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An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology.

ABSTRACT: The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies.A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the ?-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented.MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ?4 allele was strongly associated with overall Alzheimer type pathology (all p?0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology.This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.

SUBMITTER: Wider C

PROVIDER: S-EPMC3623699 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology.

Wider Christian C Ross Owen A OA Nishioka Kenya K Heckman Michael G MG Vilariño-Güell Carles C Jasinska-Myga Barbara B Erketin-Taner Nilufer N Rademakers Rosa R Graff-Radford Neill R NR Mash Deborah C DC Papapetropoulos Spiridon S Duara Ranjan R Uchikado Hirotake H Wszolek Zbigniew K ZK Farrer Matthew J MJ Dickson Dennis W DW

Journal of neurology, neurosurgery, and psychiatry 20120130 4

<h4>Purpose</h4>The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies.<h4>Methods</h4>A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assess ...[more]

PMID: 22291217

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Project description:BackgroundAPOE ?4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ?4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ?4 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 ?4 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 ?4 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 ?4 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 ?4 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 ?4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ?4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ?4 carriers. This supports the hypothesis that APOE ?4 differentially impacts initial cognitive symptoms together with underlying neuropathology.

Project description:ImportanceCognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.ObjectiveTo determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.Design, setting, and participantsWe studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.Main outcomes and measuresNine variables derived from 7 psychometric tests.ResultsThe APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.Conclusions and relevanceOur data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

Project description:Misfolded α-synuclein (α-syn) is believed to contribute to neurodegeneration in Lewy body disease (LBD) based on considerable evidence including a gene-dosage effect observed in relation to point mutations and multiplication of SNCA in familial Parkinson's disease. A contradictory concept proposes early loss of the physiological α-syn as the major driver of neurodegeneration. There is a paucity of data on SNCA transcripts in various α-syn immunoreactive cytopathologies. Here, the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD (n = 5) were evaluated using RNAscope combined with immunofluorescence for disease-associated α-syn. Single-nucleus RNA sequencing was performed to elucidate cell-type specific SNCA expression in non-diseased frontal cortex (n = 3). SNCA transcripts were observed in the neuronal nucleus and cytoplasm in neurons without α-syn, those containing punctate α-syn immunoreactivity, irregular-shaped compact inclusion, and brainstem-type and cortical-type LBs. However, SNCA transcripts were only rarely found in the α-syn immunoreactive LB areas. The total cell body SNCA transcript area densities in neurons with punctate α-syn immunoreactivity were preserved but were significantly reduced in neurons with compact α-syn inclusions both in the substantia nigra and amygdala. This reduction was also observed in the cytoplasm but not in the nucleus. Only single SNCA transcripts were detected in astrocytes with or without disease-associated α-syn immunoreactivity in the amygdala. Single-nucleus RNA sequencing revealed that excitatory and inhibitory neurons, oligodendrocyte progenitor cells, oligodendrocytes, and homeostatic microglia expressed SNCA transcripts, while expression was largely absent in astrocytes and microglia. The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies might provide a pool for local protein production that can aggregate and serve as a seed for misfolded α-syn. Successful segregation of disease-associated α-syn is associated with the exhaustion of SNCA production in the terminal cytopathology, the Lewy body. Our observations inform therapy development focusing on targeting SNCA transcription in LBD.

Dataset Information

An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology.

Publications

An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology.

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