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INTRODUCTION: We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains. METHODS: Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aß) and tau positivity. Survival analyses investigated the link between OPN and rate of conversion to AD. RESULTS: In PREVENT-AD, CSF OPN was positively correlated with synaptic biomarkers. In PREVENT-AD and ADNI, OPN was elevated in CSF Aß42/40(+)/total tau(+) and CSF Aß42/40(+)/phosphorylated tau181(+) individuals. In ADNI, OPN was increased in Aß(+) positron emission tomography (PET) and tau(+) PET individuals, and associated with an accelerated rate of conversion to AD. OPN was elevated in autopsy-confirmed AD brains. DISCUSSION: Strong associations between CSF OPN and key markers of AD pathophysiology suggest a significant role for OPN in tau neurobiology, particularly in the early stages of the disease. HIGHLIGHTS: In the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease cohort, we discovered that cerebrospinal fluid (CSF) osteopontin (OPN) levels can indicate early synaptic dysfunction, tau deposition, and neuronal loss in cognitively unimpaired elderly with a parental history. CSF OPN is elevated in amyloid beta(+) positron emission tomography (PET) and tau(+) PET individuals. Elevated CSF OPN is associated with an accelerated rate of conversion to Alzheimer's disease (AD). Elevated CSF OPN is associated with an accelerated rate of cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive subscale 13, Montreal Cognitive Assessment, Mini-Mental State Examination, and Clinical Dementia Rating Scale Sum of Boxes. OPN mRNA and protein levels are significantly upregulated in the frontal cortex of autopsy-confirmed AD brains.
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We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early Tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower p(181)Tau and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.
Subject(s)
Alzheimer Disease , Biomarkers , Polymorphism, Single Nucleotide , Synapses , tau Proteins , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/pathology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Biomarkers/cerebrospinal fluid , Brain/metabolism , Brain/pathology , Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , Synapses/metabolism , Synapses/pathology , Synaptosomal-Associated Protein 25/metabolism , Synaptosomal-Associated Protein 25/genetics , Synaptosomal-Associated Protein 25/cerebrospinal fluid , Synaptotagmin I/metabolism , Synaptotagmin I/genetics , tau Proteins/cerebrospinal fluid , tau Proteins/metabolismABSTRACT
We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower P-tau181 and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.
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The e4 allele of the apolipoprotein E gene is the strongest genetic risk factor for sporadic Alzheimer's disease. Nevertheless, how APOE is regulated is still elusive. In a trans-eQTL analysis, we found a genome-wide significant association between transmembrane protein 106B (TMEM106B) genetic variants and cortical APOE mRNA levels in human brains. The goal of this study is to determine whether TMEM106B is mis-regulated in Alzheimer's disease or in other neurodegenerative conditions. Available genomic, transcriptomic and proteomic data from human brains were downloaded from the Mayo Clinic Brain Bank and the Religious Orders Study and Memory and Aging Project. An in-house mouse model of the hippocampal deafferentation/reinnervation was achieved via a stereotaxic lesioning surgery to the entorhinal cortex, and mRNA levels were measured using RNAseq technology. In human temporal cortices, the mean TMEM106B expression was significantly higher in Alzheimer's disease compared to cognitively unimpaired individuals. In the mouse model, hippocampal Tmem106b reached maximum levels during the early phase of reinnervation. These results suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling.
Subject(s)
Alzheimer Disease , Membrane Proteins , Nerve Tissue Proteins , Membrane Proteins/genetics , Membrane Proteins/metabolism , Humans , Animals , Mice , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Apolipoproteins E/genetics , Male , Female , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Hippocampus/metabolism , Aged , Genome-Wide Association Study , Disease Models, AnimalABSTRACT
Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (nâ=â93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (nâ=â57) and control subjects (nâ=â31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (pâ=â5.4×10-8), D (pâ=â1.86×10-4), E (pâ=â2.92×10-9), J (pâ=â2.65×10-9), and with cholesterol (pâ=â0.0096) in the CSF, and with cholesterol (pâ=â0.02), HDL (pâ=â0.0143), and LDL (pâ=â0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (pâ=â0.034) and APOE (pâ=â0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (pâ< â0.05), while apob (pâ=â0.023) and apod (pâ=â0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.
