APOE Effect on Amyloid-β PET Spatial Distribution, Deposition Rate, and Cut-Points.
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ABSTRACT:
SUBMITTER: Toledo JB
PROVIDER: S-EPMC8634544 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:The deposition of the amyloid ?-protein (A?) in senile plaques is one of the histopathological hallmarks of Alzheimer's disease (AD). A?-plaques arise first in neocortical areas and, then, expand into further brain regions in a process described by 5 phases. Since it is possible to identify amyloid pathology with radioactive-labeled tracers by positron emission tomography (PET) the question arises whether it is possible to distinguish the neuropathological A?-phases with amyloid PET imaging. To address this question we reassessed 97 cases of the end-of-life study cohort of the phase 3 [18F]flutemetamol trial (ClinicalTrials.gov identifiers NCT01165554, and NCT02090855) by combining the standardized uptake value ratios (SUVRs) with pons as reference region for cortical and caudate nucleus-related [18F]flutemetamol-retention. We tested them for their prediction of the neuropathological pattern found at autopsy. By defining threshold levels for cortical and caudate nucleus SUVRs we could distinguish different levels of [18F]flutemetamol uptake termed PET-A? phase estimates. When comparing these PET-A? phase estimates with the neuropathological A?-phases we found that PET-A? phase estimate 0 corresponded with A?-phases 0-2, 1 with A?-phase 3, 2 with A?-phase 4, and 3 with A?-phase 5. Classification using the PET-A? phase estimates predicted the correct A?-phase in 72.16% of the cases studied here. Bootstrap analysis was used to confirm the robustness of the estimates around this association. When allowing a range of?±?1 phase for a given A?-phase correct classification was given in 96.91% of the cases. In doing so, we provide a novel method to convert SUVR-levels into PET-A? phase estimates that can be easily translated into neuropathological phases of A?-deposition. This method allows direct conclusions about the pathological distribution of amyloid plaques (A?-phases) in vivo. Accordingly, this method may be ideally suited to detect early preclinical AD-patients, to follow them with disease progression, and to provide a more precise prognosis for them based on the knowledge about the underlying pathological phase of the disease.
| S-EPMC6132944 | biostudies-literature
Project description:Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.
| S-EPMC3661739 | biostudies-literature
Project description:PurposeThe abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-β (Aβ), APOE, sex, and longitudinal cognitive decline.MethodsWe included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aβ status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread.ResultsWe found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aβ-positive compared with Aβ-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas.ConclusionsThese findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aβ, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.
| S-EPMC7338820 | biostudies-literature
Project description:BACKGROUND:The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated ?-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. METHODS:Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine ?-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. RESULTS:Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their ?-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising ?-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. CONCLUSIONS:Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising ?-amyloid load show correlated levels of microglial activation which then later decline when the ?-amyloid load approaches AD levels. Later, as tau tangles form in ?-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.
| S-EPMC7203856 | biostudies-literature
Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid ? peptide (A?) levels, the extent of A? deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that A? deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that A? deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, A? deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with A? plaques and those without. A? deposition was significantly associated with the presence of the APOE ?4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (? = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both A? plaques and total levels of A?1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that A? deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that A? is associated with both pathological and clinical progression of CTE independent of age.
| S-EPMC4529056 | biostudies-literature
Project description:ObjectiveTo develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability.MethodsThree thousand twenty-seven individuals (1,763 cognitively unimpaired [CU], 658 impaired, 467 with Alzheimer disease [AD] dementia, 111 with non-AD dementia, and 28 with missing diagnosis) from 6 cohorts (European Medical Information Framework for AD, Alzheimer's and Family, Alzheimer's Biomarkers in Daily Practice, Amsterdam Dementia Cohort, Open Access Series of Imaging Studies [OASIS]-3, Alzheimer's Disease Neuroimaging Initiative [ADNI]) who underwent amyloid PET were retrospectively included; 1,049 individuals had follow-up scans. With application of dataset-specific cutoffs to global standard uptake value ratio (SUVr) values from 27 regions, single-tracer and pooled multitracer regional rankings were constructed from the frequency of abnormality across 400 CU individuals (100 per tracer). The pooled multitracer ranking was used to create a staging model consisting of 4 clusters of regions because it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables, and longitudinal cognitive decline were investigated.ResultsSUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices and then the associative, temporal, and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of individuals in stage 0 to 4, respectively. Baseline stage predicted decline in Mini-Mental State Examination (MMSE) score (ADNI: n = 867, F = 67.37, p < 0.001; OASIS: n = 475, F = 9.12, p < 0.001) and faster progression toward an MMSE score ≤25 (ADNI: n = 787, hazard ratio [HR]stage1 2.00, HRstage2 3.53, HRstage3 4.55, HRstage4 9.91, p < 0.001; OASIS: n = 469, HRstage4 4.80, p < 0.001).ConclusionThe pooled multitracer staging model successfully classified the level of amyloid burden in >3,000 individuals across cohorts and radiotracers and detects preglobal amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive individuals.
