Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10-7). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.

Alzheimer’s disease is a devastating neurodegenerative disorder with a complex pathogenesis. One main pathological feature utilised in diagnosis is neurodegeneration or neuronal injury, which is reflected in reductions in cerebral glucose metabolism measured by [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). Here we evaluated the involvement of glial reactivity measured with magnetic resonance spectroscopy (MRS) and cerebral blood flow measured with arterial spin labelling (ASL) on [18F]FDG PET as a measure of cerebral glucose metabolism. 123 people living with early Alzheimer’s disease who completed baseline evaluations on the evaluating liraglutide in Alzheimer’s disease trial were enrolled. Participants completed [18F]FDG PET scans with arterial input, T1 weighted MRI, single-voxel 1 HMRS, and pulsed ASL scans at Imperial College London Clinical Imaging Facility. The Totally Automatic Robust Quantitation in NMR (TARQUIN) package was used to process MRS scans and identify the concentration of myo-inositol within the posterior cingulate cortex (PCC), a marker of glial activation. Oxford-ASL was utilised to process ASL and quantify cerebral blood flow in the PCC. Finally, spectral analysis was performed on the [18F]FDG PET scans to assess the cerebral metabolic rate of glucose in the PCC. Pearson’s correlations were performed between the cerebral metabolic rate of glucose, cerebral blood flow and glial activity measured by the level of myo-inositol in the PCC. Increased cerebral glucose metabolism was correlated with higher myo-inositol in this sample of Alzheimer’s disease participants. In contrast, cerebral blood flow was not associated with cerebral glucose metabolism. Here we demonstrate that increased glial reactivity contributes to [18F]FDG PET signal in the early stages of Alzheimer’s disease. In response to early neuronal injury, astrocytes and microglia may become activated and enhance regional rates of glucose consumption. Hence, the contribution from these cells in addition to neurons should be considered in interpreting [18F]FDG PET as a measure of cerebral glucose metabolism. Interestingly, cerebral blood flow did not influence glucose metabolism. Microglia and astrocyte reactivity may contribute to an increase the cerebral glucose metabolism while neuronal loss and synaptic function may contribute to lower glucose metabolism measured by [18F]FDG in the early stages of Alzheimer's disease.

OBJECTIVES:To investigate the association between tooth loss and the incidence of mild cognitive impairment (MCI) and dementia, focusing on diet quality as a potential mediator. DESIGN:Prospective cohort study. SETTING AND PARTICIPANTS:Community-dwelling older men enrolled in the Northern Ireland PRIME study (Prospective Epidemiological Study of Myocardial Infarction). MEASUREMENTS:A group of men, aged 58-71 years, underwent dental examinations in 2001-2003. Surviving participants were invited to attend a cognitive rescreening in 2016-2020, which included a food frequency questionnaire. Cognitive outcomes were categorised as normal, MCI or dementia, based on standardised neurocognitive tests. Dietary diversity scores (DDS) were calculated based on the frequency of intake of food groups. Analyses included multiple logistic regression to evaluate the associations between tooth loss, defined as <20 remaining natural teeth, and MCI/dementia incidence adjusting for potential confounders. Mediation analysis assessed the role of diet quality in this relationship. RESULTS:A total of 628 men were included, with a mean baseline age of 63.2 years (SD 2.8) and a median follow-up of 15.0 years (IQR 14.2-17.0). At rescreening, 485 (77.2%) were cognitively normal, 112 (17.8%) had MCI, and 31 (4.9%) had dementia. In fully adjusted models, tooth loss was significantly associated with MCI/dementia (OR = 2.06, 95% CI 1.20-3.55, p < 0.01). DDS partially mediated this relationship, explaining approximately 23% of the total effect. CONCLUSION:In this cohort of older men, tooth loss was associated with incidence of MCI/dementia over 15 years, and diet diversity partially mediated this association. These findings highlight an important pathway connecting oral health, dietary quality, and cognitive outcomes.

