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INTRODUCTION: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS: Genome‐wide association meta‐analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations. [ABSTRACT FROM AUTHOR]

Background: The accumulation of age‐associated cognitive deficits can lead to Mild Cognitive Impairment (MCI) and dementia. This is a major public health issue for the modern ageing population, as it impairs health, independence and overall quality of life. Keeping the brain active during life has been associated with an increased cognitive reserve, therefore reducing the risk of cognitive impairment in older age. Previous research has identified a potential relationship between musicality and cognition. Objectives: Explore the relationship between musicality and cognitive function in a large cohort of older adults. Methods: This was a nested study within the PROTECT‐UK cohort, which collects longitudinal computerised assessments of cognitive function in adults over 40. Participants were invited to complete the validated Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ) to assess their musical experience and lifetime exposure to music. Linear regression analysis was performed using cognitive data from PROTECT‐UK. Results: Analysis identified an association between musicality and cognition in this cohort. Playing a musical instrument was associated with significantly better performance in working memory and executive function. Significant associations were also found between singing and executive function, and between overall musical ability and working memory. Conclusions: Our findings confirm previous literature, highlighting the potential value of education and engagement in musical activities throughout life as a means of harnessing cognitive reserve as part of a protective lifestyle for brain health. Key points: Playing a musical instrument was associated with significantly better working memory and executive function.Singing and overall musical ability was associated with more favourable cognition.Engagement with musical activities should be considered as part of public health initiatives to promote a protective lifestyle for brain health. [ABSTRACT FROM AUTHOR]

Objective: Sleep is vital for normal cognitive function in daily life, but is commonly disrupted in older adults. Poor sleep can be detrimental to mental and physical health, including cognitive function. This study assessed the association between self‐reported short (<6 h) and long (>9 h) sleep duration and sleep fragmentation (3≥ nightly awakenings) in cognitive function. Methods: Cross‐sectional data from 8508 individuals enroled in the PROTECT study aged 50 and above formed the basis of the univariate linear regression analysis conducted on four cognitive outcomes assessing visuospatial episodic memory (VSEM), spatial working memory, verbal working memory (VWM), and verbal reasoning (VR). Results: Short (ß = −0.153, 95% CI [−0.258, −0.048], p = 0.004) and long sleep duration (ß = −0.459, 95% CI [−0.826, −0.091], p = 0.014) were significantly associated with poorer cognitive performance in VWM. Long sleep duration (ß = −2.986, 95% CI [−5.453, −0.518], p = 0.018) was associated with impaired VR. Short sleep (ß = −0.133, 95% CI [−0.196, −0.069], p = <0.001) and sleep fragmentation (ß = −0.043, 95% CI [−0.085, −0.001], p = 0.043) were associated with reduced VSEM. These associations remained significant when including other established risk factors for dementia and cognitive decline (e.g., depression, hypertension). Conclusions: Our findings suggest that short and long sleep durations and fragmented sleep, may be risk factors for a decline in cognitive processes such as working memory, VR and episodic memory thus might be potential targets for interventions to maintain cognitive health in ageing. Key points: This study assessed the association between self‐reported short (<6 h) and long (>9 h) sleep duration and sleep fragmentation (3 or more nightly awakenings) in cognitive function.Univariate linear regression analysis indicated that short and long sleep duration, and sleep fragmentation impaired cognitive processes such as working memory, verbal reasoning (VR) and episodic memory in individuals aged 50+, even when including other established risk factors for dementia and cognitive decline, such as low educational level, hearing loss, traumatic brain injury, hypertension, diabetes, alcohol consumption, obesity, smoking, depression, social isolation, and physical inactivity.Both sleep duration and sleep fragmentation are highlighted as potential risk factors for reduced cognitive function and might be a possible target for interventions to maintain cognitive health in ageing. [ABSTRACT FROM AUTHOR]

