Aims

Alzheimer’s disease (AD) is a progressively debilitating, neurodegenerative disorder. We report on the epidemiology of mild cognitive impairment (MCI), AD, and AD Related Dementia (ADRD) using electronic health records (EHR) over the past 20 years from the U.S. Veterans Affairs health care system (VA).

Methods

Incident and prevalent cases were identified from outpatient, inpatient, and extended care EHR for all Veterans aged 50 years and older in VA care from 2000-2019 based on ≥2 days with relevant ICD-9/10-CM codes. Alternative criteria were explored. Estimates of annual prevalence and incidence rates were age- and sex-standardized to the 2010 U.S. Census general population. Poisson regression was used to evaluate trends.

Results

A total of 176,674 veterans with MCI, 294,617 with AD, and 450,199 with ADRD were identified. Standardized MCI rates increased steeply, with prevalence of less than 0.09% before 2007, increasing to 1.16% in 2019. Standardized AD prevalence decreased from 0.65% in 2000 to 0.41% in 2019, with similar declines in incidence from 0.26% to 0.08%. Standardized ADRD prevalence declined from 1.97% in 2000 to 0.75% in 2007 and then increased to 1.05% in 2019, with most of the increase in the category of dementia not-otherwise-specified. ADRD Incidence was similar from 0.42% in 2002 decreasing to 0.23% in 2007 then increasing to 0.31% in 2019. For all three conditions, rates increased steeply with age, and were higher in women and African Americans.

Conclusions

We observed recent trends of declining clinical identification of AD but increasing MCI and ADRD.

Aims

Hippocampal atrophy is related to Alzheimer's disease, a neurodegenerative disease involved with innate immunity mechanisms through alterations in microglia functions. Using monocyte, a peripheral corresponding cell type to the microglia, we aimed to identify the peripheral transcriptional gene signatures associated with hippocampal volume.

Methods

We included 126 individuals from the Religious Order Study or the Rush Memory and Aging Project who have both measurements of monocyte RNA sequencing and MRI data, and 28 individuals with measurements at two time points. CD14+CD16- monocytes were isolated from the peripheral blood mononuclear cells. Hippocampal volumes were estimated by Freesurfer software. We conducted mixed linear analyses to control the random intra-individual variation and adjusted for age at blood collection, differences in age at blood collection and MRI measurement, sex, total intracranial volume. Those genes with false discovery rate (FDR) P value less than 0.05 were considered as genome-wide significant ones.

Results

There were 8 genes with significantly negative associations with hippocampal volume (BETA<0 and FDR≤0.05), which are TRDMT1, PBLD, RAB29, AHDC1, C18ORF21, HIGD2A, XXYLT1, and PPP1R26. There were 5 genes with significantly positive associations with hippocampal volume (BETA>0 and FDR≤0.05), which are MAPKAPK5, MAPRE1, NHSL1, FAM13A, and NELFB. The pathway enrichment analysis showed that these 13 significant genes were involved in DNA methyltransferase activity, calcium-dependent protein kinase activity, microtubule plus-end binding, tRNA methyltransferase activity, and mitogen-activated protein kinase binding.

Conclusions

We have identified the transcriptomic gene signatures of the hippocampal volume, which needs to be further validated.

Aims

Recent genetic studies demonstrate the alteration of the innate immune system in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), whereas the functional alterations and mechanisms are not really understood. We, therefore, hypothesize that AD and PD susceptibility genes modulate disease risk by dysregulation of gene expression networks and cellular function within the innate immune cells.

Methods

To address this question, we have generated a large scale dataset of genomic, bulk and single cell transcriptomic and proteomic of human derived CD14+ monocytes from disease and healthy donors. Using this dataset composed of over 500 human monocytes, we are performing integrative analysis using disease-phenotype, expression QTL, network analysis, and functional validation.

