APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology.
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ABSTRACT: Objective
To evaluate whether APOE ε4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology.Methods
Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE ε4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with ε4 according to severity of AD pathology.Results
As expected, APOE ε4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all p ≤ 0.004). Of note, ε4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, ε4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all p ≤ 0.002).Conclusions
Our results indicate that APOE ε4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of ε4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that ε4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.
SUBMITTER: Dickson DW
PROVIDER: S-EPMC6161556 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).MethodsA total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed.ResultsA significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only.ConclusionAPOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.
| S-EPMC6946485 | biostudies-literature
Project description:Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB-), sole LB pathology (AD-LB+), or no pathology (AD-LB-). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD-LB-), and compared the AD+LB+ to AD+LB- groups. APOE-ε4 was significantly associated with risk of AD+LB- and AD+LB+ compared to AD-LB-. However, APOE-ε4 was not associated with risk of AD-LB+ compared to AD-LB- or risk of AD+LB+ compared to AD+LB-. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.
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Project description:INTRODUCTION:Meta-analyses of genome-wide association studies (GWAS) have established common genetic risk factors for clinical Parkinson's disease (PD); however, associations between these risk factors and quantitative neuropathologic markers of disease severity have not been well-studied. This study evaluated associations of nominated variants from the most recent PD GWAS meta-analysis with Lewy body disease (LBD) subtype (brainstem, transitional, or diffuse) and pathologic burden of LB pathology as measured by LB counts in five cortical regions in a series of LBD cases. METHODS:547 autopsy-confirmed cases of LBD were included and genotyped for 29 different GWAS-nominated PD risk variants. LB counts were measured in middle frontal (MF), superior temporal (ST), inferior parietal (IP), cingulate (CG), and parahippocampal (PH) gyri. RESULTS:None of the variants examined were significantly associated with LB counts in any brain region or with LBD subtype after correcting for multiple testing. Nominally significant (P < 0.05) associations with LB counts where the direction of association was in agreement with that observed in the PD GWAS meta-analysis were observed for variants in BCKDK/STX1B (MF, ST, IP) and SNCA (ST). Additionally, MIR4697 and BCKDK/STX1B variants were nominally associated with LBD subtype. CONCLUSION:The lack of a significant association between PD GWAS variants and severity of LB pathology is consistent with the generally subtle association odds ratios that have been observed in disease-risk analysis. These results also suggest that genetic factors other than the susceptibility loci may determine quantitative neuropathologic outcomes in patients with LBD.
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Project description:BackgroundAPOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP).MethodsA retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer's Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups.ResultsOne thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7-2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47-0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02-110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance.ConclusionsThe odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.
| S-EPMC7825215 | biostudies-literature
Project description:ObjectivesMutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.MethodsWe screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).ResultsAmong white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (χ(2)(1) = 19.3; p = 1.1 × 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.ConclusionsGBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.
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Project description:IntroductionThe role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).MethodsWe dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls.ResultsTOMM 40-L/APOE-ε4 alleles were associated with DLB (OR TOMM40 -L = 3.61; P value = 3.23 × 10-9; OR APOE -ε4 = 3.75; P value = 4.90 × 10-10) and earlier age at onset of DLB (HR TOMM40 -L = 1.33, P value = .031; HR APOE -ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR TOMM40 -L = 4.40, P value = 1.15 × 10-6; OR APOE - ε 4 = 5.65, P value = 2.97 × 10-8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10-99; ORDLB+AD = 5.36, P value = 1.56 × 10-47).DiscussionAPOE-ε4/TOMM 40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.
