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.
Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase ...the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18-85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.
Contactin-associated protein-like 2 (CASPR2) is encoded by CNTNAP2 and clusters voltage-gated potassium channels (K(v)1.1) at the nodes of Ranvier. We report a homozygous mutation of CNTNAP2 in Old ...Order Amish children with cortical dysplasia, focal epilepsy, relative macrocephaly, and diminished deep-tendon reflexes. Intractable focal seizures began in early childhood, after which language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation developed in all children. Resective surgery did not prevent the recurrence of seizures. Temporal-lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2.
Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele ...associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.
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•Multiple system atrophy (MSA) is a rare neurodegenerative disorder with rapid symptom progression.•In this study, we investigated the RNA changes in the brain of a mouse model of ...MSA.•We report on transcript overlap between the mouse model and previously published human data.•The Tsr2 gene was downregulated in both the mouse model and human MSA patients.•These results help to enable the comparison of human MSA patients and the mouse model.
Multiple system atrophy (MSA) is a rare, neurodegenerative disorder with rapid motor and non-motor symptom progression. MSA is characterized by protein aggregations of α-synuclein found in the cytoplasm of oligodendrocytes. Despite this pathological hallmark, there is still little known about the cause of this disease, resulting in poor treatment options and quality of life post-diagnosis. In this study, we investigated differentially expressed genes (DEGs) via RNA-sequencing of brain samples from a validated PLP-α-synuclein transgenic mouse model, identifying a total of 40 DEGs in the PLP group compared to wild-type (WT), with top detected genes being Gm15446, Mcm6, Aldh7a1 and Gm3435. We observed a significant enrichment of immune pathways and endothelial cell genes among the upregulated genes, whereas downregulated genes were significantly enriched for oligodendrocyte and neuronal genes. We then calculated possible overlap of these DEGs with previously profiled human MSA RNA, resulting in the identification of significant downregulation of the Tsr2 gene. Identifying key gene expression profiles specific to MSA patients is crucial to further understanding the cause, and possible prevention, of this rapidly progressive neurodegenerative disorder.
The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using ...phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5 ± 1.2 years versus 77.6 ± 2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.
Angiotensin converting enzyme 2 (ACE2), a newly discovered member of the reninâangiotensin system (RAS), is a potential therapeutic
target for the control of cardiovascular disease owing to its key ...role in the formation of vasoprotective peptides from angiotensin
II. The aim of the present study was to evaluate whether overexpression of ACE2 could protect the heart from angiotensin II-induced
hypertrophy and fibrosis. Lentiviral vector encoding mouse ACE2 (lenti-mACE2) or GFP was injected intracardially in 5-day-old
SpragueâDawley rats. This resulted in expression of mACE2 in cardiac tissue for the duration of the study. Infusion of 200
ng kg â1 min â1 angiotensin II for 4 weeks resulted in an 80 mmHg increase in systolic blood pressure, a significant increase in the heart
weight to body weight ratio (HW : BW), and marked myocardial fibrosis in control rats. Transduction with lenti-mACE2 resulted
in significant attenuation of the increased HW : BW and myocardial fibrosis induced by angiotensin II infusion. These observations
demonstrate that ACE2 overexpression results in protective effects on angiotensin II-induced cardiac hypertrophy and fibrosis.
We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) ...gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.
The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, ...although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions. Differential expression analysis of RNA-seq data within the HP based on the rs17070145 genotype revealed an overexpression of genes involved in the MAPK signaling pathway, potentially driven by the T/T genotype. The most important contribution comes from genes dysregulated within the DG region. Other genes significantly dysregulated, and not involved in the MAPK pathway (Adj P < 0.01 and Fold Change > |1.00|) were: RSPO4 (HP); ARC, DUSP5, DNAJB5, EGR4, PPP1R15A, WBP11P1, EGR1, GADD45B (DG); CH25H, HSPA1A, HSPA1B, TNFSF9, and NPAS4 (PC). Several evidences suggested that the MAPK signaling pathway is linked with memory and learning processes. In non-neuronal cells, the KIBRA protein is phosphorylated by ERK1/2 (involved in the MAPK signaling) in cells as well as in vitro. Several of the other dysregulated genes are involved in memory and learning processes, as well as in Alzheimer's Disease. In conclusion, our results suggest that the effect of the WWC1 rs17070145 polymorphism on memory performance and Alzheimer's disease might be due to a differential regulation of the MAPK signaling, a key pathway involved in memory and learning processes.
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