Results

Results generated to this point show profound transcriptional alterations in myeloid cells during neurodegeneration. Some key findings are that PD derived monocytes show an upregulation of mitochondrial signature, specifically oxidative phosphorylation genes, and a downregulation of proteo-lysosomal pathway, among others. The mitochondrial signature seems to be cell type specific, as directionality is flipped when compared to human microglia and macrophages. Moreover, the single cell resolution reveals that PD and AD associated genes are highly enriched in the intermediate/non-classical monocyte subclusters. Finally, the integration of expression with genetics, show how a high number of GWAS risk variants modulates gene expression in peripheral monocytes.

Conclusions

Our work shows that peripheral immune cells derived from AD/PD patients show profound dysregulation being the intermediate/non-classical subclusters key in pathology. This dataset will serve as a useful resource for further mechanistic studies and biomarker discovery.

Aims

Unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene-based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impact on protein function before computing gene-based statistical associations is critical.

Methods

We used semantic similarity to identify candidate genes associated with Mendelian disorders that share phenotypic features with AD. Spatial algorithms were used to identify Alzheimer’s Disease Sequencing Project (ADSP) variants significantly clustered within 3D protein structures with known ClinVar pathogenic variants, relative to benign variants from ExAC. We completed gene-based testing using only identified variants and compared these results to published gene-based results. Finally, we assessed differences in case percentage and age-of-onset between carriers of identified variants and non-carriers.

Results

A total of 230 of 1,365 ADSP missense variants in 26 genes were proximal to known pathogenic variants. Four genes associated with AD status using gene-based testing (EPM2A, SERPINI1, PSEN1 and TREM2), either with improved p-values or nominally the same but with attenuated sample sizes. In total, 79.6% of variant carriers were cases, compared to 55.4% of non-carriers. Carriers of identified variants in SERPINI1, PSEN1 and TREM2 were, on average, younger at age-of-onset than non-carriers.

Conclusions

We have identified subsets of missense variants likely to impact the function of proteins associated with neurodegenerative diseases in the ADSP. We demonstrated that carriers of these variants are more likely to be cases and have an earlier age-of-onset than non-carriers.

Aims

Alzheimer’s disease (AD) is characterized pathologically by neuronal loss and the deposition of misfolded proteins. Research on β-amyloid and tau have led to important advances in AD, but resulting therapeutic strategies have not shown clinical success. It is therefore important to examine pathogenesis from a broader lens.

Neurons each harbor somatic single nucleotide variants (sSNV) in their genomes, which increase with age, at a rate of ~20 sSNV per year, a phenomenon known as genosenium. In AD, DNA damage is increased, leading to the question of whether pathogenesis increases the somatic mutation burden.

Methods

We performed single cell whole genome sequencing on neurons from AD and age-matched controls, and analyzed the burden of somatic mutations and associated nucleotide change signatures for mutational patterns.

Results

We found significantly increased sSNV in AD, with >800 additional somatic mutations per neuron, and a distinct mutation pattern. Unlike normal aging, where clock-related Signature A accumulates, AD neurons show an increase in Signature C, which contains distinct nucleotide changes including C>A variants. Mutations show influences of transcription in sSNV generation. Somatic mutations are predicted to produce deleterious effects on the neuron, including gene inactivation and neoantigen-stimulated immune attack.

Conclusions

AD neurons show increased somatic mutations, with mutagenic causes that illuminate upstream components of disease pathogenesis including DNA oxidation and transcription-coupled DNA repair. Furthermore, somatic mutations position neurons for dysfunction and death. Somatic mutation accumulation is a novel process in neurodegeneration, through which we can dissect the cascade of events in disease pathogenesis.

Aims

ABCA7 is one of the most compelling risk genes for Alzheimer’s disease (AD). However, it remains unclear what the exact role is of ABCA7 (isoforms) in AD pathogenesis and which cell-types it is expressed in. Gaining a better understanding of ABCA7 spatial expression could lead to increased insight into the disease.