Subject(s)
Alzheimer Disease , Humans , Mice , Animals , Alzheimer Disease/metabolism , Apolipoproteins/genetics , Apolipoproteins E/metabolism , Apolipoproteins B , Cholesterol , ContactinsABSTRACT
STUDY OBJECTIVES: Although short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer's disease (AD) onset and neuroinflammation. METHODS: We tested 203 dementia-free participants (68.5â ±â 5.4 years old, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participants' age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, and sleep duration) and general profiles (sleep fragmentation, phase delay, and hypersomnia). Cerebrospinal fluid (CSF) inflammatory biomarkers were assessed with OLINK multiplex technology. RESULTS: Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep and later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, and global score). Interaction analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance. CONCLUSIONS: Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits.
Subject(s)
Alzheimer Disease , Biomarkers , Humans , Alzheimer Disease/physiopathology , Alzheimer Disease/genetics , Male , Female , Aged , Biomarkers/cerebrospinal fluid , Actigraphy , Sleep/physiology , Neuroinflammatory Diseases/physiopathology , Age of Onset , Parents , Middle Aged , Cohort Studies , Sleep DurationABSTRACT
INTRODUCTION: Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. METHODS: In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3 ± 5.4; 78 males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. RESULTS: Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-ß (Aß)42, and higher plasma p-tau231/Aß42 were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. DISCUSSION: Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.
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Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signaling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein (IGFBP) in the cerebrospinal fluid (CSF) - IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD biomarkers and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aß) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aß42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the QFP cohort, a unique population isolate from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and was negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 (CSF Aß(+)/t-tau(+)). In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (HR = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049), however IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2, in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aß(+)/t-tau(+) individuals and those with a greater risk of AD conversion.
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INTRODUCTION: We investigate the CNTN5 rs1461684 G variant and the contactin 5 protein in sporadic Alzheimer's disease (sAD). METHODS: Contactin 5, sAD biomarkers, and synaptic markers were measured in the cerebrospinal fluid (CSF). Amyloid and tau deposition were assessed using positron emission tomography. Contactin 5 protein and mRNA levels were measured in brain tissue. RESULTS: CSF contactin 5 increases progressively in cognitively unimpaired individuals and is decreased in mild cognitive impairment and sAD. CSF contactin 5 correlates with sAD biomarkers and with synaptic markers. The rs1461684 G variant associates with faster disease progression in cognitively unimpaired subjects. Cortical full-length and isoform 3 CNTN5 mRNAs are decreased in the presence of the G allele and as a function of Consortium to Establish a Registry for Alzheimer's Disease stages. DISCUSSION: The newly identified rs1461684 G variant associates with sAD risk, rate of disease progression, and gene expression. Contactin 5 protein and mRNA are affected particularly in the early stages of the disease.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/genetics , Alzheimer Disease/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Cognitive Dysfunction/metabolism , Positron-Emission Tomography , Biomarkers/cerebrospinal fluid , Disease Progression , ContactinsABSTRACT
BACKGROUND: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. OBJECTIVE: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aß1-42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer's disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). METHODS: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aß1-42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex's multiplex technology. Brain MSR1, APOE, and CLU (APOJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. RESULTS: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aß1-42, ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. CONCLUSION: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aß1-42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages.
