| 1. |
- Cedres, Nira, et al.
(författare)
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Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals
- 2022
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 99:15, s. e1619-e1629
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals.Methods The contribution of amyloid and tau pathology was assessed through CSF levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest.Results We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = −1.55; p = 0.123).Discussion In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
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| 2. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 3. |
- Fuller, Franklin D, et al.
(författare)
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Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers
- 2017
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Ingår i: Nature Methods. - : Macmillan Publishers Ltd.. - 1548-7091 .- 1548-7105. ; 14, s. 443-449
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Tidskriftsartikel (refereegranskat)abstract
- X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly affects the data quality. We present here a robust way of delivering controlled sample amounts on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.
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| 4. |
- Le Guen, Yann, et al.
(författare)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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| 5. |
- Marseglia, Anna, et al.
(författare)
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Metabolic Syndrome Is Associated With Poor Cognition : A Population-Based Study of 70-Year-Old Adults Without Dementia
- 2021
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 76:12, s. 2275-2283
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Tidskriftsartikel (refereegranskat)abstract
- Background: Individual conditions of metabolic syndrome (MetS) have been related to dementia; however, their combined impact on the preclinical stage is unknown. We investigated the associations between MetS and domain-specific cognitive function as well as the role of sociodemographic, cardiovascular, and genetic factors.Methods: Within the Gothenburg H70 Birth Cohort Study-Birth cohort 1944, 1131 dementia-free participants (aged 70 years) were examined during 2014-2016. MetS (central obesity plus at least 2 factors [reduced HD11.-cholesterol, elevated triglycerides, blood pressure, or blood glucose]) was identified according to the International Diabetes Federation criteria. Five cognitive domains (memory, attention/perceptual speed, executive function, verbal fluency, visuospatial abilities) were generated after z-standardizing raw scores from 10 neuropsychological tests. Education, heart disease, claudication (indicating peripheral atherosclerosis), and apolipoprotein genotype were ascertained by trained staff. Data were analyzed with linear regression models.Results: Overall, 618 participants (55%) had MetS. In multiadjusted linear regressions, MetS was related to poorer performance in attention/ perceptual speed (beta -0.14 [95% CI -0.25, -0.02]), executive function (beta -0.12 [95% CI -0.23, -0.01]), and verbal fluency (beta -0.19 [95% CI -0.30, -0.08]). These associations were present only among individuals who did not carry any APOE-epsilon 4 allele or were highly educated. However, among those with MetS, high education was related to better cognitive performance. MetS together with comorbid heart disease or claudication was associated with even worse cognitive performance than each alone.Conclusions: MetS is associated with poor attention/perceptual speed, executive function, and verbal fluency performance. Education, apolipoprotein E-epsilon 4 allele, and comorbid cardiovascular disease influenced the observed associations.
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| 6. |
- Wetterberg, Hanna, et al.
(författare)
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Decreasing Incidence and Prevalence of Dementia Among Octogenarians: A Population-Based Study on 3 Cohorts Born 30 Years Apart
- 2023
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Ingår i: Journals of Gerontology Series a-Biological Sciences and Medical Sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 78:6, s. 1069-1077
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Tidskriftsartikel (refereegranskat)abstract
- Background Recent studies suggest a decline in the age-specific incidence and prevalence of dementia. However, results are mixed regarding trends among octogenarians. We investigated time trends in the prevalence and incidence of dementia in 3 population-based cohorts of 85-90-year olds. We also examined if there were different time trends for men and women. Methods We examined population-based birth cohorts within the Gothenburg H70 Birth Cohort Studies born 1901-02, 1923-24, and 1930, at ages 85 (N = 1481) and 88 (N = 840) years. The first 2 cohorts were also examined at age 90 (N = 450). The incidence was examined in 1 109 individuals free from dementia at baseline using information from the examination at age 88 or register data. All 3 cohorts were examined with identical methods. Results The prevalence of dementia decreased from 29.8% in 1986-87 to 21.5% in 2008-10 and 24.5% in 2015-16 among 85-year olds, and from 41.9% in 1989-90 to 28.0% in 2011-12 to 21.7% in 2018-19 among 88-year olds, and from 41.5% in 1991-92 to 37.2% in 2013-14 among 90-year olds. The decline was most accentuated among women. The incidence of dementia per 1 000 risk-years from ages 85 to 89 declined from 48.8 among those born 1901-02 to 37.9 in those born 1923-24 to 22.5 among those born 1930. Conclusions The prevalence and incidence of dementia decreased substantially over 3 decades among octogenarians. This might slow down the projected increase in cases of dementia expected by the increasing number of octogenarians during the following decades.
