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1.	Bocchetta, Martina, et al. (author) The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey. 2015 In: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 11:2, s. 195-206 Journal article (peer-reviewed)abstract We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
2.	Escott-Price, Valentina, et al. (author) Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 2014 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661- 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.
3.	Ferreira, Daniel, et al. (author) The interactive effect of demographic and clinical factors on hippocampal volume : A multicohort study on 1958 cognitively normal individuals 2017 In: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 27:6, s. 653-667 Journal article (peer-reviewed)abstract Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.
4.	Hibar, Derrek P., et al. (author) Novel genetic loci associated with hippocampal volume 2017 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8 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.
5.	Jekel, Katrin, et al. (author) Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review. 2015 In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 7:1 Research review (peer-reviewed)abstract Introduction: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. Methods: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. Results: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls. Conclusion: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.
6.	Jones, Lesley, et al. (author) Convergent genetic and expression data implicate immunity in Alzheimer's disease 2015 In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671 Journal article (peer-reviewed)abstract Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
7.	Kaufmann, Tobias, et al. (author) Common brain disorders are associated with heritable patterns of apparent aging of the brain 2019 In: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617- Journal article (peer-reviewed)abstract Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
8.	Khan, Wasim, et al. (author) A Multi-Cohort Study of ApoE epsilon 4 and Amyloid-beta Effects on the Hippocampus in Alzheimer's Disease 2017 In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 56:3, s. 1159-1174 Journal article (peer-reviewed)abstract The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer's disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-beta (A beta) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compare hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in epsilon 4 carriers with positron emission tomography (PET) A beta who were dichotomized (A beta+/A beta-) using previous cut-offs. We found a linear reduction in hippocampal volumes with epsilon 4 carriers possessing the smallest volumes, epsilon 3 carriers possessing intermediate volumes, and epsilon 2 carriers possessing the largest volumes. Moreover, AD and MCI epsilon 4 carriers possessed the smallest hippocampal volumes and control epsilon 2 carriers possessed the largest hippocampal volumes. Subjects with both APOE epsilon 4 and A beta positivity had the lowest hippocampal volumes when compared to A beta-epsilon 4 carriers, suggesting a synergistic relationship between APOE epsilon 4 and A beta. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE epsilon 4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.
9.	Le Guen, Yann, et al. (author) Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB104 subtypes. 2023 In:* 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 Journal article (peer-reviewed)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-DRB104 subtypes best accounted for the association, strongest with HLA-DRB104:04 and HLA-DRB104:07, and intermediary with HLA-DRB104:01 and HLA-DRB104:03. 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-DRB104 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.
10.	Luo, Jiao, et al. (author) Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease 2023 In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5 Journal article (peer-reviewed)abstract IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
11.	Mangialasche, Francesca, et al. (author) High plasma levels of vitamin E forms and reduced Alzheimer's disease risk in advanced age 2010 In: Journal of Alzheimer's disease : JAD. - Amsterdam, Washington : IOS Press. - 1875-8908. ; 58:3, s. 131-140 Journal article (peer-reviewed)abstract In this study we investigated the association between plasma levels of eight forms of vitamin E and incidence of Alzheimer's disease (AD) among oldest-old individuals in a population-based setting. A dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (alpha-, beta-, gamma, and delta-tocopherol; alpha-, beta-, gamma-, and delta-tocotrienol) were measured at baseline. Vitamin E forms-AD association was analyzed with Cox proportional hazard model after adjustment for several potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total vitamin E in the highest tertile had a reduced risk of developing AD in comparison to persons in the lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32-0.94) for total tocopherols, 0.46 (0.23-0.92) for total tocotrienols, and 0.55 (0.32-0.94) for total vitamin E. When considering each vitamin E form, the risk of developing AD was reduced only in association with high plasma levels of beta-tocopherol (HR: 0.62, 95% CI 0.39-0.99), whereas alpha-tocopherol, alpha- tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model [HR (95% CI): alpha-tocopherol: 0.72 (0.48-1.09); alpha-tocotrienol: 0.70 (0.44-1.11); beta-tocotrienol: 0.69 (0.45-1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is currently debated.
12.	Mangialasche, Francesca, et al. (author) Lymphocytic Mitochondrial Aconitase Activity is Reduced in Alzheimer's Disease and Mild Cognitive Impairment 2015 In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 44:2, s. 649-660 Journal article (peer-reviewed)abstract Background: Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radicalmediated damage. Objective: We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age >= 65 years), and younger adults with normal cognition (YCN, age < 65 years). Plasma levels and activities of antioxidants were also measured. Methods: Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and 19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. Results: ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64 +/- 0.21 U/mg protein for AD, 0.93 +/- 0.28 U/mg protein for MCI, 1.17 +/- 0.78 U/mg protein for OCN subjects, and 1.23 +/- 0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p < 0.001) and Mini- Mental State Examination total score (rho: 0.82, p < 0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. Conclusion: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression.