Subject(s)
Alzheimer Disease , Amyloidosis , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloidogenic Proteins/metabolism , Animals , Apolipoprotein E4/genetics , Apolipoproteins E/metabolism , Biomarkers/cerebrospinal fluid , Carrier Proteins , Humans , Macrophages/metabolism , Neprilysin/genetics , Neprilysin/metabolism , Peptide Fragments/cerebrospinal fluid , RNA, Messenger , Scavenger Receptors, Class A/metabolism , tau Proteins/metabolismABSTRACT
INTRODUCTION: We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS: Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aß), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aß (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS: CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION: CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Apolipoprotein B-100 , Apolipoproteins , Apolipoproteins B , Biomarkers/cerebrospinal fluid , Cognitive Dysfunction/metabolism , Humans , Positron-Emission Tomography/methods , tau Proteins/cerebrospinal fluidABSTRACT
Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer's disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32-63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10-6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin free females compared to 6.9% in the entire sample and improved prediction of hypercholesterolemia (receiver operator characteristics analysis revealed area under the curve increase from 70.8% to 80.5%). The TC-PGS was further evaluated for association with AD risk and pathology. We found no association between the TC-PGS and either of the AD hallmark pathologies, assessed by cerebrospinal fluid levels of Aß-42, p-Tau, and t-Tau, and 18F-NAV4694 and 18F-AV-1451 positron emission tomography. Similarly, we found no association with the risk of developing amyloid pathology or becoming cognitively impaired in individuals with amyloid pathology.
Subject(s)
Aging/cerebrospinal fluid , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Cholesterol/blood , Multifactorial Inheritance , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Adolescent , Adult , Aged , Aging/blood , Aging/pathology , Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Apolipoproteins E/blood , Apolipoproteins E/genetics , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Humans , Middle AgedABSTRACT
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. METHODS AND FINDINGS: To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. CONCLUSIONS: PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.
Subject(s)
Alzheimer Disease/enzymology , Alzheimer Disease/genetics , Proprotein Convertase 9/genetics , Proprotein Convertase 9/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Apolipoproteins B/cerebrospinal fluid , Apolipoproteins E/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Biomarkers/metabolism , Clusterin/cerebrospinal fluid , Cohort Studies , Female , Frontal Lobe/enzymology , Genetic Association Studies , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Proprotein Convertase 9/cerebrospinal fluid , Proteomics , Quantitative Trait Loci , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sex Factors , tau Proteins/cerebrospinal fluidABSTRACT
In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease (AD), a genome-wide association study was performed on a population isolate from Eastern Canada, referred to as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 is associated with higher AD risk and younger age at AD onset in APOE4- individuals. After surveying the region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when compared with age-matched controls. Using an independent cohort of cognitively normal individuals with a parental history of AD, we found that the rs10406151 C variant is significantly associated with lower visuospatial and constructional performances. The association of the rs10406151 C variant with AD risk appears to involve brain PPP2R1A gene expression alterations. However, the exact pathological pathway by which this variant modulates AD remains elusive.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/psychology , Cognition , Protein Phosphatase 2/genetics , Aged , Apolipoprotein E4/genetics , Brain/metabolism , Chromosomes, Human, Pair 19 , Female , Gene Expression , Genome-Wide Association Study , Humans , Male , Middle Aged , Protein Phosphatase 2/metabolism , Psychomotor Performance , Space Perception/physiology , Visual Perception/physiologyABSTRACT
INTRODUCTION: A coding variant in the TLR4 receptor (rs4986790), previously associated with longevity and Alzheimer's disease (AD) risk reduction, was examined in a population isolate (Québec Founder Population [QFP]) and in presymptomatic individuals with a parental history of AD (Pre-Symptomatic Evaluation of Novel or Experimental Treatment for Alzheimer's Disease [PREVENT-AD]). METHODS: Genotyping was performed using the Illumina HumanHap 550k (QFP) and the Illumina Omni2.5 beadchips (PREVENT-AD). Cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Whole-brain cortical thickness data were analyzed using CIVET 1.12. Cerebrospinal fluid concentrations of cytokines were obtained by using Milliplex. RESULTS: The minor allele of the rs4986790 polymorphism (G) is associated with a reduced risk of developing AD in the QFP, as well as higher visuospatial and constructional abilities, higher cortical thickness in visual-related regions, and stable cerebrospinal fluid IL-1ß levels in the PREVENT-AD cohort. DISCUSSION: The rs4986790 G coding variant in the TLR4 gene appears to reduce AD risk through the modulation of IL-1ß synthesis and secretion in the presymptomatic phase of the disease.
