Publications by authors named "Lars Bertram"

189 Publications

CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals.

Proteomes 2021 Aug 2;9(3). Epub 2021 Aug 2.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, 1007 MB Amsterdam, The Netherlands.

We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p-tau and amyloid β 1-42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p-tau increased (β = 2.6 pg/mL per year, = 0.01) and Aβ42 decreased over time (β = -4.4 pg/mL per year, = 0.03), in the innate immune activation subtype p-tau increased (β = 3.1 pg/mL per year, = 0.01) while in the blood-brain barrier dysfunction subtype Aβ42 decreased (β = -3.7 pg/mL per year, = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
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http://dx.doi.org/10.3390/proteomes9030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396164PMC
August 2021

Increased Menopausal Age Reduces the Risk of Parkinson's Disease: A Mendelian Randomization Approach.

Mov Disord 2021 Aug 23. Epub 2021 Aug 23.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Background: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur.

Objective: We used MR to assess the association between age at menopause and age at menarche with PD risk.

Methods: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics.

Results: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29).

Conclusions: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28760DOI Listing
August 2021

Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies.

Front Aging Neurosci 2021 21;13:712545. Epub 2021 Jul 21.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. : To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. : An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. : The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.
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http://dx.doi.org/10.3389/fnagi.2021.712545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335587PMC
July 2021

Cohort profile: follow-up of a Berlin Aging Study II (BASE-II) subsample as part of the GendAge study.

BMJ Open 2021 06 23;11(6):e045576. Epub 2021 Jun 23.

Department of Psychology, Humboldt University of Berlin, Berlin, Berlin, Germany.

Purpose: The study 'Sex- and gender-sensitive prevention of cardiovascular and metabolic disease in older adults in Germany', the GendAge study, focuses on major risk factors for cardiovascular and metabolic diseases and on the development of major outcomes from intermediate phenotypes in the context of sex and gender differences. It is based on a follow-up examination of a subsample (older group) of the Berlin Aging Study II (BASE-II).

Participants: The GendAge study assessments took place between 22 June 2018 and 10 March 2020. A total of 1100 participants (older BASE-II subsample, aged ≥65 years) with baseline data assessed at least by one of the BASE-II partner sites were investigated in the follow-up. These participants had a mean age of 75.6 years (SD ±3.8), with a mean follow-up at 7.4 years (SD ±1.5).

Findings To Date: Data from different domains such as internal medicine, geriatrics, immunology and psychology were collected, with a focus on cardiometabolic diseases and in the context of sex and gender differences. Diabetes mellitus type 2 was reported by 15.6% and 8.6% of men and women, respectively. In contrast, this disease was diagnosed in 20.7% of men and 13.3% of women, indicating that a substantial proportion of almost 30% was unaware of the disease. Echocardiography revealed that left ventricular ejection fraction was higher in women than in men, in agreement with previous reports.

Future Plans: A gender questionnaire assessing sociocultural aspects implemented as part of the follow-up described here will allow to calculate a gender score and its evaluation based on the newly collected data. At the same time, the other BASE-II research foci established over the past 10 years will be continued and strengthened by the BASE-II transition into a longitudinal study with follow-up data on the older subsample.

Trial Registration Number: DRKS00016157.
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http://dx.doi.org/10.1136/bmjopen-2020-045576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230995PMC
June 2021

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

Alzheimers Dement 2021 May 14. Epub 2021 May 14.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.

Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.

Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.

Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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http://dx.doi.org/10.1002/alz.12330DOI Listing
May 2021

Self-Reported Sleep Relates to Microstructural Hippocampal Decline in β-Amyloid Positive Adults Beyond Genetic Risk.

Sleep 2021 Apr 27. Epub 2021 Apr 27.

Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, 0317 Oslo, Norway.

Study Objectives: A critical role linking sleep with memory decay and β-amyloid (Aβ) accumulation, two markers of Alzheimer's disease (AD) pathology, may be played by hippocampal integrity. We tested the hypotheses that worse self-reported sleep relates to decline in memory and intra-hippocampal microstructure, including in the presence of Aβ.

