Supplementary_Data_1 - Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for <i>GNG4</i> and <i>KCNQ2</i> Genes

<p>Supplementary_Data_1 for Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for <i>GNG4</i> and <i>KCNQ2</i> Genes by Luke W. Bonham, Daniel S. Evans, Yongmei Liu, Steven R. Cummings, Kristine Yaffe, and Jennifer S. Yokoyama in American Journal of Alzheimer’s Disease & Other Dementias</p

Supplemental_Figure_1 - Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for <i>GNG4</i> and <i>KCNQ2</i> Genes

<p>Supplemental_Figure_1 for Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for <i>GNG4</i> and <i>KCNQ2</i> Genes by Luke W. Bonham, Daniel S. Evans, Yongmei Liu, Steven R. Cummings, Kristine Yaffe, and Jennifer S. Yokoyama in American Journal of Alzheimer’s Disease & Other Dementias</p

Data_Sheet_1_RETRACTED: Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer’s Disease.docx

Alzheimer’s disease (AD) prevalence varies by sex, suggesting that sex chromosomes, sex hormones and/or their signaling could potentially modulate AD risk and progression. Low testosterone levels are reported in men with AD. Further, variation in the androgen receptor (AR) gene has been associated with AD risk and cognitive impairment. We assessed measures of plasma testosterone levels as a biomarker of AD in male participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Baseline testosterone levels were significantly different between clinical diagnosis groups [cognitively normal controls, mild cognitive impairment (MCI), or AD], with the lowest testosterone levels in men with AD. Lower baseline testosterone levels were associated with higher baseline clinical severity. Change in testosterone levels between baseline and 1-year follow-up varied by diagnosis; MCI had the greatest decreases in testosterone levels between baseline and 1-year follow-up. Despite differences by clinical diagnosis, there was no association between plasma testosterone and CSF biomarkers of AD pathology. We also tested single nucleotide polymorphisms (SNPs) in AR for association with AD risk in a separate cohort from ADNI and found 26 SNPs associated with risk for AD. The top associated SNP is predicted to be an expression quantitative trait locus for AR in multiple tissues, including brain, with the AD-associated risk allele predicted to confer lower AR expression. Our findings suggest a link between the androgen pathway and AD through Aβ/tau independent pathways. These effects may be most pronounced during conversion from MCI to dementia.</p

Table_1_Insulin-Like Growth Factor Binding Protein 2 Is Associated With Biomarkers of Alzheimer’s Disease Pathology and Shows Differential Expression in Transgenic Mice.DOCX

<p>There is increasing evidence that metabolic dysfunction plays an important role in Alzheimer’s disease (AD). Brain insulin resistance and subsequent impairment of insulin and insulin-like growth factor (IGF) signaling are associated with the neurodegenerative and clinical features of AD. Nevertheless, how the brain insulin/IGF signaling system is altered in AD and the effects of these changes on AD pathobiology are not well understood. IGF binding protein 2 (IGFBP-2) is an abundant cerebral IGF signaling protein and there is early evidence suggesting it associates with AD biomarkers. We evaluated the relationship between protein levels of IGFBP-2 with cerebrospinal fluid (CSF) biomarkers and neuroimaging markers of AD progression in 300 individuals from across the AD spectrum. CSF IGFBP-2 levels were correlated with CSF tau levels and brain atrophy in non-hippocampal regions. To further explore the role of IGFBP2 in tau pathobiology, we evaluated the expression of IGFBP2 in different human and mouse brain cell types and brain tissue from two transgenic mouse models: the P301L-tau model of tauopathy and TASTPM model of AD. We observed significant differential expression of IGFBP2 in both transgenic mouse models relative to wild-type mice in cortex but not in hippocampus. In both humans and mice, IGFBP2 is most highly expressed in astrocytes. Taken together, our findings suggest that IGFBP-2 may be linked to tau pathology and provides further evidence for a relationship between metabolic dysregulation and neurodegeneration. Our results also raise the possibility that this relationship may extend beyond neurons.</p

Image_1_Insulin-Like Growth Factor Binding Protein 2 Is Associated With Biomarkers of Alzheimer’s Disease Pathology and Shows Differential Expression in Transgenic Mice.pdf

<p>There is increasing evidence that metabolic dysfunction plays an important role in Alzheimer’s disease (AD). Brain insulin resistance and subsequent impairment of insulin and insulin-like growth factor (IGF) signaling are associated with the neurodegenerative and clinical features of AD. Nevertheless, how the brain insulin/IGF signaling system is altered in AD and the effects of these changes on AD pathobiology are not well understood. IGF binding protein 2 (IGFBP-2) is an abundant cerebral IGF signaling protein and there is early evidence suggesting it associates with AD biomarkers. We evaluated the relationship between protein levels of IGFBP-2 with cerebrospinal fluid (CSF) biomarkers and neuroimaging markers of AD progression in 300 individuals from across the AD spectrum. CSF IGFBP-2 levels were correlated with CSF tau levels and brain atrophy in non-hippocampal regions. To further explore the role of IGFBP2 in tau pathobiology, we evaluated the expression of IGFBP2 in different human and mouse brain cell types and brain tissue from two transgenic mouse models: the P301L-tau model of tauopathy and TASTPM model of AD. We observed significant differential expression of IGFBP2 in both transgenic mouse models relative to wild-type mice in cortex but not in hippocampus. In both humans and mice, IGFBP2 is most highly expressed in astrocytes. Taken together, our findings suggest that IGFBP-2 may be linked to tau pathology and provides further evidence for a relationship between metabolic dysregulation and neurodegeneration. Our results also raise the possibility that this relationship may extend beyond neurons.</p