Subject(s)
Alzheimer Disease/genetics , Biomarkers/cerebrospinal fluid , Cytokines/cerebrospinal fluid , Inflammation , Interleukin-1beta/cerebrospinal fluid , Toll-Like Receptor 4/genetics , Aged, 80 and over , Autopsy , Brain , Cohort Studies , Female , Humans , Male , Neuropsychological Tests/statistics & numerical data , QuebecABSTRACT
One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (pâ=â0.001 and pâ=â0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (pâ=â0.0367 and pâ=â0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (pâ=â0.0055 and pâ=â0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.
Subject(s)
Alzheimer Disease , Cytokines/metabolism , Hippocampus/injuries , Hippocampus/physiopathology , Toll-Like Receptor 4/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/complications , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Case-Control Studies , Cerebellum/metabolism , Cerebellum/pathology , Cohort Studies , Cytokines/genetics , Female , Humans , Male , Mice , Mice, Inbred C57BL , RNA, Messenger/metabolism , Toll-Like Receptor 4/geneticsABSTRACT
See Tijms and Visser (doi:10.1093/brain/awy113) for a scientific commentary on this article.Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years, during which subtle brain changes occur in the absence of overt cognitive symptoms. Predicting when the onset of disease symptoms will occur is an unsolved challenge in individuals with sporadic Alzheimer's disease. In individuals with autosomal dominant genetic Alzheimer's disease, the age of symptom onset is similar across generations, allowing the prediction of individual onset times with some accuracy. We extend this concept to persons with a parental history of sporadic Alzheimer's disease to test whether an individual's symptom onset age can be informed by the onset age of their affected parent, and whether this estimated onset age can be predicted using only MRI. Structural and functional MRIs were acquired from 255 ageing cognitively healthy subjects with a parental history of sporadic Alzheimer's disease from the PREVENT-AD cohort. Years to estimated symptom onset was calculated as participant age minus age of parental symptom onset. Grey matter volume was extracted from T1-weighted images and whole-brain resting state functional connectivity was evaluated using degree count. Both modalities were summarized using a 444-region cortical-subcortical atlas. The entire sample was divided into training (n = 138) and testing (n = 68) sets. Within the training set, individuals closer to or beyond their parent's symptom onset demonstrated reduced grey matter volume and altered functional connectivity, specifically in regions known to be vulnerable in Alzheimer's disease. Machine learning was used to identify a weighted set of imaging features trained to predict years to estimated symptom onset. This feature set alone significantly predicted years to estimated symptom onset in the unseen testing data. This model, using only neuroimaging features, significantly outperformed a similar model instead trained with cognitive, genetic, imaging and demographic features used in a traditional clinical setting. We next tested if these brain properties could be generalized to predict time to clinical progression in a subgroup of 26 individuals from the Alzheimer's Disease Neuroimaging Initiative, who eventually converted either to mild cognitive impairment or to Alzheimer's dementia. The feature set trained on years to estimated symptom onset in the PREVENT-AD predicted variance in time to clinical conversion in this separate longitudinal dataset. Adjusting for participant age did not impact any of the results. These findings demonstrate that years to estimated symptom onset or similar measures can be predicted from brain features and may help estimate presymptomatic disease progression in at-risk individuals.
Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/pathology , Brain/diagnostic imaging , Brain/physiopathology , Cognition Disorders/etiology , Age of Onset , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Apolipoproteins E/genetics , Brain Mapping , Cognition Disorders/diagnostic imaging , Cognitive Dysfunction , Cohort Studies , Disease Progression , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
Genome-wide association studies have identified several cholesterol metabolism-related genes as top risk factors for late-onset Alzheimer's disease (LOAD). We hypothesized that specific genetic variants could act as disease-modifying factors by altering the expression of those genes. Targeted association studies were conducted with available genomic, transcriptomic, proteomic, and histopathological data from 3 independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Quebec Founder Population (QFP), and the United Kingdom Brain Expression Consortium (UKBEC). First, a total of 273 polymorphisms located in 17 cholesterol metabolism-related loci were screened for associations with cerebrospinal fluid LOAD biomarkers beta amyloid, phosphorylated tau, and tau (from the ADNI) and with amyloid plaque and tangle densities (from the QFP). Top polymorphisms were then contrasted with gene expression levels measured in 134 autopsied healthy brains (from the UKBEC). In the end, only SREBF2 polymorphism rs2269657 showed significant dual associations with LOAD pathological biomarkers and gene expression levels. Furthermore, SREBF2 expression levels measured in LOAD frontal cortices inversely correlated with age at death; suggesting a possible influence on survival rate.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Cholesterol/metabolism , Genome-Wide Association Study , Polymorphism, Genetic , Sterol Regulatory Element Binding Protein 2/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Cohort Studies , Frontal Lobe/metabolism , Gene Expression , Genetic Loci/genetics , Humans , Plaque, Amyloid/cerebrospinal fluid , Risk Factors , Sterol Regulatory Element Binding Protein 2/metabolism , tau Proteins/cerebrospinal fluidABSTRACT
The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP)ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i.e., protein tau phosphorylated) production in the brain. In this study, a significant positive correlation was observed between the synthases mRNA prevalence and disease status (FPPS, p < 0.001, n = 123; GGPPS, p < 0.001, n = 122). The levels of mRNA for hFPPS and hGGPPS were found to significantly correlate with the amount of p-Tau protein levels (p < 0.05, n = 34) and neurofibrillary tangle density (p < 0.05, n = 39) in the frontal cortex. Interestingly, high levels of hFPPS and hGGPPS mRNA prevalence are associated with earlier age of onset in AD (p < 0.05, n = 58). Together, these results suggest that accumulation of p-Tau in the AD brain is related, at least in part, to increased levels of neuronal isoprenoids.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Cerebellum/metabolism , Cerebellum/pathology , Frontal Lobe/metabolism , Frontal Lobe/pathology , Terpenes/metabolism , tau Proteins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/etiology , Farnesyltranstransferase/physiology , Female , Geranyltranstransferase/physiology , Humans , Male , Mevalonic Acid/metabolism , Neurofibrillary Tangles/metabolism , Neurofibrillary Tangles/pathology , Polyisoprenyl Phosphates/biosynthesis , Protein Prenylation , Sesquiterpenes , cdc42 GTP-Binding Protein/metabolism , rhoA GTP-Binding Protein/metabolismABSTRACT
INTRODUCTION: Because currently known Alzheimer's disease (AD) single-nucleotide polymorphisms only account for a small fraction of the genetic variance in this disease, there is a need to identify new variants associated with AD. METHODS: Our team performed a genome-wide association study in the Quebec Founder Population isolate to identify novel protective or risk genetic factors for late-onset sporadic AD and examined the impact of these variants on gene expression and AD pathology. RESULTS: The rs10984186 variant is associated with an increased risk of developing AD and with a higher CDK5RAP2 mRNA prevalence in the hippocampus. On the other hand, the rs4837766 variant, which is among the best cis-expression quantitative trait loci in the CDK5RAP2 gene, is associated with lower mild cognitive impairment/AD risk and conversion rate. DISCUSSION: The rs10984186 risk and rs4837766 protective polymorphic variants of the CDK5RAP2 gene might act as potent genetic modifiers for AD risk and/or conversion by modulating the expression of this gene.