| S-EPMC7713745 | biostudies-literature
Project description:Positron emission tomography (PET)-based staging of regional amyloid deposition has recently emerged as a promising tool for sensitive detection and stratification of pathology progression in Alzheimer's Disease (AD). Here we present an updated methodological framework for PET-based amyloid staging using region-specific amyloid-positivity thresholds and assess its longitudinal validity using serial PET acquisitions. We defined region-specific thresholds of amyloid-positivity based on Florbetapir-PET data of 13 young healthy individuals (age ≤ 45y), applied these thresholds to Florbetapir-PET data of 179 cognitively normal older individuals to estimate a regional amyloid staging model, and tested this model in a larger sample of patients with mild cognitive impairment (N = 403) and AD dementia (N = 85). 2-year follow-up Florbetapir-PET scans from a subset of this sample (N = 436) were used to assess the longitudinal validity of the cross-sectional model based on individual stage transitions and data-driven longitudinal trajectory modeling. Results show a remarkable congruence between cross-sectionally estimated and longitudinally modeled trajectories of amyloid accumulation, beginning in anterior temporal areas, followed by frontal and medial parietal areas, the remaining associative neocortex, and finally primary sensory-motor areas and subcortical regions. Over 98% of individual amyloid deposition profiles and longitudinal stage transitions adhered to this staging scheme of regional pathology progression, which was further supported by corresponding changes in cerebrospinal fluid biomarkers. In conclusion, we provide a methodological refinement and longitudinal validation of PET-based staging of regional amyloid accumulation, which may help improving early detection and in-vivo stratification of pathologic disease progression in AD.
| S-EPMC7502828 | biostudies-literature
Project description:ObjectiveTo evaluate differences in amyloid deposition in a community-based cohort without dementia by age, sex, race, education, and APOE ε4 allele status.MethodsRecruited from the longitudinal Atherosclerosis Risk in Communities study, 329 participants without dementia, ages 67-88 years, were imaged using florbetapir PET at 3 US community sites (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi). Standardized uptake value ratios (SUVRs) were calculated; global cortical SUVR >1.2 was evaluated as the primary outcome. Age, race, sex, education level, and number of APOE ε4 alleles were evaluated in multivariable models including vascular risk factors, brain white matter hyperintensity and total intracranial volume, and cognitive status.ResultsA total of 141 of the participants (43%) were black. In multivariable models, odds of elevated SUVR was increased in participants with increasing age (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.01-2.65 per 10 years of age) and black race (OR 2.08, 95% CI 1.23-3.51) but did not differ by educational level. Each ε4 allele was associated with increased odds of elevated SUVR (OR 2.65, 95% CI 1.61-4.39).ConclusionsIn this community-based cohort without dementia, florbetapir uptake is associated with older age and APOE genotype. Black race was associated with higher SUVR, after adjusting for demographics, vascular risk factors, cognitive status, white matter hyperintensity volume, and APOE genotype, with effect sizes nearing those seen for APOE ε4. Replication of these findings is needed in other cohorts, and reasons for and consequences of these observed differences by race warrant further study.
| S-EPMC4970663 | biostudies-literature
Project description:A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid β (Aβ) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aβ deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aβ plaques across age in three APP-overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aβ deposition patterns described in AD.
| S-EPMC8026112 | biostudies-literature