Methods: Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index once, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in intra-hippocampal microstructure as indexed by increased mean diffusivity. We measured memory decay at each imaging session using verbal delayed recall. One session of positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled control for APOE ε4 status, and polygenic scores for sleep and AD, respectively.

Results: Worse global sleep quality and sleep efficiency related to more rapid reduction of hippocampal microstructure over time. Focusing on efficiency (the percentage of time in bed at night spent asleep), the relation was stronger in presence of Aβ accumulation, and hippocampal integrity decline mediated the relation with memory decay. The results were not explained by genetic risk for sleep efficiency or AD.

Conclusions: Worse sleep efficiency related to decline in hippocampal microstructure, especially in the presence of Aβ accumulation, and Aβ might link poor sleep and memory decay. As genetic risk did not account for the associations, poor sleep efficiency might constitute a risk marker for AD, although the driving causal mechanisms remain unknown.
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http://dx.doi.org/10.1093/sleep/zsab110DOI Listing
April 2021

Educational attainment does not influence brain aging.

Proc Natl Acad Sci U S A 2021 May;118(18)

Center for Lifespan Changes in Brain and Cognition, University of Oslo, 0317 Oslo, Norway;

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.
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http://dx.doi.org/10.1073/pnas.2101644118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106299PMC
May 2021

Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development.

Alzheimers Dement 2021 Apr 2. Epub 2021 Apr 2.

Genetics and Aging Research Unit and The Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Introduction: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk.

Methods: We performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals.

Results: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2.

Discussion: Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome.
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http://dx.doi.org/10.1002/alz.12319DOI Listing
April 2021

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 Mar 31. Epub 2021 Mar 31.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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http://dx.doi.org/10.1002/alz.12322DOI Listing
March 2021

BDNF serum concentrations in 2053 participants of the Berlin Aging Study II.

Neurobiol Aging 2021 05 2;101:221-223. Epub 2021 Feb 2.

Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Berlin, Germany.

Serum BDNF concentrations in 2053 participants of the Berlin Aging Study II (BASE-II; 1572 individuals from the older age group [60-85 years], 481 individuals from the younger-age reference group [22-37 years]) were studied. There was no effect of age, sex, body mass index, self-reported depression, or BDNF Val66Met variant on serum BDNF concentrations. Multiple linear regression analysis failed to detect significant relationships of Digit Symbol Substitution Test score and Consortium to Establish a Registry for Alzheimer's Disease memory score to BDNF levels. However, we detected a positive correlation between platelet counts and BDNF levels (r = 0.303, p < 0.001). Our findings do not support an effect of aging, self-reported depression, or the Val66Met variant on serum BDNF concentrations. The role of thrombocytes in the biology of serum BDNF merits further study.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.020DOI Listing
May 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.

Brain 2020 12;143(12):3776-3792

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands.

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
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http://dx.doi.org/10.1093/brain/awaa325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805814PMC
December 2020

Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.

Transl Psychiatry 2020 11 22;10(1):403. Epub 2020 Nov 22.

Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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http://dx.doi.org/10.1038/s41398-020-01074-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680793PMC
November 2020

Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development.

medRxiv 2020 Nov 4. Epub 2020 Nov 4.

Introduction: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permit genome-wide analyses to identify rare variants contributing to AD risk.

Methods: We performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency ≤1%) in a family-based WGS-based association study of 2,247 subjects from 605 multiplex AD families, followed by replication in 1,669 unrelated individuals.

Results: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, CLSTN2.

Discussion: Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity. These loci have not been previously associated with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of coding regions.
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http://dx.doi.org/10.1101/2020.11.03.20225540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654884PMC
November 2020

Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
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http://dx.doi.org/10.1101/2020.10.29.20211920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654872PMC
November 2020

Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan.

Neurol Genet 2020 Oct 8;6(5):e506. Epub 2020 Sep 8.

