| 1. |
- Hibar, Derrek P., et al.
(author)
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Novel genetic loci associated with hippocampal volume
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 2. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 3. |
- Kivipelto, Miia, et al.
(author)
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World-Wide FINGERS Network : A global approach to risk reduction and prevention of dementia
- 2020
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:7, s. 1078-1094
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Journal article (peer-reviewed)abstract
- Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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| 4. |
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| 5. |
- van Waalwijk van Doorn, Linda J C, et al.
(author)
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Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes
- 2017
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 56:2, s. 543-555
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r=-0.28; p<0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r=-0.15; p-tau: r=-0.13; both p<0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.
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| 6. |
- Bos, Isabelle, et al.
(author)
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Cerebrovascular and amyloid pathology in predementia stages : the relationship with neurodegeneration and cognitive decline
- 2017
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In: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 9:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia.METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics.RESULTS: MTA and t-tau were elevated in the Aβ - WMH+, Aβ + WMH-, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline.CONCLUSIONS: In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.
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| 7. |
- Bos, Isabelle, et al.
(author)
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Correction to : Cerebrovascular and amyloid pathology in predementia stages
- 2018
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In: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 10:56
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Journal article (peer-reviewed)abstract
- Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.
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| 8. |
- Escott-Price, Valentina, et al.
(author)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 9. |
- Eskelinen, Marjo H, et al.
(author)
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Midlife healthy-diet index and late-life dementia and Alzheimer's disease
- 2011
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In: Dementia and Geriatric Cognitive Disorders Extra. - Basel : S. Karger. - 1664-5464. ; 1:1, s. 103-112
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Journal article (peer-reviewed)abstract
- AIM: To study long-term effects of dietary patterns on dementia and Alzheimer's disease (AD). METHODS: Of 525 subjects randomly selected from population-based cohorts surveyed at midlife, a total of 385 (73%) subjects were re-examined 14 years later in the CAIDE study. A healthy-diet index (range 0-17) was constructed including both healthy and unhealthy dietary components. RESULTS: Persons with a healthy diet (healthy-diet index >8 points) had a decreased risk of dementia (OR 0.12, 95% CI 0.02-0.85) and AD (OR 0.08, 95% CI 0.01-0.89) compared with persons with an unhealthy diet (0-8 points), adjusting for several possible confounders. CONCLUSIONS: Healthy diet at midlife is associated with a decreased risk of dementia/AD in late life. These findings highlight the importance of dietary patterns and may make more effective measures for dementia/AD prevention or postponement possible.
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| 10. |
- Handels, Ron L. H., et al.
(author)
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Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers
- 2017
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In: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 13:8, s. 903-912
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Journal article (peer-reviewed)abstract
- INTRODUCTION: We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia.METHODS: The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers.RESULTS: Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up.DISCUSSION: An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care.
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