Table_2_Insulin-Like Growth Factor Binding Protein 2 Is Associated With Biomarkers of Alzheimer’s Disease Pathology and Shows Differential Expression in Transgenic Mice.docx

<p>There is increasing evidence that metabolic dysfunction plays an important role in Alzheimer’s disease (AD). Brain insulin resistance and subsequent impairment of insulin and insulin-like growth factor (IGF) signaling are associated with the neurodegenerative and clinical features of AD. Nevertheless, how the brain insulin/IGF signaling system is altered in AD and the effects of these changes on AD pathobiology are not well understood. IGF binding protein 2 (IGFBP-2) is an abundant cerebral IGF signaling protein and there is early evidence suggesting it associates with AD biomarkers. We evaluated the relationship between protein levels of IGFBP-2 with cerebrospinal fluid (CSF) biomarkers and neuroimaging markers of AD progression in 300 individuals from across the AD spectrum. CSF IGFBP-2 levels were correlated with CSF tau levels and brain atrophy in non-hippocampal regions. To further explore the role of IGFBP2 in tau pathobiology, we evaluated the expression of IGFBP2 in different human and mouse brain cell types and brain tissue from two transgenic mouse models: the P301L-tau model of tauopathy and TASTPM model of AD. We observed significant differential expression of IGFBP2 in both transgenic mouse models relative to wild-type mice in cortex but not in hippocampus. In both humans and mice, IGFBP2 is most highly expressed in astrocytes. Taken together, our findings suggest that IGFBP-2 may be linked to tau pathology and provides further evidence for a relationship between metabolic dysregulation and neurodegeneration. Our results also raise the possibility that this relationship may extend beyond neurons.</p

Summary of association results with combined data from all stages of study.^a

a<p>SNP: marker name (location information); A1: risk allele; A2: reference allele; Fr_Case: allele frequency of A1 in cases; Fr_Cont: allele frequency of A1 in controls; P: p-values from allelic association analysis; OR: odds ratio with 95% confidence interval; Comb. P: combined p-value from meta-analysis.</p><p>The strength of association of the three variants is shown. Chr6.24500625 in <i>RBBP6</i> and Chr6.25681850 in <i>USP31</i> remain highly significant after inclusion of more cases and controls.</p

Manhattan plot of GWAS for adult-onset deafness.

<p>Chromosome markers are plotted on the x-axis in order and alternately shaded. The -log₁₀(p-value) is plotted on the y-axis. The red line indicates significance at the Bonferroni-corrected level for 30,000 SNPs. There is extensive regional support for an association on CFA6. The inset shows an enlargement of the 25-Mb association region, including genes of interest. The raw GWAS and permuted p-values (P_perm-gw) for the top SNP are also given.</p

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

<div><p>Background</p><p>Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.</p><p>Methods and findings</p><p>Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (<i>n</i> = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype <i>A*03</i>:<i>01~B*07</i>:<i>02~DRB1*15</i>:<i>01~DQA1*01</i>:<i>02~DQB1*06</i>:<i>02</i> (<i>p</i> = 9.6 x 10⁻⁴, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E <i>(APOE</i>) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype <i>A*03</i>:<i>01~B*07</i>:<i>02</i> (<i>p</i> = 0.03, OR = 1.11 [1.01–1.23]) and class II haplotype <i>DRB1*15</i>:<i>01- DQA1*01</i>:<i>02- DQB1*06</i>:<i>02</i> (<i>DR15</i>) (<i>p</i> = 0.03, OR = 1.08 [1.01–1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying <i>A*03</i>:<i>01~B*07</i>:<i>02</i> was associated with higher CSF amyloid levels (<i>p</i> = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the <i>DR15</i> haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS11] over time [<i>p</i> = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [<i>p</i> = 0.02, β ± standard error = −0.2 ± 0.06]). In a subset of the same cohort, dose of <i>DR15</i> was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (<i>p</i> = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes.</p><p>Conclusions</p><p>We provide evidence that variation in the HLA locus—including risk haplotype <i>DR15</i>—contributes to AD risk. <i>DR15</i> has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that <i>DR15</i>-associated mechanisms may contribute to pan-neuronal disease vulnerability.</p></div

Summary statistics for ADNI participants with longitudinal cognitive measures.

<p>Summary statistics for ADNI participants with longitudinal cognitive measures.</p