Center for Lifespan Changes in Brain and Cognition (K.B.W., A.M.F., Ø.S., A.M.M., C.S.R., A.-V.I., L.B., Y.W.), Department of Psychology, University of Oslo; Division of Radiology and Nuclear Medicine (K.B.W., A.M.F.), Oslo University Hospital, Rikshospitalet; Oslo Delirium Research Group (A.-V.I., L.O.W.), Department of Geriatric Medicine, and Institute of Basic Medical Sciences (A.-V.I., L.O.W.), University of Oslo, Norway; Institute of Clinical Molecular Biology (A.F.), Christian-Albrechts-University of Kiel; and Lübeck Interdisciplinary Platform for Genome Analytics (V.D., F.K., L.B.), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.

Methods: Using general additive mixed models, we assessed the relations of PGS for AD, including variants in with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4-95 years, mean visit age 39.7 years, SD 26.9 years), followed for up to 11 years.

Results: AD-PGS and ε4 in isolation showed a significant negative effect on hippocampal volume. The effect of a 1 sample SD increase in AD-PGS on hippocampal volume was estimated to -36.4 mm (confidence interval [CI]: -71.8, -1.04) and the effect of carrying ε4 allele(s) -107.0 mm (CI: -182.0, -31.5). Offset effects of AD-PGS and ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed.

Conclusions: Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in cognitively healthy persons, not being confined to clinical populations or older age. This emphasizes that a broader population and age range may be relevant targets for attempts to prevent AD.
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http://dx.doi.org/10.1212/NXG.0000000000000506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577559PMC
October 2020

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.

J Alzheimers Dis 2020 ;77(3):1353-1368

University of Geneva, Geneva, Switzerland.

Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

Results: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

Conclusions: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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http://dx.doi.org/10.3233/JAD-200208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683080PMC
September 2021

Genetic risk scores and hallucinations in patients with Parkinson disease.

Neurol Genet 2020 Oct 20;6(5):e492. Epub 2020 Jul 20.

Department of Epidemiology (C.D.J.K., K.C.P., A.D.F., B.R.R.), UCLA Fielding School of Public Health, Los Angeles, CA, USA; Department of Human Genetics (C.D.J.K., J.S.S.), David Geffen School of Medicine, Los Angeles, CA; Department of Neurology (A.M.K., J.M.B., B.R.R.), David Geffen School of Medicine, Los Angeles, CA; Parkinson's Disease Research (A.M.K.), Education, and Clinical Center, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA; Brain Research Institute (J.M.B.), University of California, Los Angeles, CA; Lübeck Interdisciplinary Platform for Genome Analytics (V.D., L.B.), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany; Department of Neurology (O.-B.T.), Haukeland University Hospital, Bergen, Norway and University of Bergen, Bergen, Norway; Department of Clinical Medicine (O.-B.T.), University of Bergen, Bergen, Norway; Department of Psychology (L.B.), Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway; The Norwegian Center for Movement Disorders (G.A., J.M.-G.), Stavanger University Hospital, Stavanger, Norway; Department of Neurology (G.A.), Stavanger University Hospital, Stavanger, Norway; Department of Chemistry (G.A., J.M.-G.), Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway; Department of Biostatistics (J.S.S.), UCLA Fielding School of Public Health, Los Angeles, CA; Department of Computational Medicine (J.S.S.), David Geffen School of Medicine, Los Angeles, CA; Section for Translational Surgical Oncology and Biobanking (C.M.L.), Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck; Ageing Epidemiology Research Unit (C.M.L.), School of Public Health, Imperial College, London, United Kingdom; and Department of Environmental Health (B.R.R.), UCLA Fielding School of Public Health, Los Angeles, CA.

Objective: We examine the hypothesized overlap of genetic architecture for Alzheimer disease (AD), schizophrenia (SZ), and Parkinson disease (PD) through the use of polygenic risk scores (PRSs) with the occurrence of hallucinations in PD.

Methods: We used 2 population-based studies (ParkWest, Norway, and Parkinson's Environment and Gene, USA) providing us with 399 patients with PD with European ancestry and a PD diagnosis after age 55 years to assess the associations between 4 PRSs and hallucinations after 5 years of mean disease duration. Based on the existing genome-wide association study of other large consortia, 4 PRSs were created: one each using AD, SZ, and PD cohorts and another PRS for height, which served as a negative control.