Introduction: Late‐life onset psychosis is associated with faster progression to dementia in cognitively normal people, but little is known about its relationship with cognitive impairment in advance of dementia. Methods: Clinical and genetic data from 2750 people ≥50 years of age without dementia were analyzed. Incident cognitive impairment was operationalized using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and psychosis was rated using the Mild Behavioral Impairment Checklist (henceforth MBI‐psychosis). The whole sample was analyzed before stratification on apolipoprotein E (APOE) ε4 status. Results: In Cox proportional hazards models, MBI‐psychosis had a higher hazard for cognitive impairment relative to the No Psychosis group (hazard ratio [HR]: 3.6, 95% confidence interval [CI]: 2.2–6, p < 0.0001). The hazard for MBI‐psychosis was higher in APOE ε4 carriers and there was an interaction between the two (HR for interaction: 3.4, 95% CI: 1.2–9.8, p = 0.02). Discussion: Psychosis assessment in the MBI framework is associated with incident cognitive impairment in advance of dementia. These symptoms may be particularly important in the context of APOE genotype. [ABSTRACT FROM AUTHOR]

Cognitive differences in memory, information processing speed (IPS), and executive functions (EF), are common in autistic and high autistic trait populations. Despite memory, IPS and EF being sensitive to age‐related change, little is known about the cognitive profile of older adults with high autistic traits. This study explores cross‐sectional memory, IPS and EF task performance in a large sample of older adults in the online PROTECT cohort (n = 22,285, aged 50–80 years), grouped by high vs. low autistic traits. Approximately 1% of PROTECT participants (n = 325) endorsed high autistic traits [henceforth Autism Spectrum Trait (AST) group]. Differences between AST and age‐, gender‐, and education‐matched comparison older adults (COA; n = 11,744) were explored on memory, IPS and EF tasks and questionnaires administered online. AST had lower performance than COA on tasks measuring memory, working memory, sustained attention, and information processing. No group differences were observed in simple attention or verbal reasoning. A similar pattern of results was observed when controlling for age, and current depression and anxiety symptoms. In addition, AST self‐reported more cognitive decline than COA, but this difference was not significant when controlling for current depression symptoms, or when using informant‐report. These findings suggest that autistic traits are associated with cognitive function in middle‐aged and later life. Older adults with high autistic traits experienced more performance difficulties in a range of memory, IPS and EF tasks compared with the low autistic traits comparison group. Further longitudinal work is needed to examine age‐related change in both older autistic and autistic trait populations. Lay Summary: Little is known about the cognitive profile of middle‐aged and older autistic or high autistic trait adults. Using data from the PROTECT cohort and a well‐validated online cognitive assessment platform, the findings from the current study suggest that higher autistic traits are associated with worse cognitive functioning throughout later adulthood. This suggests that older adults with high autistic traits may require additional support as they age. [ABSTRACT FROM AUTHOR]

Introduction: Despite the association of vitamin D deficiency with incident dementia, the role of supplementation is unclear. We prospectively explored associations between vitamin D supplementation and incident dementia in 12,388 dementia‐free persons from the National Alzheimer's Coordinating Center. Methods: Baseline exposure to vitamin D was considered D+; no exposure prior to dementia onset was considered D−. Kaplan–Meier curves compared dementia‐free survival between groups. Cox models assessed dementia incidence rates across groups, adjusted for age, sex, education, race, cognitive diagnosis, depression, and apolipoprotein E (APOE) ε4. Sensitivity analyses examined incidence rates for each vitamin D formulation. Potential interactions between exposure and model covariates were explored. Results: Across all formulations, vitamin D exposure was associated with significantly longer dementia‐free survival and lower dementia incidence rate than no exposure (hazard ratio = 0.60, 95% confidence interval: 0.55–0.65). The effect of vitamin D on incidence rate differed significantly across the strata of sex, cognitive status, and APOE ε4 status. Discussion: Vitamin D may be a potential agent for dementia prevention. Highlights: In a prospective cohort study, we assessed effects of Vitamin D on dementia incidence in 12,388 participants from the National Alzheimer's Coordinating Center dataset.Vitamin D exposure was associated with 40% lower dementia incidence versus no exposure.Vitamin D effects were significantly greater in females versus males and in normal cognition versus mild cognitive impairment.Vitamin D effects were significantly greater in apolipoprotein E ε4 non‐carriers versus carriers.Vitamin D has potential for dementia prevention, especially in the high‐risk strata. [ABSTRACT FROM AUTHOR]