BackgroundPeriodontitis is a chronic bacterial infection that elicits systemic inflammation. While retrospective studies have linked periodontal pathogens with Alzheimer's disease (AD) and dementia, few have combined cognitive assessments, pathogen exposure, and inflammatory markers.ObjectiveTo investigate the longitudinal risk between periodontitis, cognitive impairment and dementia.MethodsWe examined the relationship between periodontitis and onset of mild cognitive impairment (MCI) and dementia over 15.6 years (SD 1.6) in older men from Northern Ireland enrolled in the PRIME-COG cohort, using logistic regression. We also assessed associations between exposure to periodontal pathogens and blood inflammatory markers.ResultsAmong 642 men, baseline periodontitis was not significantly associated with later onset of dementia and/or MCI (severe versus mild/none, OR 0.83, 95% CI 0.45-1.50, p = 0.923). However, having more teeth predicted lower risk (OR 0.95, 95% CI 0.91-0.99, p = 0.023). Dementia and/or MCI was associated with higher serum IL-6, IL-8, and IFN-γ at baseline, and IL-8 and TGF-β at follow-up. IgG levels to periodontal pathogens remained stable in men who developed dementia and/or MCI but declined in cognitively normal men. A positive correlation between IgG to periodontal pathogens and proinflammatory cytokines was observed in men who developed dementia and/or MCI.ConclusionsClinical periodontitis was not associated with dementia or MCI onset, but tooth retention was protective. Elevated inflammatory markers in affected men suggest systemic inflammation may contribute to cognitive decline. Larger, more diverse cohort studies are needed to clarify the role of periodontal disease in dementia and AD risk.

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer's disease syndrome. 'Evaluating liraglutide in Alzheimer's disease' (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer's disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = -0.17; 95% confidence interval: -0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome-score on the Alzheimer's Disease Assessment Scale-Executive domain (ADAS-Exec)-performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03-0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (-0.58; 95% confidence interval: -3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (-0.06; 95% confidence interval: -0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer's disease. ClinicalTrials.gov identifier: NCT01843075 .

Introduction: The relationship between cognitive impairment and a phenotype comprising low muscle strength coupled with excess adiposity, representative of sarcopenic obesity, is not well defined. The present study aimed to elucidate the relationship between low hand grip strength (HGS), representative of "probable sarcopenia," coupled with obesity, thus representing "probable sarcopenic obesity" and cognitive impairment. METHODS:Logistic regression models were implemented between probable sarcopenia and cognitive impairment in older men residing in Northern Ireland within the Prospective Epidemiological Study of Myocardial Infarction (PRIME)-COG cohort, a nested study in the PRIME cohort. In addition, associations across BMI strata were evaluated, including probable sarcopenic obesity (low HGS and BMI ≥30 kg/m2). Models were adjusted for demographics, cardiometabolic disease and risk factors, APOE-ε4, and lifestyle behaviours. RESULTS:Among 792 men (79.1, SD 3.2 years), low HGS was associated with a significantly increased odds ratio (OR) of cognitive impairment (OR 2.14; 95% confidence intervals [CIs] 1.51-3.03, p < 0.001). The risk was broadly consistent across BMI strata, including men with probable sarcopenic obesity (OR 2.36 [95% CI: 0.85-6.35], p = 0.05). The consistent risk across BMI strata was supported by a non-significant interaction between BMI and probable sarcopenia (likelihood ratio test, p = 0.772). CONCLUSIONS:Probable sarcopenia, indicated by low HGS, was associated with an increased risk of cognitive impairment in older men, with risk consistent across BMI strata, including men living with probable sarcopenic obesity. Our findings have clinical relevance, suggesting that phenotypes comprising low muscle strength, in the presence of excess adiposity, must not be overlooked and appropriate interventions explored to attenuate physical perturbations which could carry significance towards ameliorating cognitive function in ageing. .