Results: A higher prevalence of hallucinations was observed with each SD increase of the AD-PRS (odds ratio [OR]: 1.37, 95% confidence interval [CI]: 1.03-1.83). This effect was mainly driven by (OR: 1.92, 95% CI: 1.14-3.22). In addition, a suggestive decrease and increase, respectively, in hallucination prevalence were observed with the SZ-PRS and the PD-PRS (OR: 0.77, 95% CI: 0.59-1.01; and OR: 1.29, 95% CI: 0.95-1.76, respectively). No association was observed with the height PRS.

Conclusions: These results suggest that mechanisms for hallucinations in PD may in part be driven by the same genetic architecture that leads to cognitive decline in AD, especially by .
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http://dx.doi.org/10.1212/NXG.0000000000000492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413629PMC
October 2020

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia.

Clin Genet 2020 11 2;98(5):457-467. Epub 2020 Sep 2.

Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.
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http://dx.doi.org/10.1111/cge.13826DOI Listing
November 2020

Genomic mechanisms in Alzheimer's disease.

Brain Pathol 2020 09;30(5):966-977

McCance Center for Brain Health and Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.

Alzheimer's disease (AD) is the most common neurodegenerative disease and, owing to its increasing prevalence, represents one of the leading public health problems in aging populations. The molecular causes underlying the onset and progression of AD are manifold and hitherto still incompletely understood. Research over nearly four decades has clearly delineated genetics to play a crucial role in AD susceptibility, likely in concert with non-genetic factors. The field has gained considerable momentum and novel insights over the past 10 years owing to the advent and application of high-throughput genomics technologies in datasets of increasing size. In this contribution to the Mini-Symposium on the Molecular Etiology of Alzheimer's Disease, we review the current status of genomics research in AD. To this end, we scrutinize and discuss the main findings from the two largest and most current genome-wide association studies (GWAS) in the field, that is, the papers published by Jansen et al (Nat Genet 51:404-413) and Kunkle et al (Nat Genet 51:414-430). Particular focus is laid on genomics findings overlapping across both studies and on the novel insights they provide in terms of improving our understanding of the "genomic mechanisms" underlying this devastating disease.
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http://dx.doi.org/10.1111/bpa.12882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018017PMC
September 2020

Relationship between Lipoprotein (a) and cognitive function - Results from the Berlin Aging Study II.

Sci Rep 2020 06 30;10(1):10636. Epub 2020 Jun 30.

Max Planck Institute for Human Development, Berlin, Germany.

It has been suggested that an age-related loss of cognitive function might be driven by atherosclerotic effects associated with altered lipid patterns. However, the relationship between Lipoprotein (a) [Lp(a)] and healthy cognitive aging has not yet been sufficiently investigated. For the current analysis we used the cross-sectional data of 1,380 Berlin Aging Study II (BASE-II) participants aged 60 years and older (52.2% women, mean age 68 ± 4 years). We employed the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-Plus test battery to establish latent factors representing continuous measures of domain specific cognitive functions. Regression models adjusted for APOE genotypes, lipid parameters and other risk factors for cognitive impairment were applied to assess the association between Lp(a) and performance in specific cognitive domains. Men within the lowest Lp(a)-quintile showed better cognitive performance in the cognitive domain executive functions and processing speed (p = 0.027). No significant results were observed in women. The results of the current analysis of predominantly healthy BASE-II participants point towards an association between low Lp(a) concentrations and better cognitive performance. However, evidence for this relationship resulting from the current analysis and the employment of a differentiated cognitive assessment is rather weak.
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http://dx.doi.org/10.1038/s41598-020-66783-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326928PMC
June 2020

APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease.

Alzheimers Res Ther 2020 05 27;12(1):65. Epub 2020 May 27.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Background: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ε4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ε4 genotype.