13.	Mangialasche, Francesca, et al. (author) Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults 2013 In: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 48:12, s. 1428-1435 Journal article (peer-reviewed)abstract Background: Vitamin E includes eight natural antioxidant compounds (four tocopherols and four tocotrienols), but a-tocopherol has been the main focus of investigation in studies of cognitive impairment and Alzheimer's disease. Objective: To investigate the association between serum levels of tocopherols and tocotrienols, markers of vitamin E oxidative/nitrosative damage (alpha-tocopherylquinone, 5-nitro-gamma-tocopherol) and incidence of cognitive impairment in a population-based study. Design: A sample of 140 non-cognitively impaired elderly subjects derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed-up for 8 years to detect cognitive impairment, defined as development of mild cognitive impairment (MCI) or Alzheimer's dementia. The association between baseline serum vitamin E and cognitive impairment was analyzed with multiple logistic regression after adjusting for several confounders. Results: The risk of cognitive impairment was lower in subjects in the middle tertile of the alpha-tocopherol/cholesterol ratio than in those in the lowest tertile: the multiadjusted odds ratio (OR) with 95% confidence interval (CI) was 0.27 (0.10-0.78). Higher incidence of cognitive impairment was found in the middle [OR (95% CI): 3.41 (1.29-9.06)] and highest [OR (95% CI): 2.89 (1.05-7.97)] tertiles of the 5-NO2-gamma-tocopherol/gamma-tocopherol ratio. Analyses of absolute serum levels of vitamin E showed lower risk of cognitive impairment in subjects with higher levels of gamma-tocopherol, beta-tocotrienol, and total tocotrienols. Conclusions: Elevated levels of tocopherol and tocotrienol forms are associated with reduced risk of cognitive impairment in older adults. The association is modulated by concurrent cholesterol concentration. Various vitamin E forms might play a role in cognitive impairment, and their evaluation can provide a more accurate measure of vitamin E status in humans.
14.	Mangialasche, Francesca, et al. (author) Tocopherols and tocotrienols plasma levels are associated with cognitive impairment 2012 In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:10, s. 2282-2290 Journal article (peer-reviewed)abstract Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. alpha-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (alpha-tocopherylquinone, 5-nitro-gamma-tocopherol) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, alpha-tocopherylquinone, and 5-nitro-gamma-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.
15.	Papenberg, Göran, et al. (author) Physical activity and inflammation : effects on gray-matter volume and cognitive decline in aging 2016 In: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 37:10, s. 3462-3473 Journal article (peer-reviewed)abstract Physical activity has been positively associated with gray-matter integrity. In contrast, pro-inflammatory cytokines seem to have negative effects on the aging brain and have been related to dementia. It was investigated whether an inactive lifestyle and high levels of inflammation resulted in smaller gray-matter volumes and predicted cognitive decline across 6 years in a population-based study of older adults (n=414). Self-reported physical activity (fitness-enhancing, health-enhancing, inadequate) was linked to gray-matter volume, such that individuals with inadequate physical activity had the least gray matter. There were no overall associations between different pro-and anti-inflammatory markers (IL-1, IL-6, IL-10, IL-12p40, IL-12p70, G-CSF, and TNF-) and gray-matter integrity. However, persons with inadequate activity and high levels of the pro-inflammatory marker IL-12p40 had smaller volumes of lateral prefrontal cortex and hippocampus and declined more on the Mini-Mental State Examination test over 6 years compared with physically inactive individuals with low levels of IL-12p40 and to more physically active persons, irrespective of their levels of IL-12p40. These patterns of data suggested that inflammation was particularly detrimental in inactive older adults and may exacerbate the negative effects of physical inactivity on brain and cognition in old age. Hum Brain Mapp 37:3462-3473, 2016.
16.	Pekkala, Timo, et al. (author) Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia 2020 In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 76:4, s. 1243-1248 Journal article (peer-reviewed)abstract We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE ɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.
17.	Pérez, Laura M., et al. (author) Glutathione Serum Levels and Rate of Multimorbidity Development in Older Adults 2020 In: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 75:6, s. 1089-1094 Journal article (peer-reviewed)abstract We aimed to investigate the association between baseline levels of total serum glutathione (tGSH) and rate of chronic disease accumulation over time. The study population (n = 2,596) was derived from a population-based longitudinal study on >= 60-year-olds living in Stockholm. Participants were clinically assessed at baseline, 3- and 6-year follow-ups. Multimorbidity was measured as the number of chronic conditions from a previously built list of 60 diseases. Linear mixed models were applied to analyze the association between baseline tGSH levels and the rate of multimorbidity development over 6 years. We found that at baseline, participants with >= 4 diseases had lower tGSH levels than participants with no chronic conditions (3.3 vs 3.6 mu mol/L; p < .001). At follow-up, baseline levels of tGSH were inversely associated with the rate of multimorbidity development (beta * time: -0.044, p < .001) after adjusting for age, sex, education, levels of serum creatinine, C-reactive protein, albumin, body mass index, smoking, and time of dropout or death. In conclusion, serum levels of tGSH are inversely associated with multimorbidity development; the association exists above and beyond the link between tGSH and specific chronic conditions. Our findings support the hypothesis that tGSH is a biomarker of multisystem dysregulation that eventually leads to multimorbidity.
18.	Satizabal, Claudia L., et al. (author) Genetic architecture of subcortical brain structures in 38,851 individuals 2019 In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624- 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.
19.	Shi, Liu, et al. (author) Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. 2020 In: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368 Journal article (peer-reviewed)abstract 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.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.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).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.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.
20.	Simrén, Joel, 1996, et al. (author) The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease 2021 In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:7, s. 1145-1156 Journal article (peer-reviewed)abstract Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
21.	van Maurik, Ingrid S., et al. (author) Biomarker-based prognosis for people with mild cognitive impairment (ABIDE) : a modelling study 2019 In: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 18:11, s. 1034-1044 Journal article (peer-reviewed)abstract BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.
22.	Vos, Stephanie J. B., et al. (author) Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage 2015 In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338 Journal article (peer-reviewed)abstract Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.

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