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co‐occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four‐class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four‐class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R2). Using a data‐driven method, we show distinct and statistically meaningful co‐occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice. Highlights: We found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Background: In the absence of clear disease‐modifying drugs for dementia, modifiable risk factors have been explored to slow disease progression. Vitamin D deficiency is a risk factor, associated with higher risk of dementia. However, the role of vitamin D supplementation has been a subject of debate. Here we explored longitudinal associations between vitamin D supplementation and incident dementia in dementia‐free older adults from the National Alzheimer's Coordinating Center (NACC). Method: All participants had normal cognition (NC) or mild cognitive impairment (MCI) at baseline. Exposure to vitamin D supplementation was based on the NACC A4 medication form. Three vitamin D formulations were considered: calcium‐vitamin D, cholecalciferol, and ergocalciferol. For the primary analysis, participants with baseline exposure to any supplement were considered D+, while those without any exposure in advance of dementia diagnosis were considered D‐. Kaplan‐Meier curves were generated to compare ten‐year dementia‐free survival between D+ and D‐ groups. Cox proportional hazards models were implemented to assess the risk of dementia across vitamin D exposure groups, adjusted for baseline age, sex, years of education, race, APOE‐e4 status, cognitive diagnosis, and depression. To distinguish the associations of various vitamin D formulations with risk of dementia, sensitivity analyses were conducted to independently examine the effect of each formulation (calcium‐vitamin D, cholecalciferol, ergocalciferol). Result: The final sample consisted of 2836 D+ (mean age = 72.1; 68.4% female) and 5075 D‐ participants (mean age = 72; 45.1% female). MCI was more prevalent in D‐ vs D+ participants (35.7% vs 26.8%; p<0.001). Similarly, depression was more prevalent in D‐ vs D+ participants (6.9% vs. 4.3%, p<0.001). Across all three vitamin D formulations, exposure was associated with longer dementia‐free survival (p<0.001) and lower adjusted hazard ratio (HR) for incident dementia compared to no exposure (calcium‐vitamin D: HR = 0.56, 95%CI: 0.47‐0.67, p<0.001; cholecalciferol: HR = 0.72, 95%CI: 0.56‐0.91, p = 0.007; ergocalciferol: HR = 0.75, 95%CI: 0.63‐0.89, p<0.001) Conclusion: Our findings demonstrate that while adjusting for demographic, cognitive, behavioral, and genetic factors, exposure to vitamin D supplementation (calcium‐vitamin D, cholecalciferol, or ergocalciferol) in dementia‐free older adults was associated with lower risk of dementia, implicating vitamin D as a potential agent for dementia prevention. [ABSTRACT FROM AUTHOR]

