a prior ADI is a strong predictor of smaller global and regional GMV. The lack of interaction between HIV serostatus or ADI with age suggests that chronic HIV infection and ADI have independent effects on brain structure, without associated accelerated lower volume with age. ADI history should be incorporated into statistical adjustments in HIV neuroimaging analysis. These findings also lend support to current HIV treatment guidelines urging prompt ART initiation after HIV diagnosis.
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http://dx.doi.org/10.1093/cid/ciaa1552DOI Listing
October 2020

Inclusion of African American/Black adults in a pilot brain proteomics study of Alzheimer's disease.

Neurobiol Dis 2020 12 10;146:105129. Epub 2020 Oct 10.

Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States of America; Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America; Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, United States of America. Electronic address:

Alzheimer's disease (AD) disproportionately affects certain racial and ethnic subgroups, such as African American/Black and Hispanic adults. Genetic, comorbid, and socioeconomic risk factors contribute to this disparity; however, the molecular contributions have been largely unexplored. Herein, we conducted a pilot proteomics study of postmortem brains from African American/Black and non-Hispanic White adults neuropathologically diagnosed with AD compared to closely-matched cognitively normal individuals. Examination of hippocampus, inferior parietal lobule, and globus pallidus regions using quantitative proteomics resulted in 568 differentially-expressed proteins in AD. These proteins were consistent with the literature and included glial fibrillary acidic protein, peroxiredoxin-1, and annexin A5. In addition, 351 novel proteins in AD were identified, which could partially be due to cohort diversity. From linear regression analyses, we identified 185 proteins with significant race x diagnosis interactions across various brain regions. These differences generally were reflective of differential expression of proteins in AD that occurred in only a single racial/ethnic group. Overall, this pilot study suggests that disease understanding can be furthered by including diversity in racial/ethnic groups; however, this must be done on a larger scale.
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http://dx.doi.org/10.1016/j.nbd.2020.105129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990397PMC
December 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Estrogen, brain structure, and cognition in postmenopausal women.

Hum Brain Mapp 2021 01 10;42(1):24-35. Epub 2020 Sep 10.

Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.
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http://dx.doi.org/10.1002/hbm.25200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721237PMC
January 2021

Associations of body composition with incident dementia in older adults: Cardiovascular Health Study-Cognition Study.

Alzheimers Dement 2020 10 17;16(10):1402-1411. Epub 2020 Aug 17.

Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.

Introduction: A body of literature reported associations between late-life general adiposity measures (eg, body mass index) and dementia. Little is known about the association of late-life body composition with dementia risk.

Methods: We determined this association among cognitively normal participants from the Cardiovascular Health Study- Cognition Study. Body composition was assessed by dual-energy x-ray absorptiometry in 1994-1995. Dementia was ascertained at annual follow-up from 1998-1999 to 2013. Associations of body composition with incident dementia were assessed by the Fine-Gray model.

Result: Among 344 participants (mean age 78, 62.2% women), body composition was significantly different between men and women, despite similar body mass indexes (BMIs). Increased dementia risk was significantly associated with lower lean mass in men and marginally with low appendicular lean mass in women.

Discussion: Decreased lean mass was an indicator of increased dementia risk in older adults. Studies should test whether preventing lean mass loss in older adults reduces dementia risk.
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http://dx.doi.org/10.1002/alz.12125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881417PMC
October 2020

Hippocampal sclerosis, TDP-43, and the duration of the symptoms of dementia of AD patients.

Ann Clin Transl Neurol 2020 09 31;7(9):1546-1556. Epub 2020 Jul 31.

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Objectives: To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR-DNA binding protein of 43kDA (TDP-43) in Alzheimer's disease (AD) patients.

Methods: The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA-Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37-95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP-43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE-4 allele, and presence of Lewy bodies (LB).

Results: HS was present in 18% (n = 64) and TDP-43 in 51.5% (n = 185) of the patients. HS and TDP-43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP-43. Age at onset was not associated with TDP-43 or HS. HS was associated with duration of symptoms and LB, TDP-43, and atherosclerosis in the CW. TDP-43 was associated with duration of symptoms, LB, and HS.

Interpretation: HS and TDP-43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP-43 are part of the later neuropathological changes in AD.
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http://dx.doi.org/10.1002/acn3.51135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480925PMC
September 2020

Orthostatic hypotension, dizziness, neurology outcomes, and death in older adults.

Neurology 2020 10 30;95(14):e1941-e1950. Epub 2020 Jul 30.