Methods: We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ε4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ε4 allele (average age 75 ± 6 years).

Results: One hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ε4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ε4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility.

Conclusions: These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.
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http://dx.doi.org/10.1186/s13195-020-00628-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254647PMC
May 2020

Identification of Novel Alzheimer's Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data.

Sci Rep 2020 03 19;10(1):5029. Epub 2020 Mar 19.

Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer's Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (P = 1.83 × 10), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.
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http://dx.doi.org/10.1038/s41598-020-61883-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081222PMC
March 2020

Self-reported Sleep Problems Related to Amyloid Deposition in Cortical Regions with High HOMER1 Gene Expression.

Cereb Cortex 2020 04;30(4):2144-2156

Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo 0317, Norway.

Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker β-amyloid (Aβ). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aβ accumulation. Here, we tested whether the relationship between cortical Aβ accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, Aβ correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-Aβ relationship followed closely the Aβ accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and Aβ accumulation may involve Homer1 activity in the cortical regions, where harbor Aβ deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.
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http://dx.doi.org/10.1093/cercor/bhz228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174994PMC
April 2020

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort.

J Alzheimers Dis 2020 ;74(1):213-225

Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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http://dx.doi.org/10.3233/JAD-190434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175945PMC
May 2021

A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort.

Alzheimers Dement (N Y) 2019 18;5:933-938. Epub 2019 Dec 18.

Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Introduction: Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers.

Methods: This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).

Results: On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.

Discussion: This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.trci.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928349PMC
December 2019

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants.

Alzheimers Dement (N Y) 2019 20;5:814-824. Epub 2019 Nov 20.

Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, UK.

Introduction: The role of 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).

Methods: We dissected genetic profiles within the region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls.

Results: -L/-ε4 alleles were associated with DLB (OR  = 3.61; value = 3.23 × 10; OR  = 3.75; value = 4.90 × 10) and earlier age at onset of DLB (HR  = 1.33, value = .031; HR  = 1.46, value = .004), but not with PDD. The -L/-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR  = 4.40, value = 1.15 × 10; OR  = 5.65, value = 2.97 × 10) but was not significant in DLB without AD. Meta-analyses combining all -ε4 data in DLB confirmed our findings (OR = 2.93, value = 3.78 × 10; OR = 5.36, value = 1.56 × 10).

Discussion: -ε4/ -L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.
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http://dx.doi.org/10.1016/j.trci.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880091PMC
November 2019

Alzheimer's disease risk SNPs show no strong effect on miRNA expression in human lymphoblastoid cell lines.

Neurobiol Aging 2020 02 20;86:202.e1-202.e3. Epub 2019 Aug 20.

Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany; Department of Psychology, Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway. Electronic address:

The role of microRNAs (miRNAs) in the pathogenesis of Alzheimer's disease (AD) is currently extensively investigated. In this study, we assessed the potential impact of AD genetic risk variants on miRNA expression by performing large-scale bioinformatic data integration. Our analysis was based on genetic variants from 3 AD genome-wide association studies (GWASs). Association with miRNA expression was tested by expression quantitative trait locus analysis using next-generation miRNA sequencing data generated in lymphoblastoid cell lines. Although, overall, we did not identify a strong effect of AD GWAS variants on miRNA expression in this cell type, we highlight 2 notable outliers, that is, miR-29c-5p and miR-6840-5p. MiR-29c-5p was recently reported to be involved in the regulation of BACE1 and SORL1 expression. In conclusion, despite 2 exceptions, our large-scale assessment provides only limited support for the hypothesis that AD GWAS variants act as miRNA expression quantitative trait loci.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.013DOI Listing
February 2020

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Differential expression of microRNAs in Alzheimer's disease brain, blood, and cerebrospinal fluid.

Alzheimers Dement 2019 11 5;15(11):1468-1477. Epub 2019 Sep 5.

Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany; Department of Psychology, University of Oslo, Oslo, Norway. Electronic address:

Introduction: Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive.

Methods: A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty.

Results: Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles.

Discussion: Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4952DOI Listing
November 2019
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