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Project description:ObjectiveThe highly conserved 14-3-3 proteins interact with key players involved in Parkinson's disease (PD) and other neurodegenerative disorders. We recently demonstrated that 14-3-3 phosphorylation is increased in PD models and that increased 14-3-3 phosphorylation reduces the neuroprotective effects of 14-3-3 proteins. Here, we investigated whether 14-3-3 phosphorylation is altered in postmortem brains from control, PD, Alzheimer's Disease (AD), Alzheimer's with Lewy Bodies (ADLB), Dementia with Lewy Bodies (DLB), and Progressive Supranuclear Palsy (PSP) subjects at three conserved sites: serine 58 (S58), serine 185 (S185), and serine 232 (S232).MethodsS58, S185, and S232 phosphorylation was measured by western blot analysis of Triton X-100 soluble and insoluble fractions from postmortem temporal cortex.ResultsThe ratio of soluble phospho-S232 to insoluble phospho-S232 was reduced by 32%, 60%, 37%, and 52% in PD, AD, ADLB, and DLB, respectively. S185 and S58 phosphorylation were mildly elevated in the soluble fraction in DLB. We also noted a dramatic reduction in soluble pan 14-3-3 levels by ~35% in AD, ADLB, and DLB. Lower ratios of soluble to insoluble S232 phosphorylation (pointing to higher insoluble pS232) correlated with lower soluble pan 14-3-3 levels, suggesting that S232 phosphorylation may promote insolubilization of 14-3-3s. The phospho-S232 ratio and soluble pan 14-3-3 levels correlated with clinical and pathological severity.InterpretationThese data reveal dysregulation of 14-3-3 proteins in neurodegeneration associated with Lewy body or Alzheimer pathology. S232 phosphorylation may drive insolubilization of 14-3-3s and thus contribute to the pathophysiology in neurodegenerative disorders associated with Lewy body or Alzheimer pathology.
| S-EPMC5497531 | biostudies-literature
Project description:While prior work reliably demonstrates that the APOE ɛ4 allele has deleterious group level effects on Alzheimer disease pathology, the homogeneity of its influence across the lifespan and spatially in the brain remains unknown. Further it is unclear what combinations of factors at an individual level lead to observed group level effects of APOE genotype. To evaluate the impact of the APOE genotype on disease trajectories, we examined longitudinal MRI and PET imaging in a cohort of 497 cognitively normal middle and older aged participants. A whole-brain regional approach was used to evaluate the spatial effects of genotype on longitudinal change of amyloid-β pathology and cortical atrophy. Carriers of the ɛ4 allele had increased longitudinal accumulation of amyloid-β pathology diffusely through the cortex, but the emergence of this effect across the lifespan differed greatly by region (e.g. age 49 in precuneus, but 65 in the visual cortex) with the detrimental influence already being evident in some regions in middle age. This increased group level effect on accumulation was due to a greater proportion of ɛ4 carriers developing amyloid-β pathology, on average doing so at an earlier age, and having faster amyloid-β accumulation even after accounting for baseline amyloid-β levels. APOE ɛ4 carriers displayed faster rates of structural loss in primarily constrained to the medial temporal lobe structures at around 50 years, although this increase was modest and proportional to the elevated disease severity in APOE ɛ4 carriers. This work indicates that influence of the APOE gene on pathology can be detected starting in middle age.
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Project description:Clinical phenotype of individuals with spinocerebellar ataxia 2 (SCA2) is characterised by cerebellar ataxia and cognitive impairment. Although L-dopa-responsive Parkinsonism is considered as a rare clinical presentation in SCA2, it has been brought to the attention of many neurologists in several studies. The authors report an autopsy case of SCA2 with Parkinsonism from a Japanese family using archival materials of our Brain Bank to describe unique neuropathologic findings. The individual clinically showed Parkinsonism as a predominant phenotype instead of cerebellar ataxia. Besides the classic SCA2 neuropathologic alterations, Lewy bodies and Lewy neurites were present in the brainstem nuclei. Genetic analysis revealed shorter abnormal expansion of CAG repeats (less than 39). In contrast, the authors could not find α-synuclein pathology in two SCA2 cases without Parkinsonism. The present case will provide a neuropathologic evidence of correlation between α-synucleinopathy and Parkinsonism of SCA2 as well as shed light on understanding the pathomechanism of Parkinsonism in SCA2.
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