From the Department of Medicine (S.P.J., L.A.L., K.J.M.), Beth Israel Deaconess Medical Center, Boston, MA; Departments of Neurology and Epidemiology (W.T.L.), University of Washington, Seattle; Department of Neurology (O.L.L.) and Department of Epidemiology, Graduate School of Public Health (L.H.K.), University of Pittsburgh, PA; Department of Medicine (J.S.G.), University of Maryland, Baltimore; and Hinda and Arthur Marcus Institute for Aging Research (L.A.L.), Hebrew SeniorLife, Roslindale, MA.

Objective: To test the hypothesis that orthostatic hypotension (OH) might cause cerebral hypoperfusion and injury, we examined the longitudinal relationship between OH or orthostatic symptoms and incident neurologic outcomes in a community population of older adults.

Methods: Cardiovascular Health Study participants (≥65 years) without dementia or stroke had blood pressure (BP) measured after lying down for 20 minutes and after standing 3 for minutes. Participants reported dizziness immediately upon standing and any dizziness in the past 2 weeks. OH was defined as a drop in standing systolic/diastolic BP ≥20/≥10 mm Hg. We determined the association between OH or dizziness with (1) MRI brain findings (ventricular size, white matter hyperintensities, brain infarcts) using linear or logistic regression, (2) cognitive function (baseline and over time) using generalized estimating equations, and (3) prospective adjudicated events (dementia, stroke, death) using Cox models. Models were adjusted for demographic characteristics and OH risk factors. We used multiple imputation to account for missing OH or dizziness (n = 534).

Results: Prior to imputation, there were 5,007 participants (mean age 72.7 ± 5.5 years, 57.6% women, 10.9% Black, 16% with OH). OH was modestly associated with death (hazard ratio [HR] 1.11; 95% confidence interval 1.02-1.20), but not MRI findings, cognition, dementia, or stroke. In contrast, dizziness upon standing was associated with lower baseline cognition (β = -1.20; -1.94 to -0.47), incident dementia (HR 1.32; 1.04-1.62), incident stroke (HR 1.22; 1.06-1.41), and death (HR 1.13; 1.06-1.21). Similarly, dizziness over the past 2 weeks was associated with higher white matter grade (β = 0.16; 0.03-0.30), brain infarcts (OR 1.31; 1.06-1.63), lower baseline cognition (β = -1.18; -2.01 to -0.34), and death (HR 1.13; 1.04-1.22).

Conclusions: Dizziness was more consistently associated with neurologic outcomes than OH 3 minutes after standing. Delayed OH assessments may miss pathologic information related to cerebral injury.
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http://dx.doi.org/10.1212/WNL.0000000000010456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682840PMC
October 2020

A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study.

Alzheimers Dement 2020 10 27;16(10):1412-1425. Epub 2020 Jul 27.

Alzheimer's Research Group, Grifols, Barcelona, Spain.

Introduction: This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD).

Methods: Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham).

Results: PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales.

Discussion: This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.
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http://dx.doi.org/10.1002/alz.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984263PMC
October 2020

Predicting resistance to amyloid-beta deposition and cognitive resilience in the oldest-old.

Neurology 2020 08 22;95(8):e984-e994. Epub 2020 Jul 22.

From the Departments of Neurology (B.E.S., O.L.L., W.E.K.), Neurological Surgery (Y.C.), Medicine (D.L.T.), Radiology (B.J.L.), Psychiatry (A.D.C., H.J.A., W.E.K.), Human Genetics (M.I.K.), and Epidemiology (L.H.K.), University of Pittsburgh, PA; Department of Neurology (S.T.D.), University of Florida, Gainesville; and Department of Mental Health (M.C.C.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Objective: To explore long-term predictors of avoiding β-amyloid (Aβ) deposition and maintaining unimpaired cognition as outcomes in the oldest old.

Methods: In a longitudinal observational cohort study, 100 former participants of the Ginkgo Evaluation of Memory Study (GEMS; 2000-2008) completed biannual Pittsburgh compound B-PET imaging and annual clinical-cognitive evaluations beginning in 2010. Most recent Aβ status and cognitive status were selected for each participant. Longitudinal outcomes included change in serial Aβ and cognitive tests. Baseline predictors from GEMS included neuropsychological tests, daily functioning, genotype, lifestyle variables, occupational measures, health history, sleep, subjective memory, physical and cognitive activities, depressive symptoms, and physical performance and health indices, among others.

Results: Mean age at the last cognitive evaluation was 92.0 (range 86-100) years. Mean follow-up time from baseline to last measured Aβ status was 12.3 (SD 1.9) years and to last cognitive evaluation was 14.1 (SD 1.9) years. The allele predicted last Aβ status (n = 34 Aβ negative vs n = 66 Aβ positive). Baseline cognition predicted cognitive status (n = 30 unimpaired vs n = 70 impaired). Predictors of cognitive status among Aβ-positive participants only (n = 14 normal cognition vs n = 52 impaired) were baseline cognitive test scores and smoking history. Baseline pulse pressure predicted longitudinal Aβ increase; paid work engagement and life satisfaction predicted less cognitive decline.