Objectives: Research with younger adults has begun to explore associations between autism/autistic traits and vulnerability to Post Traumatic Stress Disorder (PTSD). Large scale studies and/or examination of age‐effects have not been conducted. Methods: Adults aged 50 years+ from the PROTECT study (n = 20,220) completed items about current and childhood socio‐communicative difficulties characteristic of autism. Approximately 1% (n = 251) endorsed high autistic traits, henceforth the Autism Spectrum Traits (AST) group. Differences between the AST and an age—and sex‐matched "Comparison Older Adults" (COA; n = 9179) group were explored for lifetime traumatic experiences and current symptoms of PTSD, depression, and anxiety. Results: Almost 30% of the AST group, compared to less than 8% of the COA, reported severe trauma in childhood/adulthood, including emotional, physical or sexual abuse. Elevated current PTSD symptoms were reported by AST compared to COA. An interaction was observed between autistic traits and trauma severity; the effect of level of trauma on PTSD symptoms was significantly greater for AST versus COA participants. This interaction remained significant when controlling for current depression and anxiety symptoms. Conclusions: The findings suggest that high autistic traits may increase the likelihood of experiencing trauma across the lifespan, and the impact of severe trauma on PTSD symptoms. Older adults with high (vs. low) autistic traits may be at greater risk of experiencing PTSD symptoms in latter life. Future research should test whether the pattern of results is similar for diagnosed autistic adults. Key points: Using data from PROTECT, a large healthy ageing cohort, approximately 30% of middle‐aged and older adults with high autistic traits reported severe trauma in childhood/adulthood compared to less than 8% of a low autistic trait comparison groupMiddle‐aged and older adults with high autistic traits also reported elevated current PTSD symptoms when compared to the low autistic trait comparison groupAn interaction was observed between autistic traits and trauma severity; the effect of level of trauma on PTSD symptoms was significantly greater for those with high autistic traits vs. low autistic traitsMiddle‐aged and older adults with high autistic traits—especially those who have experienced severe trauma ‐ may need additional support to mitigate this vulnerability to poor mental health later in life [ABSTRACT FROM AUTHOR]

Background: The neuropsychiatric syndrome mild behavioral impairment (MBI) describes an at-risk state for dementia and may be a useful screening tool for sample enrichment.We hypothesized that stratifying a cognitively normal sample onMBI status would enhance the association between genetic risk for Alzheimer’s disease (AD) and cognition. Methods: Data from 4458 participants over age 50 without dementia was analyzed. A cognitive composite score was constructed and the MBI Checklist was used to stratify those with MBI and those without. Polygenic scores for AD were generated using summary statistics from the IGAP study. Results: AD genetic risk was associated with worse cognition in the MBI group but not in the no MBI group (MBI: β = –0.09, 95% confidence interval: –0.13 to –0.03, P = 0.002, R² = 0.003). The strongest association was in those with more severe MBI aged ≥65. Conclusions: MBI is an important feature of aging; screening on MBI may be a useful sample enrichment strategy for clinical research. [ABSTRACT FROM AUTHOR]

Autism commonly aggregates in families, with twin studies estimating heritability to be around 80%. Subclinical autism‐like characteristics have also been found at elevated rates in relatives of autistic probands. Physical and psychiatric conditions have been reported at elevated rates in autistic children and adults, and also in their relatives. However, to date, there has been no exploration of how aging may affect this pattern. This study examined cross‐sectional data from the ongoing online PROTECT study. A total of 20,220 adults aged 50 years and older reported whether they have an autistic first‐degree relative. In total, 739 older adults reported having an autistic first‐degree relative (AFDR group) and 11,666 were identified as having no family history of any neurodevelopmental disorder (NFD group). The AFDR group demonstrated significantly higher frequencies of self‐reported psychiatric diagnoses and a greater total number of co‐occurring psychiatric diagnoses than the NFD group. Furthermore, the AFDR group reported elevated current self‐report symptoms of depression, anxiety, traumatic experience, and post‐traumatic stress than the NFD group. By contrast, few differences between AFDR and NFD groups were observed in physical health conditions, and no differences were observed in the total number of co‐occurring physical health diagnoses. These findings suggest that adults who have an AFDR may be at greater risk of poor mental, but not physical, health in later life. Older adults with autistic relatives may benefit from close monitoring to mitigate this susceptibility and to provide timely intervention. Autism Res 2020, 13: 641–654. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Children and adults with an autistic relative have been found to experience more psychiatric difficulties than those with no family links to autism. However, a few studies have explored what happens when these individuals get older. Examining over 20,000 adults age 50+, we found that older adults with an autistic relative experienced elevated rates of most psychiatric conditions but not physical conditions. Older adults with autistic relatives may benefit from close monitoring to mitigate this susceptibility and to provide timely intervention. [ABSTRACT FROM AUTHOR]