Neuroinflammation and activation of the immune system can influence Alzheimer’s disease (AD) progression. This is mediated by inflammatory molecules, which exacerbate the production of β-amyloid, the propagation of tau pathology, and neuronal loss. By measuring CSF markers of inflammation in a heterogeneous clinical cohort we found that levels of Adenosine Deaminase (ADA) and Matrix-Metaloproteinase-10 (MMP-10) increase in patients with AD. Despite promising results of immune markers in CSF, a substantial limitation for wide clinical application is the requirement for a lumbar puncture, which is an invasive procedure only available in specialist settings. Using alternative fluid markers, such as blood sample measurements, would enable wider use of immune markers in AD diagnosis. Here we evaluate if measurement of ADA and MMP-10 markers in blood samples is associated with cognitive decline. Blood samples from 98 participants, including 41 healthy controls and 57 patients with amnestic mild cognitive impairment (aMCI) in the ICOS study were analysed. Participants were monitored at six-monthly intervals over two years. Blood samples obtained during the third monitoring visit at 12 months post recruitment were analysed in this study. The levels of MMP-10 and ADA in these samples were measured using the OLINK platform. Correlation analysis and Receiver Operator Characteristic (ROC) curves were used to evaluate if these markers of inflammation are associated with cognitive function. ADA, an enzyme that regulates immune homeostasis, showed a weak but statistically significant increase in blood concentration with decreasing MoCA cognitive test scores (Rho=-0.2, p=0.023). MMP-10, an enzyme involved in blood brain barrier function, also showed a weak but statistically significant increase with decreasing MoCA scores (Rho=-0.25, p=0.006). ROC analysis indicates that both ADA and MMP-10 are weak predictors of amnestic MCI. They can differentiate between healthy controls (MoCA 26-30) and patients with aMCI (MoCA 18-25) with Areas Under the Curve of only 0.57 and 0.64, respectively. In this study, blood levels of ADA and MMP-10 were significantly associated with cognitive impairment. Their predictive ability of aMCI is weak and further work is required to establish the prognostic capabilities of immune markers in blood samples in larger patient cohorts.

Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is 8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Aims: In Alzheimer's disease (AD), the locus coeruleus (LC) undergoes early and extensive neuronal loss, preceded by abnormal intracellular tau aggregation, decades before the onset of clinical disease. Neuromelanin-sensitive MRI has been proposed as a method to image these changes during life. Surprisingly, human post-mortem studies have not examined how changes in LC during the course of the disease relate to cerebral pathology following the loss of the LC projection to the cortex. Methods: Immunohistochemistry was used to examine markers for 4G8 (pan-A beta) and AT8 (ptau), LC integrity (neuromelanin, dopamine beta-hydroxylase [D beta H], tyrosine hydroxylase [TH]) and microglia (Iba1, CD68, HLA-DR) in the LC and related temporal lobe pathology of 59 post-mortem brains grouped by disease severity determined by Braak stage (0-II, III-IV and V-VI). The inflammatory environment was assessed using multiplex assays. Results: Changes in the LC with increasing Braak stage included increased neuronal loss (p < 0.001) and microglial Iba1 (p = 0.005) together with a reduction in neuromelanin (p < 0.001), D beta H (p = 0.002) and TH (p = 0.041). Interestingly in LC, increased ptau and loss of neuromelanin were detected from Braak stage III-IV (p = 0.001). At Braak stage V/VI, the inflammatory environment was different in the LC vs TL, highlighting the anatomical heterogeneity of the inflammatory response. Conclusions: Here, we report the first quantification of neuromelanin during the course of AD and its relationship to AD pathology and neuroinflammation in the TL. Our findings of neuromelanin loss early in AD and before the neuroinflammatory reaction support the use of neuromelanin-MRI as a sensitive technique to identify early changes in AD.