Conclusions: The allele and lower pulse pressure predict resistance to Aβ deposition in advanced aging. Cognitive test scores 14 years prior, likely reflecting premorbid abilities, predict cognitive status and maintenance of unimpaired cognition in the presence of Aβ. Several lifestyle factors appear protective.
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http://dx.doi.org/10.1212/WNL.0000000000010239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668550PMC
August 2020

Dual sensory impairment in older adults and risk of dementia from the GEM Study.

Alzheimers Dement (Amst) 2020 7;12(1):e12054. Epub 2020 Jul 7.

Department of Epidemiology University of Washington Seattle Washington USA.

Introduction: Hearing and vision loss are independently associated with dementia, but the impact of dual sensory impairment (DSI) on dementia risk is not well understood.

Methods: Self-reported measures of hearing and vision were taken from 2051 participants at baseline from the Gingko Evaluation of Memory Study. Dementia status was ascertained using standardized criteria. Cox models were used to estimate risk of dementia associated with number of sensory impairments (none, one, or two).

Results: DSI was significantly associated with higher risk of all-cause dementia (hazard ratio [HR] = 1.86; 95% confidence interval [CI] = 1.25-2.76) and Alzheimer's disease (HR = 2.12; 95% CI = 1.34-3.36). Individually only visual impairment was independently associated with an increased risk of all-cause dementia (HR = 1.32; 95% CI = 1.02-1.71).

Discussion: Older adults with DSI are at a significantly increased risk for dementia. Further studies are needed to evaluate whether treatments can modify this risk.
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http://dx.doi.org/10.1002/dad2.12054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340796PMC
July 2020

Whole-Exome Sequencing Analysis of Alzheimer's Disease in Non-APOE*4 Carriers.

J Alzheimers Dis 2020 ;76(4):1553-1565

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

The genetics of late-onset Alzheimer's disease (AD) is complex due to the heterogeneous nature of the disorder. APOE*4 is the strongest genetic risk factor for AD. Genome-wide association studies have identified more than 30 additional loci, each having relatively small effect size. Known AD loci explain only about 30% of the genetic variance, and thus much of the genetic variance remains unexplained. To identify some of the missing heritability of AD, we analyzed whole-exome sequencing (WES) data focusing on non-APOE*4 carriers from two WES datasets: 720 cases and controls from the University of Pittsburgh and 7,252 cases and controls from the Alzheimer's Disease Sequencing Project. Following separate WES analyses in each dataset, we performed meta-analysis for overlapping markers present in both datasets. Among the four variants reaching the exome-wide significance threshold, three were from known AD loci: APOE/rs7412 (odds ratio (OR) = 0.40; p = 5.46E-24), TOMM40/rs157581 (OR = 1.49; p = 4.04E-07), and TREM2/rs75932628 (OR = 4.00; p = 1.15E-07). The fourth significant variant, rs199533, was from a novel locus on chromosome 17 in the NSF gene (OR = 0.78; p = 2.88E-07). NSF was also significant in the gene-based analysis (p = 1.20E-05). In the GTEx data, NSF/rs199533 is a cis-eQTL for multiple genes in the brain and blood, including NSF that is highly expressed across all brain tissues, including regions that typically show amyloid-β accumulation. Further characterization of genes that are affected by NSF/rs199533 may help to shed light on the roles of these genes in AD etiology.
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http://dx.doi.org/10.3233/JAD-200037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484092PMC
June 2021

Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia.

JAMA Netw Open 2020 07 1;3(7):e209250. Epub 2020 Jul 1.

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

Importance: The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk.

Objective: To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia.

Design, Setting, And Participants: This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019.

Exposures: Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ.

Main Outcomes And Measures: Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline.

Results: Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes.

Conclusions And Relevance: In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.9250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352155PMC
July 2020

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Neurology 2020 08 1;95(5):e519-e531. Epub 2020 Jul 1.