Introduction: Visual hallucinations (VH) have a significant impact on quality of life for people with Parkinson's disease (PD). A major reason for this is the well‐established link with cognitive impairment, but there is still a need for more longitudinal studies examining the specific cognitive domains which may be affected. The aim of this study was to profile decline in cognition associated with VH in a cohort of 69 individuals with PD over 1 year. Method: Visual hallucinations assessments were carried out every 3 months. Executive function and episodic memory were assessed at baseline and 1 year. All evaluations were performed via phone interviews. The presence or absence of VH was categorized based on the entirety of the year's data (i.e., no episodes and >0 episodes). We also defined a persistent VH group who had VH present at more than one time point and compared these with a no‐VH group and a group with transient VH (i.e., only one episode). Results: Linear mixed‐effect models showed that VH were associated with more rapid overall cognitive decline (−0.26, t = −2.39, p =.02), which was driven by executive function (−0.28, t = −2.48, p =.02). Persistent VH were associated with decline in executive function (−0.33, t = −2.4, p =.02), while no relationship was found for non‐persistent VH, suggesting that persistent VH be the major driver of this relationship. Conclusion: This finding brings greater clarity to the relationship between cognitive decline and VH in PD. Future research should examine the robustness of this phenotype for biomarkers studies and treatment interventions. [ABSTRACT FROM AUTHOR]

Background: Late‐life onset psychosis assessed in the Mild Behavioral Impairment framework (MBI‐psychosis) is a risk factor for dementia and known to be associated with impaired reasoning and memory in people without dementia. There is evidence that psychotic symptoms across diagnostic boundaries share some common genetic and neuropsychological correlates. In this study we aimed to determine whether MBI‐psychosis is associated cognitive deficits typically associated with other psychoses. To do this, we examined the relationship between MBI‐psychosis and scores on a specialised decision making and risk‐taking test, the Cambridge Gambling Task (CGT), performance on which is impaired in people with earlier life psychotic syndromes. Method: 476 participants were drawn from the online PROTECT registry on the basis of the Mild Behavioural Impairment Checklist (MBI‐C) ratings indicating psychosis and invited to complete the Cambridge Gambling Task. The association between performance on six CGT outcome measures, assessing elements of risk taking and decision making, and MBI‐psychosis was tested using linear regression (controlling for age, sex and education level). Result: Overall, there was little evidence of a substantial impact of MBI‐psychosis on CGT scores. Our study was powered to detect medium effect sizes. We found modest evidence of higher risk taking associated with more severe MBI‐psychosis scores (β = ‐0.1, SE = 0.05, p = 0.04) but this did not survive multiple testing correction. Conclusion: This is the first time a specialist decision making and risk‐taking test has been conducted in MBI‐psychosis. Although MBI‐psychosis is associated with a range of cognitive impairments in later‐life and dementia risk it appears that any shared neuropsychological basis with other psychoses is limited (though we cannot rule out a small non‐clinically significant effect size). This has possible implications for the diagnostic classification of later‐life onset mild psychotic symptoms. [ABSTRACT FROM AUTHOR]

Background: Psychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer's disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD is associated with a distinct profile of microbiological changes, but little is known about the molecular processes driving etiology. Method: Genome‐wide DNA methylation, small non‐coding (nc) RNAs (microRNA, transfer RNA, piwiRNA) and long coding and ncRNAs (mRNA, lincRNA, cicular RNAs) were quantified from 248 whole blood samples obtained from the Norwegian registry of persons assessed for cognitive symptoms (NorCog) cohort. Multi‐omics profiles of AD patients with psychosis (AD+P) were compared to the patients without psychosis (AD‐P). Result: There were significant differences in DNA methylation, small ncRNAs, and long coding and ncRNAs between AD+P and AD‐P patients. Further analysis revealed specific genomic regions and molecular pathways that were differentially methylated or expressed in AD+P patients compared to AD‐P patients. Conclusion: Our findings suggest that there may be distinct molecular signatures associated with AD psychosis, and that these differences may potentially be used as biomarkers for the early detection and diagnosis of AD psychosis. [ABSTRACT FROM AUTHOR]

