APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.
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ABSTRACT:
SUBMITTER: Ramanan VK
PROVIDER: S-EPMC3661739 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
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Project description:BackgroundSporadic cerebral amyloid angiopathy shows progressive amyloid-β deposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex.ObjectiveTo investigate whether amyloid load and distribution, assessed by florbetapir positron emission tomography (PET), differs between patients with probable CAA-related intracerebral hemorrhage (CAA-ICH) and mild cognitive impairment due to Alzheimer's disease (MCI-AD).MethodsWe assessed [18F]florbetapir uptake in 15 patients with probable CAA-ICH and 20 patients with MCI-AD patients. Global and regional florbetapir retention were assessed using standard uptake values ratio (SUVr) in region-based and voxel-wise approaches. Visual reading of florbetapir scans was performed for all participants. Group comparisons were performed using univariate and multivariate analysis.ResultsGlobal florbetapir retention was lower in patients with CAA-ICH than MCI-AD (median SUVr, 1.33 [1.21-1.41] versus 1.44 [1.35-1.66]; p = 0.032). In the region-based analysis, regional florbetapir distribution was similar between the two groups. There was a trend for an increased occipital/global ratio in CAA-ICH patients compared to MCI-AD (p = 0.060). In the voxel-wise approach, two clusters, one in parietal regions and the other in temporal regions, had higher uptake in MCI-AD relative to CAA patients.ConclusionsPatients with CAA-ICH had a lower global florbetapir PET burden than patients with MCI-AD. Relative florbetapir retention in the posterior regions tended to be higher in CAA patients in region-based analysis but was not statistically different between groups. Investigation on differences in amyloid deposits distribution between groups required a fine-grained voxel-wise analysis. In future studies, selective amyloid tracers are needed to differentiate vascular from parenchymal amyloid.
| S-EPMC7081105 | biostudies-literature
Project description:BACKGROUND:Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS:Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS:The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS:In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.
| S-EPMC5849499 | biostudies-literature
Project description:There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer's disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer's Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1 - 42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOEɛ4 genotype influences brain amyloid deposition pattern; 2) APOEɛ4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOEɛ4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing.
| S-EPMC8634544 | biostudies-literature
Project description:BackgroundFlorbetapir (AV-45) has been shown to be a reliable tool to assess amyloid load in patients with Alzheimer's disease (AD) at demential stages. Longitudinal studies also suggest that AV-45 has the ability to bind amyloid in the early stages of AD. In this study, we investigated AV-45 binding and its relation with cognitive performance in a group of patients at the prodromal stage of Alzheimer's disease, recruited according to strict inclusion criteria.MethodsWe recruited patients at the prodromal stage of AD and matched control subjects. AV-45 binding was assessed using an innovative extraction method allowing quantifying uptake in the cortex only. AV-45 uptake was compared between groups in the precuneus, posterior cingulate, anterior cingulate, and orbito-frontal regions. Correlations between AV-45 uptake and cognitive performance were assessed.ResultsTwenty-two patients and 17 matched control subjects were included in the study. We report a significant increase of cortical AV-45 uptake in the patients compared to the control subjects in all regions of interest. Specific correlations were found within the patient group between mean global amyloid cortical load and cognitive performance in three different memory tests.ConclusionsThese findings suggest that at the prodromal stage of AD, memory decline is linked to an increase of cortical β-amyloid load.
| S-EPMC3733998 | biostudies-literature
Project description:Fibrillar amyloid-? (A?) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the accumulation of A? in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of A? deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18-60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar A? deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar A? deposition.We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar A? began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3-33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. (18)F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3-40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease.Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
| S-EPMC3515078 | biostudies-literature
Project description:Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.
| S-EPMC6219464 | biostudies-literature
Project description:PurposeTo examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer's disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia.MethodsWe analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau.ResultsCompared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: - 0.31 [- 0.45, - 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [- 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ.ConclusionOur data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.
| S-EPMC8175302 | biostudies-literature
Project description:IntroductionAlzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented.MethodsSixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months.ResultsCAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic).DiscussionDespite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD.HighlightsThis was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.
| S-EPMC10984441 | biostudies-literature
Project description:Our objective was to examine associations of head injury with total and regional brain amyloid deposition. We performed cross-sectional analyses of 329 non-demented participants (81 with prior head injury) in the Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) Study who underwent 18-florbetapir PET imaging in 2012-2014. A history of head injury was defined by self-report or emergency department/hospitalization International Classification of Diseases, Ninth Revision codes. Generalized linear regression models adjusted for demographic, socioeconomic, and dementia/cardiovascular risk factors were used to estimate prevalence ratios (PRs; 95% confidence intervals [CIs]) for elevated (> 1.2) global and regional standard uptake value ratios (SUVRs). Mean age of participants was 76 years, 57% were women, and 43% were black. Head injury was associated with increased prevalence of elevated SUVR >1.2 globally (PR: 1.31; 95% CI: 1.19-1.57), as well as in the orbitofrontal cortex (PR: 1.23); (95% CI: 1.04-1.46), prefrontal cortex (PR: 1.18; 95% CI: 1.00-1.39), superior frontal cortex (PR: 1.24; 95% CI: 1.05-1.48), and posterior cingulate (PR: 1.26; 95% CI: 1.04-1.52). There also was evidence for a dose-response relationship, whereby a history of ≥1 head injury was associated with elevated SUVR >1.2 in the prefrontal cortex and superior frontal cortex compared with persons with a history of one head injury (all, p < 0.05). In conclusion, head injury was associated with increased amyloid deposition globally and in the frontal cortex and posterior cingulate, with suggestion of a dose-response association of head injuries with beta-amyloid deposition. Further work is needed to determine if increased amyloid deposition contributes to dementia in this population.
| S-EPMC6909743 | biostudies-literature
Project description:BackgroundRecently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer's disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks-the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)-on AD-related brain changes in cognitively normal (CN) middle-aged and older adults.Methods[11C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [18F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses.ResultsA significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aβ) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions.ConclusionsStrong synergistic effects of APOE4 and FH on Aβ deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aβ. Other unspecified risk factors-genes and/or environmental-that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.
| S-EPMC6106945 | biostudies-literature