Methods

We conducted a pilot study on the use of Cartana’s in-situ sequencing (ISS) to study spatial expression using post-mortem brain samples (hippocampus, prefrontal cortex, cerebellum) of four AD patients, with varying ABCA7 mutations, and one healthy control. A custom assay was designed including 7 probes for different ABCA7 isoforms and 15 cell-type specific markers. After ISS, DAPI staining was performed. Cell-type enrichment was studied in 14 unique subregions using both a cell-segmentation method using Fiji in Image J, and spatial clustering using Ripley’s K in the R package spatstat.

Results

Expression of ABCA7 was generally low with lowest expression in the hippocampal fimbriae (less than 0.2% of all transcripts) and highest in the granular layer of the cerebellum (1.8%) and especially the choroid plexus (almost 8%). Both cell segmentation and spatial clustering seemed to give an indication of enrichment of ABCA7 in neurons (1.35 enrichment, p-value 0.03), but not microglia.

Conclusions

Although further optimization of the technique and analysis is needed, our data proves that it could be a useful technique to study AD-related genes and pinpoint neurons and choroid plexus as being of specific interest for further ABCA7 studies.

Aims

Previous studies suggested a role for the immune system in Parkinson’s disease (PD), and one of the hits in recent genome-wide association studies (GWASs) of PD is within the human leukocyte antigen (HLA) locus. Several associations of different HLA genes have been suggested, yet it is not clear which associations are relevant for PD.

Methods

We performed a thorough analysis of the HLA locus for 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression models to examine the association of specific HLA types, different haplotypes and specific amino acid changes. We further performed conditional analyses to identify specific alleles or genetic variants that drive the association with PD.

Results

Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01 and HLA-DRB1*04:04. Haplotype analyses followed by amino-acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes - 11V, 13H and 33H (OR=0.87 95%CI=0.83-0.90, p<8.23x10^-9 for all three variants). No other effects were present after adjustment for these amino acids.

Conclusions

Our results suggest that specific variants in the HLA-DRB1 gene are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to identification of new targets for therapeutics development.

Aims

This study is aimed to explore the relationship between the single nucleotide polymorphisms (SNPs) in dopamine and serotonin metabolism genes and levodopa-induced dyskinesias (LID) development in patients with Parkinson's disease (PD).

Methods

We investigated 320 sporadic PD patients. Dyskinesia is estimated using of MDS-UPDRS scale (parts IV). PD patients were divided into PD with LID (PD-LID) and PD without LID (PD-NORM). The analysis of 18 SNPs of dopamine and serotonin receptors, catechol-O-methyltransferase, monoamine oxidase B, tryptophan and tyrosine hydroxilase, leucine-rich repeat kinase 2 was performed. The SPSS software is used for statistical analysis. Linear regression analysis and one-way ANOVA test are used.

Results

The presence of LID is evaluated in 80 PD patients, and dyskinesias are reported in 55 (68,75%) cases. Patients homozygous for the rs6275*С/С of DRD2 gene had higher values ​​of the MDS-UPDRS scale compared with heterozygous of *С/T (p=0,024; OR=1,05). It is founded that PD-LID patients have a lower frequency of the rs6280*C/C of DRD3 gene (p=0,022; OR=0,05) compared to the PD-NORM patients. Carriers of minor allele rs1491942*C of LRRK2 gene had a higher values of the MDS-UPDRS scale compared with carriers of allele *G (p=0,035; OR=3,04). Linear regression demonstrated increased LID risk for allele rs1800532*T of TPH (p=0,038; F=4,24) – this allele was associated with a higher values of the MDS-UPDRS scale.

Conclusions

Alleles rs1491942*C and rs1800532*T, and genotype rs6275*С/С could be genetic risk factors for the levodopa-induced dyskinesia development in PD patients. This pilot study continues.

The study was supported by RFBR grant No.19-015-00331