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| 7. |
- Zapater-Fajari, Mariola, et al.
(författare)
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Biomarkers of Alzheimer's Disease and Cerebrovascular Disease in Relation to Depressive Symptomatology in Individuals With Subjective Cognitive Decline
- 2024
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press. - 1079-5006 .- 1758-535X. ; 79:2
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Tidskriftsartikel (refereegranskat)abstract
- Background Subjective cognitive decline (SCD) has gained recent interest as a potential harbinger of neurodegenerative diseases such as Alzheimer's disease (AD) and cerebrovascular disease (CVD). In addition, SCD can be related to depressive symptomatology. However, the association between AD and CVD biomarkers, depressive symptomatology, and SCD is still unclear. We investigated the association of AD and CVD biomarkers and depressive symptomatology with SCD in individuals with subjective memory complaints (SCD-memory group) and individuals with subjective concentration complaints (SCD-concentration group). Methods We recruited a population-based cohort of 217 individuals (all aged 70 years, 53% female participants, 119 SCD-memory individuals, 23 SCD-concentration individuals, and 89 controls). AD and CVD were assessed through cerebrospinal fluid levels of the A beta 42/40 ratio and phosphorylated tau, and white matter signal abnormalities on magnetic resonance imaging, respectively. Associations between biomarkers, depressive symptomatology, and SCD were tested via logistic regression and correlation analyses. Results We found a significant association between depressive symptomatology with SCD-memory and SCD-concentration. Depressive symptomatology was not associated with AD and CVD biomarkers. Both the phosphorylated tau biomarker and depressive symptomatology predicted SCD-memory, and the A beta 42/40 ratio and depressive symptomatology predicted SCD-concentration. Conclusions The role of depressive symptomatology in SCD may differ depending on the stage within the spectrum of preclinical AD (as determined by amyloid-beta and tau positivity), and does not seem to reflect AD pathology. Our findings contribute to the emerging field of subclinical depressive symptomatology in SCD and clarify the association of different types of subjective complaints with distinct syndromic and biomarker profiles.
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| 8. |
- Zettergren, Anna, 1978, et al.
(författare)
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Passive and active suicidal ideation in a population-based sample of older adults: Associations with polygenic risk scores of relevance for suicidal behavior
- 2023
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Ingår i: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThere are few studies investigating genetic factors related to suicidal ideation or behavior in older adult populations. Our aim was to test associations between passive and active suicidal ideation and polygenic risk scores (PRSs) for suicidality and other traits of relevance for suicidality in old age (i.e. depression, neuroticism, loneliness, Alzheimer's disease, cognitive performance, educational attainment, and several specified vascular diseases) in a population-based sample aged 70 years and older. MethodsParticipants in the prospective H70 study in Gothenburg, Sweden, took part in a psychiatric examination that included the Paykel questions on active and passive suicidal ideation. Genotyping was performed with the Neurochip (Illumina). After quality control of the genetic data the sample included 3467 participants. PRSs for suicidality and other related traits were calculated based on summary statistics from recent GWASs of relevance. Exclusion of persons with dementia or incomplete data on suicidal ideation yielded 3019 participants, age range 70-101 years. Associations between past year suicidal ideation (any level) and selected PRSs were analysed using general estimation equation (GEE) models, adjusted for sex and age. ResultsWe observed associations between passive/active suicidal ideation and PRSs for depression (three versions), neuroticism, and general cognitive performance. After excluding individuals with current major depressive disorder (MDD), similar associations were seen with PRS for neuroticism, general cognitive performance and two PRSs for depression. No associations were found between suicidal ideation and PRSs for suicidality, loneliness, Alzheimer's disease, educational attainment, or vascular disease. DiscussionOur results could indicate which types of genetic susceptibility that are of importance for suicidality in old age, and these findings can help to shed light on potential mechanisms that may be involved in passive and active suicidal ideation in late-life, also in those with no current MDD. However, due to the limited sample size, the results need to be interpreted with caution until replicated in larger samples.
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