AbstractRare coding single nucleotide variants (SNV) and short insertions or deletions (indels) contribute to Alzheimer disease (AD) genetic risk, from pathogenic variants in autosomal dominant genes to risk factors with diverse effects. In contrast, copy number variants (CNV) have been scarcely studied, with the exception of a few autosomal dominant examples, such asAPPgene duplications.We took advantage from a large case-control dataset of 22,319 exomes (4,150 early-onset AD (EOAD, onset ≤65 years), 8,519 late onset AD (LOAD) and 9,650 controls) to detect CNVs. We first identified 17 causative CNVs in autosomal dominant genes (9 novel: 7APPand 2MAPTduplications). After exclusion of carriers of these, we performed an original two-step analysis: (i) a protein-coding genome-wide analysis at the transcript level using a gene dosage strategy (EOAD versus controls) and then (ii) an integrated loss-of-function (LOF) analysis gathering short truncating variants with CNV-deletions in genes prioritized in (i) and in a list of known AD risk genes.We identified AD association with dosage of 20 genes at 4 differentlociwith a false discovery rate (FDR) below 10%, including the chr22q11.21 central region (FDR=0.0386), a region in linkage disequilibrium with theAPOElocus on chr19 (FDR=0.0271), and two single-gene loci, namelyFADS6(FDR=0.0271), andADI1(FDR=0.0916). Replication in an independent dataset made of genotyping array data from 2,780 EOAD cases, 15,222 LOAD cases and 273,979 controls was consistent with the results obtained in the discovery dataset. The integrated LOF analysis helped narrowing the region of interest to theSCARF2-KLHL22-MED15region at the 22q11.21 locus. In addition, the integrated LOF analysis highlighted rare deletions in the known AD-risk genesABCA1andABCA7that represented 10% (3/30) and 8.6% (10/115) of LOF alleles of these genes, respectively, as well as 4TYROBPdeletions. Finally, we identifyCTSBLOF alleles as candidate rare AD risk factors (p=0.0089).In conclusion, our results show that carriers of a deletion ofFADS6or a 22q11.21 deletion encompassing theSCARF2-KLHL22-MED15region, including some patients with DiGeorge syndrome, may have a higher risk of developing AD. CNVs represent a source of genomic variation that can contribute to AD etiology in new genes but also in GWAS defined-genes.

In Alzheimer's disease (AD), the locus coeruleus (LC) undergoes early and extensive neuronal loss, preceded by abnormal intracellular tau aggregation, decades before the onset of clinical disease. Neuromelanin-sensitive MRI has been proposed as a method to image these changes during life. Surprisingly, human post-mortem studies have not examined how changes in LC during the course of the disease relate to cerebral pathology following the loss of the LC projection to the cortex. Immunohistochemistry was used to examine markers for 4G8 (pan-Aβ) and AT8 (ptau), LC integrity (neuromelanin, dopamine β-hydroxylase [DβH], tyrosine hydroxylase [TH]) and microglia (Iba1, CD68, HLA-DR) in the LC and related temporal lobe pathology of 59 post-mortem brains grouped by disease severity determined by Braak stage (0-II, III-IV and V-VI). The inflammatory environment was assessed using multiplex assays. Changes in the LC with increasing Braak stage included increased neuronal loss ( p  < 0.001) and microglial Iba1 ( p  = 0.005) together with a reduction in neuromelanin ( p  < 0.001), DβH ( p  = 0.002) and TH ( p  = 0.041). Interestingly in LC, increased ptau and loss of neuromelanin were detected from Braak stage III-IV ( p  = 0.001). At Braak stage V/VI, the inflammatory environment was different in the LC vs TL, highlighting the anatomical heterogeneity of the inflammatory response. Here, we report the first quantification of neuromelanin during the course of AD and its relationship to AD pathology and neuroinflammation in the TL. Our findings of neuromelanin loss early in AD and before the neuroinflammatory reaction support the use of neuromelanin-MRI as a sensitive technique to identify early changes in AD.

Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer’s disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = –1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = –0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention.