From the Department of Epidemiology (F.J.W., L.B.C., R.W., D. Blacker, D. Bos, J.G., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Departments of Epidemiology (F.J.W., D. Bos, S.K.L.D., M.A.I., M.K.I., A.H.), Radiology and Nuclear Medicine (D. Bos), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (L.B.C.), Massachusetts General Hospital, Boston; Department of Infectious Disease Epidemiology (R.A., F.d.W., C. Hadjichrysanthou, K.M.-M., M.M.W.), School of Public Health, Imperial College London, UK; Neuropsychiatry and Epidemiology and Clinical Research (C. Berr), INSERM, UMR 1061 Montpellier, Universite de Montpellier, France; Boston University School of Medicine (A.B., M.P.P., C.L.S., S.S.); Framingham Heart Study (A.B., M.P.P., C.L.S., S.S.), MA; Department of Biostatistics (A.B., K.L.D.-P.), Boston University School of Public Health, MA; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.) and Epidemiology and Health Services (B.M.P.), University of Washington, Seattle; Department of Psychiatry (D. Blacker), Massachusetts General Hospital, Charlestown; University of Cambridge (C. Brayne), UK; Bordeaux Population Health Research Center (J.-F.D., S.D., C.D., L.G., C. Helmer), INSERM, UMR 1219, University of Bordeaux; Department of Neurology (S.D.), Memory Clinic, Bordeaux University Hospital, France; McGovern Medical School (M.F.), University of Texas Health Science Center at Houston; Icelandic Heart Association (V.G.), Kopavogur; Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Institute of Neuroscience and Physiology (E.J., S.K., I.S., H.W., A.Z.), Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Epidemiology, Graduate School of Public Health (L.H.K.), and Departments of Neurology and Psychiatry (O.L.L.), University of Pittsburgh, PA; Laboratory of Epidemiology and Population Sciences (L.L., O.M.), National Institute on Aging, Bethesda, MD; Institute of Health and Society (F.E.M., B.C.M.S.), Newcastle University, Newcastle upon Tyne, UK; MIND Center (T.H.M.), University of Mississippi Medical Center, Jackson; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).

Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
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http://dx.doi.org/10.1212/WNL.0000000000010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455342PMC
August 2020

Influence of apolipoprotein-E genotype on brain amyloid load and longitudinal trajectories.

Neurobiol Aging 2020 10 31;94:111-120. Epub 2020 May 31.

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

To characterize the influence of apolipoprotein-E (APOE) genotype on cerebral Aβ load and longitudinal Aβ trajectories, [C]Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants with known APOE genotype. Serial [C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies Alzheimer's disease risk through a direct influence on amyloidogenic processes, which manifests as an earlier age of onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483397PMC
October 2020

Cerebral Blood Flow Is Associated with Diagnostic Class and Cognitive Decline in Alzheimer's Disease.

J Alzheimers Dis 2020 ;76(3):1103-1120

Department of Computer Science, State University of New York at Binghamton, Binghamton, NY, USA.

Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer's disease (AD).

Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort.

Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study Cognition Study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors.

Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBF in the bilateral posterior and middle cingulate and parietal (p < 0.001), bilateral superior medial frontal (p < 0.001), bilateral temporoparietal (p < 0.02), and right hippocampus (p = 0.02) regions.

Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as a staging biomarker of cognitive status.
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http://dx.doi.org/10.3233/JAD-200034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970411PMC
June 2021

A randomized controlled trial of amyloid positron emission tomography results disclosure in mild cognitive impairment.

Alzheimers Dement 2020 09 26;16(9):1330-1337. Epub 2020 Jun 26.

Alzheimer's Disease Research Center, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: Recent studies suggest that Alzheimer's disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers.

Methods: Randomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow-up.

Results: Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms.

Discussion: These findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.
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http://dx.doi.org/10.1002/alz.12129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541680PMC
September 2020

Brachial Flow-mediated Dilation and Risk of Dementia: The Cardiovascular Health Study.

Alzheimer Dis Assoc Disord 2020 Jul-Sep;34(3):272-274

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.

Introduction: Brachial flow-mediated dilation (FMD) is a physiologic measure of endothelial function. We determined the prospective association of brachial FMD with incident dementia among older adults.

Methods: We included 2777 Cardiovascular Health Study participants who underwent brachial FMD measurement. Incident dementia was ascertained by medication use, International Classification of Diseases-9 codes, requirement for a proxy, and death certificates and calibrated to gold-standard assessments performed in a subset of the cohort.

Results: Mean participant age at time of brachial FMD measurement was 77.9 years. We identified 1650 incident dementia cases (median follow-up=10.5 y). After adjusting for age, race, sex, education, clinic site, and baseline arterial diameter, risk of dementia for participants in the highest quartile of percent brachial FMD did not differ from those in lowest quartile (hazard ratio=0.89, 95% confidence interval: 0.77, 1.03).

Conclusions: Brachial FMD, measured late in life, is not associated with an increased risk of incident dementia.
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http://dx.doi.org/10.1097/WAD.0000000000000394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483388PMC
June 2020