Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Prazosin use in a patient with rare Neurobeachin gene deletion shows improvement in paranoid behavior: a case report.

BackgroundDisruption of the Neurobeachin gene is a rare genetic mutation that has been implicated in the development of autism and enhanced long-term potentiation of the hippocampal CA1 region, causing a heightened conditioned fear response and impaired fear extinction. Prazosin, an alpha-1 receptor antagonist, has been used in patients with posttraumatic stress disorder to mitigate the increased alpha-1 activity involved in fear and startle responses. Here we report a case of a patient with a rare Neurobeachin gene deletion, who demonstrated marked and sustained improvement in paranoid behavior within days of prazosin initiation.Case presentationThe patient is a 27-year-old White male with autism spectrum disorder, obsessive-compulsive disorder, and schizophrenia, with a chromosome 13q12 deletion including deletion of the Neurobeachin gene, who presented to the emergency department due to worsening functional status and profound weight loss as a result of only eating prepackaged foods. He had not showered or changed clothes in several months prior to presentation. He was hospitalized in the inpatient psychiatric unit for 2&nbsp;months before prazosin was initiated. During that time, he demonstrated paranoia as evidenced by heightened sensitivity to doors opening, guarded interactions, and limited communication with providers and other patients. He also exhibited poor grooming habits, with aversion to showering, shaving, and changing clothes. Since initiating prazosin, he has demonstrated a brighter affect, initiates and maintains conversations, showers and changes clothes on a regular basis, and eats a variety of foods. At the time of this report, the patient was discharged to live in an apartment with a caregiver after a 7-month inpatient hospitalization.ConclusionsLow-dose prazosin shows rapid and sustained improvement in paranoid behavior in a patient with a rare Neurobeachin gene deletion. Prazosin has a relatively favorable side effect profile with once-daily dosing and low cost. Prazosin may provide clinical improvement in patients with Neurobeachin gene deletions due to its theoretical attenuation in fear response through alpha-1 antagonism

Non-ulcerative pathologies of the diabetic foot

Many of the complications of the diabetes are well studied but robust research documenting the cutaneous effects of the disease remains sparse.Various studies have suggested that the majority of patients with diabeteswill suffer a skin disorder during the course of their disease and for some, the skin changes may even precede the diagnosis of diabetes. Cutaneous pathology of the diabetic foot and lower leg can arise as a result of the direct or indirect effects of diabetic complications. The most common manifestations include fungal and bacterial skin infection, nail disease and diabetic dermopathy. Other less commonly observed conditions include diabetic bullae, necrobiosis lipoidica diabeticorum (NLD), granulomaannulare and reddening of the soles. For many of the less common disorders,there is little in the way of effective treatment. However, much can be done in the clinical setting in the management of the more common manifestation such as bacterial and fungal infection. Fungal infection, in particular, although relatively inconspicuous, is a very common foot problem and if left untreated can threaten tissue viability in the diabetic foot leading to secondary bacterial infection and cellulitis. Management of fungal disease is often considered difficult due to high relapse and re-infection rates, although by introducing a combination of therapies including mechanical and pharmacological the success in treating this stubborn condition can be greatly improved

Tributes to Daniel H. Teitelbaum, MD, PhD

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141090/1/jpen1079.pd