Magnetic resonance spectroscopy (MRS) is a non-invasive method of evaluating metabolite levels in the cerebral cortex. Measurable metabolites can provide markers of neuronal damage, glial activation and, neurotransmission, pathological features of Alzheimer’s disease. Here we sought to establish the effectiveness of several metabolites as biomarkers for Alzheimer’s disease. 198 participants with a single-voxel 1 H MRS scan were enrolled (n = 170 participants living with Alzheimer’s disease, n = 28 healthy controls). All participants underwent 3-tesla magnetic resonance imaging and cognitive assessment with the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-cog). An experienced radiographer placed an 8cm 3 voxel within the posterior cingulate cortex for single-voxel 1 H MRS acquisition. Scans were then processed to evaluate levels of N-acetylaspartate, myo-inositol, choline, and glutamate. Creatine peak was additionally evaluated as a reference. N-acetylaspartate/creatine, myo-inositol /creatine, choline/creatine ratios and glutamate were compared between Alzheimer’s participants and controls to calculate the effect size. Correlations were then performed between metabolite ratios and ADAS-cog scores. N-acetylaspartate/creatine effectively distinguished between Alzheimer’s patients and healthy controls (Cohens D = 0.83) with a lowered ratio in Alzheimer’s participants. Elevated glutamate signal and myo-inositol/creatine ratios were also displayed in Alzheimer’s patients (Cohens D = 0.62 and 0.69, respectively). Choline/creatine ratio displayed no significant difference between groups (Cohens D = 0.26). Lower N-acetylaspartate /creatine and glutamate correlated with higher ADAS-cog scores (r = -0.29, p < 0.001, CIs: -0.42 to -0.14 and r = -0.30, p < 0.001, CIs: -0.44 to -0.16, respectively). Myo-inositol and choline failed to correlate with cognitive impairment. N-acetylaspartate, a signature of neuronal damage, is an effective biomarker of Alzheimer’s disease and associated cognitive decline. Enhanced glial activity, measured with myo-inositol, was shown in Alzheimer’s disease, suggesting that glial-reactivity markers deserve consideration in the diagnosis of Alzheimer’s disease. Glutamate demonstrated the strongest association with cognitive impairment, despite showing a smaller effect size than N-acetylaspartate and myo-inositol in distinguishing between Alzheimer’s patients and controls. Together we establish MRS is a useful, non-invasive biomarker of several pathological processes involved in the development of Alzheimer’s. Evaluation of N-acetylaspartate, glutamate, and myo-inositol may aid in the diagnosis of neurodegenerative disease, detecting markers undetectable by conventional MRI methodology.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation in the joint synovium. Considering growing research interest into the role that systemic inflammation might play in the pathogenesis of Alzheimer’s disease (AD), studying cognitive decline in RA patients can provide important insights into the potential effects of inflammation on cognitive health. Furthermore, evidence suggests that biological drugs used to treat RA, specifically TNF inhibitors (TNFi), may protect against AD progression by reducing systemic inflammation. The rheumatoid arthritis medication and memory study (RESIST) is a multicentre longitudinal observational study which aims to compare rates of cognitive decline in adults with both RA and mild cognitive impairment who are on either a conventional synthetic disease modifying anti-rheumatic drug (csDMARD) or a TNFi. 251 participants were recruited (160 on csDMARDs, 91 on TNFis). Participants completed assessments at six-month intervals for eighteen months. The primary outcome was performance on the Free and Cued Selective Reminding Test (FCSRT). It was hypothesised that the rate of decline in FCSRT score would be lower among participants taking TNFis. Between-groups ANCOVA was conducted to compare mean FCSRT scores at 12/18 months, adjusting for baseline score, age, disease activity, pain, wellbeing, depressive symptoms and physical function. Results showed that neither group declined in FCSRT free recall score on average over the 18 month follow-up period, and that there was no significant difference between groups at 12 (mean difference = 0.59, 95% CI = -1.54, 2.72) or 18 months (mean difference = 1.24, 95% CI = -0.99, 3.47). The absence of decline in FCSRT performance in either group was unexpected. These findings raise the possibility that both csDMARDs and TNFis may protect against cognitive decline However, a major limitation of the study was attrition due to the COVID-19 pandemic, which may have influenced results – those who experienced a greater degree of cognitive decline may have been more likely to withdraw from the study. Additional planned analyses will examine the potential moderating effect of APOE genotype, and the relationship between peripheral serum C reactive protein, cytokine levels and cognitive outcomes.

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

Aims 1) To compare blood brain barrier (BBB) permeability between AD and controls. 2) To examine the relationship between BBB permeability and cognitive decline in AD. 3) To examine the relationship between BBB permeability and peripheral markers of inflammation. Methods This pilot study combines the use whole brain DCE-MRI, with measures of peripheral inflammation in serum and urine. This is a clinical cohort study with longitudinal and cross-sectional arms, involving n = 15 AD and n = 17 age and gender matched controls. BBB permeability is measured using DCE-MRI and inflammation is measured by comparing serum cytokine and urine neopterin concentrations. AD participants attend three study visits over 12 months; control participants attend two over one week. Urinary neopterin analysis is being conducted in February 2023.The 12 month follow up visits complete in May 2023. Both neopterin and longitudinal cognitive assessment data will be included in the poster presentation in July. Results AD and control groups were well matched with no significant differences in demographics and multi-morbidity. We measured blood cytokine profiles for IL-6, IL-8, IL-2, IL-4, IL-1b, IL-10, IL13, IL-12p70-, TNF-alpha and INF-gamma. Only INF-Gamma was significantly different; higher in AD vs Controls (mean ± SD; 28.758 ± 90.226 AD, 3.773 ± 2.256 Control, P = 0.03). There were no significant differences in markers of neurodegeneration NfL and pTau-181, or vascular markers VCAM1, ICAM1, CRP and SAA between the groups. Ki is being calculated for overall whole brain, white matter, grey matter and hippocampus regions; an interim analysis showed no significant differences between the tissue categories, but analysis is ongoing. Conclusion There are currently no prognostic biomarkers that accurately predict decline in AD. We believe this pilot study will add to the literature about the utility and feasibility of DCE-MRI to measure BBB permeability. We hope that combining DCE-MRI with blood and urine biomarkers will further our knowledge of the pathophysiology of AD and help to develop minimally invasive biomarkers for identifying patients with AD, including those who are at risk of faster progression.

Preclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin resistance, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild to moderate AD conducted at 24 centres in the UK. As a part of this study, a total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline and during follow up. Volumetric changes from baseline to follow up in MRI scans were evaluated using both regional volume analysis and voxel based morphometric analysis MRI analysis demonstrated that temporal lobe volume, total grey matter volume and frontoparietal volume change was lower in liraglutide treated patients compared to the placebo group. Voxel based morphometry (VBM) analysis demonstrated that liraglutide-treated participants showed a slower reduction in whole cortical grey matter, frontal, temporal and parietal lobe volume in participants treated with liraglutide compared to placebo. In the ELAD study, participants with mild to moderate AD who received liraglutide had slower reduction in MRI volume and cognition compared to the placebo demonstrating a potential benefit of liraglutide in the treatment of Alzheimer’s disease. These findings highlight the potential of GLP-1 analogues in the treatment of Alzheimer’s disease

Periodontitis (gum disease) is a is a chronic inflammatory disorder. Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Aggregatibacter actinomyecetemcomitans (Aa), and Treponema denticola (Td) are the most common periodontal pathogens. Evidence of a longitudinal association between periodontitis and dementia is currently lacking. We therefore proposed that prior periodontitis in 60-70 year old men increases the longitudinal risk of cognitive decline. PRIME-COG is a nested in PRIME (Prospective Epidemiological Study of Myocardial Infarction), a cohort study of men in Northern Ireland (NI). Between 2001 and 2003, 1400 men underwent a periodontal examination, had inflammatory markers measured in blood, exposure to periodontopathogens identified within dental plaques, and a cognitive assessment. 874 men had a comprehensive cognitive assessment fifteen to twenty years later from which a consensus diagnosis of normal cognition, mild cognitive impairment (MCI) or dementia was made by experienced clinical researchers. Logistic regression models were performed to assess the association between periodontitis and future cognitive endpoints. In addition, serum IgG levels to Pg, Tf, Aa and Td and a panel of pro-inflammatory cytokines were determined at baseline and follow-up visits. We did not identify any significant associations between periodontitis and dementia and/or MCI or cognitive decline in the extended follow up period. No differences in IgG serum titres to pathogens in baseline and follow-up visits were seen for patients diagnosed with dementia or MCI, whereas levels were significantly decreased in the normal cognition group. Serum levels of IL-6 at baseline were significantly higher in patients with MCI and dementia compared to those with normal cognition among men aged 76 years plus (p = 0.002); and 81 years plus (p = 0.02) respectively. IL-8 levels were significantly different in patients with MCI aged 81+ years compared to those with normal cognition at baseline (p = 0.014) and follow-up (p = 0.012). Within a cohort of older men residing in the NI, periodontitis was not associated with later onset of dementia or MCI following an extended follow up. Maintenance of high IgG levels over the years might indicate ongoing persistent infection associated with dampened immune response. This could contribute to increased risk of dementia/MCI.

Genetic discoveries of Alzheimer ’ s disease are the drivers of our understanding, and together with polygenetic risk strati fi cation can contribute towards planning of feasible and ef fi cient preventive and curative clinical trials. We fi rst perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer ’ s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer ’ s disease patients in APOE ɛ 4 carriers. Because of this study, the underlying mechanisms of APP can be studied to re fi ne the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer ’ s disease.