Background: Psychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer's disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving aetiology. In this study, we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of post‐mortem brain samples. Method: Brain samples were obtained from the University of Pittsburgh Alzheimer's disease Research Centre (PITT‐ADRC). AD pathology was assessed and classified using CERAD neurotic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. We used the presence or absence of delusions and hallucinations, Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) to categorise our samples into AD with Psychosis (AD+P) and AD without Psychosis (AD‐P) groups. DNA was extracted, bisulfite‐treated and profiled on the Illumina Methylation EPIC Array and genotyping was carried out on the Illumina Global Screening Array (GSA). Result: After data quality control, 153 samples (40 AD‐P, 113 AD+P) remained for further analysis. The normalized beta values and the effect estimate values were used to extract Differentially Methylated positions (DMP) and differentially methylated regions (DMRs), respectively. To identify methylation quantitative trait loci (mQTLs) in both cis and trans, SNP‐CpG pairs with a p‐value threshold of <1e‐5 were calculated. We performed a colocalization analysis for the most significant DMPs and mQTLs, using publicly available summary statistics of relevant genome‐wide association studies (GWAS). Conclusion: The development of effective therapies for AD+P is an urgent priority and requires a better understanding of the molecular mechanisms underlying this syndrome. To address this, we have collated a well‐powered study cohort to interrogate the epigenetic basis of AD+P in the brain and have identified several loci of interest that require further study. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Parkinson's disease dementia (PDD) are termed Lewy body diseases (LBDs). These neurodegenerative diseases are classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). Whilst pathologically similar, symptomatic staging is different. Previous genome wide association studies (GWAS) have identified classic Alzheimer's disease (AD) and PD loci as risk loci in DLB. Therefore, we have used polygenic risk score (PRS) analysis to investigate the contribution of AD and PD variants in the LBDs. Method: DNA was extracted from bulk brain tissue from 481 individuals (162 controls, 95 DLB, 156 PDD and 68 PD) and genotyped on the Illumina global screening array. After a strict quality control and imputation pipeline, PRSs for multiple relevant traits using reference GWAS summary statistics were calculated using PRSice2. Result: Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. All groups, including controls are stratified for age and concomitant AD pathology. Assessing multiple PRSs for association with pathological development and clinical outcomes we have identified the contribution of genetic risk from related neurodegenerative and neuropsychiatric disorders in our cohort of PD, PDD and DLB samples. Conclusion: We have collated a well powered study cohort to interrogate the genetic basis of the Lewy body dementias and the relative contribution of AD and PD risk loci in the LBDs. We are currently generating methylation quantitative trait loci (mQTLs) for this dataset using previously generated matched DNA methylation data in the brain. [ABSTRACT FROM AUTHOR]

Background: Mild Behavioral Impairment (MBI) is a validated neurobehavioral syndrome characterized by later life emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. Psychosis is one of the five domains of MBI, although dementia risk with MBI‐psychosis is not well quantified. Here, we assessed the longitudinal association of MBI‐psychosis with incident dementia in dementia‐free participants. Method: Data were obtained from the National Alzheimer Coordinating Centre (NACC). Participants with neurodevelopmental, neurological and/or psychiatric disorders were excluded. Participants with normal cognition (NC) or mild cognitive impairment (MCI) at baseline were included. MBI‐psychosis status was defined based on persistence of Neuropsychiatric Inventory Questionnaire delusions and hallucinations symtoms across two consecutive visits. Kaplan‐Meier curves of ten‐year dementia‐free survival probability were generated for MBI‐psychosis versus those with no NPS prior to dementia diagnosis. Cox proportional hazard models were implemented to assess the risk of dementia, adjusted for age, sex, education, race, APOE e4 status, and clinical cognitive diagnosis. Interaction terms were included for relevant demographic variables. Secondary analyses were implemented to compare the risk associated with MBI‐psychosis to MBI without psychosis. Result: The final sample consisted of 3,446 participants with no NPS (age = 73.1±9.6; 63% female; 13.2% MCI), and 58 with MBI‐psychosis (age = 74.9±9.9; 55.2% female; 69% MCI). MBI‐psychosis was associated with lower chance of dementia‐free survival over ten years and 3.36 times greater risk for dementia compared to no NPS (CI:2.19‐5.15, p<0.001). Moderation analysis revealed that in NC, those with MBI‐psychosis were at 8.15 times greater risk of dementia than those with no NPS (CI:2.57‐25.88, p<0.001). In MCI, the MBI‐psychosis‐associated dementia risk was 3.08 times greater (CI:1.95‐4.85, p<0.001). In the secondary analysis comparing MBI‐psychosis to MBI without psychosis (n = 2068), MBI‐psychosis was associated with 2.29 times greater risk of dementia (CI: 1.52‐3.4, p<0.001). Conclusion: Although psychosis is an infrequently endorsed MBI domain, when present, it is associated with substantial risk for dementia. This risk differs between cognitive strata and is significantly greater when MBI‐psychosis emerges in NC versus MCI. The emergence of persistent psychotic symptoms in later life should be flagged for clinical attention, and a dementia assessment considered. [ABSTRACT FROM AUTHOR]

