| 1. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 2. |
- Mattsson, Niklas, et al.
(författare)
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Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimers disease
- 2018
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Ingår i: Alzheimer's & Dementia. - : ELSEVIER SCIENCE INC. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimers disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P amp;lt;.05) but not in A beta+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE E4 prevalence in AD was higher than that in previous studies, which did not require presence of A beta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location. (C) 2018 the Alzheimers Association. Published by Elsevier Inc. All rights reserved.
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| 3. |
- Mattsson, Niklas, et al.
(författare)
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Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease
- 2018
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P <.05) but not in Aβ+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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| 4. |
- Jansen, Willemijn J, et al.
(författare)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P=.16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P<.001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P<.001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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| 5. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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Ingår i: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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| 6. |
- Deming, Yuetiva, et al.
(författare)
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Sex-specific genetic predictors of Alzheimer’s disease biomarkers
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
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| 7. |
- Ehrenberg, Alexander J., et al.
(författare)
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Relevance of biomarkers across different neurodegenerative
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12
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Forskningsöversikt (refereegranskat)abstract
- Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.
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| 8. |
- Tosun, Duygu, et al.
(författare)
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Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers.
- 2021
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Ingår i: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.
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| 9. |
- Korecka, Magdalena, et al.
(författare)
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Analytical and Clinical Performance of Amyloid-Beta Peptides Measurements in CSF of ADNIGO/2 Participants by an LC-MS/MS Reference Method.
- 2020
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 66:4, s. 587-597
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ42) reliably detects brain amyloidosis based on its high concordance with plaque burden at autopsy and with amyloid positron emission tomography (PET) ligand retention observed in several studies. Low CSF Aβ42 concentrations in normal aging and dementia are associated with the presence of fibrillary Aβ across brain regions detected by amyloid PET imaging.An LC-MS/MS reference method for Aβ42, modified by adding Aβ40 and Aβ38 peptides to calibrators, was used to analyze 1445 CSF samples from ADNIGO/2 participants. Seventy runs were completed using 2 different lots of calibrators. For preparation of Aβ42 calibrators and controls spiking solution, reference Aβ42 standard with certified concentration was obtained from EC-JRC-IRMM (Belgium). Aβ40 and Aβ38 standards were purchased from rPeptide. Aβ42 calibrators' accuracy was established using CSF-based Aβ42 Certified Reference Materials (CRM).CRM-adjusted Aβ42 calibrator concentrations were calculated using the regression equation Y (CRM-adjusted) = 0.89X (calibrators) + 32.6. Control samples and CSF pools yielded imprecision ranging from 6.5 to 10.2% (Aβ42) and 2.2 to 7.0% (Aβ40). None of the CSF pools showed statistically significant differences in Aβ42 concentrations across 2 different calibrator lots. Comparison of Aβ42 with Aβ42/Aβ40 showed that the ratio improved concordance with concurrent [18F]-florbetapir PET as a measure of fibrillar Aβ (n=766) from 81 to 88%.Long-term performance assessment substantiates our modified LC-MS/MS reference method for 3 Aβ peptides. The improved diagnostic performance of the CSF ratio Aβ42/Aβ40 suggests that Aβ42 and Aβ40 should be measured together and supports the need for an Aβ40 CRM.
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| 10. |
- Lockhart, Samuel N, et al.
(författare)
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Amyloid and Tau PET Demonstrate Region-Specific Associations in Normal Older People.
- 2017
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Ingår i: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 150, s. 191-199
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Tidskriftsartikel (refereegranskat)abstract
- β-amyloid (Aβ) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [(18)F]AV-1451 (for tau) and [(11)C]PiB (for Aβ) positron emission tomography (PET) and 1.5T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB-AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p < .01) were identified between PiB in multiple regions of association cortex and AV-1451 in temporal cortical ROIs. There were also less frequent and weaker positive associations of regional PiB with frontoparietal AV-1451 uptake. Particularly in temporal lobe ROIs, AV-1451 uptake was strongly predicted by PiB across multiple ROI locations. These data indicate that Aβ and tau pathology show significant local and non-local regional associations among cognitively normal elderly, with increased PiB uptake throughout the cortex correlating with increased temporal lobe AV-1451 uptake. The spatial relationship between Aβ and tau accumulation does not appear to be specific to Aβ location, suggesting a regional vulnerability of temporal brain regions to tau accumulation regardless of where Aβ accumulates.
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