Background: There are at least 50 million people with Alzheimer's Disease (AD) or other dementias worldwide. About 50% of people with AD may develop psychotic symptoms (delusions and hallucinations). However, there is no effective pharmacological therapy for psychosis in AD and all current treatments are based on antipsychotics originally designed for other disorders like schizophrenia. In this study, we identify the molecular signature of psychosis in AD in post‐mortem brain samples and then use the connectivity map (CMAP) and library of network‐based cellular signatures (LINC) to predict candidate drugs based on the disease transcriptional signature. Method: We generated RNA‐Seq data (Illumina Stranded mRNA Prep) and compared the gene expression levels across 4 groups: Control, AD with no psychosis (AD), AD with Delusions (ADD), and AD with both Delusions and Hallucinations (ADDH). The final identified differentially expressed up and down‐regulated genes (DEGs) were used as query signatures in the CMAP and LINC databases to identify drugs that could potentially reverse the gene expression signatures in disease samples. To investigate the disease mechanisms and the effect of repurposed drugs on it, a drug‐target interaction network was reconstructed and combined with the human interactome. Enrichment analysis of this network identifies AD and psychosis‐related pathways and the potential effect the nominated drugs have on them. Result: After filtering out the common DEGs, 357, 171, and 66 unique genes remained in the AD, ADD, and ADDH signature sets, respectively. The signatureSearch package was used to search transcriptome signatures against CMAP and LINC. The top ranked drugs, based on negative connectivity scores, were selected as final results. Gene set enrichment analysis of the drug target genes presented some key pathways and activities related to psychiatric disorders. For example, serotonin receptor signalling pathway is one of the most over‐represented pathway of target genes in both ADD and ADDH groups. Conclusion: This study can improve our understanding of the molecular mechanisms underlying AD psychosis. The candidate drugs we have identified could be repurposed for clinical trials of psychosis in AD and provide valuable knowledge for future pharmacological research. [ABSTRACT FROM AUTHOR]

Background: Previous research suggests around 5–10% of cognitively normal older people report some degree of psychotic experiences as measured in the Mild Behavioral Impairment framework. Such late‐onset symptoms potentially confer a relatively high risk for neurodegenerative disease so there is a need for studies examining their clinical correlates prior to dementia onset. We compared the relationship between psychotic symptoms and progression to cognitive impairment in a large community‐dwelling sample of adults over 50. Method: 5,085 participants were drawn from the PROTECT study. These individuals had no reported neurological diseases (including MCI), psychotic disorders or cognitive impairment as rated by the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE). Cognitive impairment was operationalised as a score of >3.3 on the IQCODE. Participants were followed up for a maximum of 5 years. IQCODE scores were taken every. Survival until 'cognitive impairment' (i.e. IQCODE >3.3) was the primary outcome. At baseline participants were dichotomised into those scoring >0 on any of the 5 items pertaining to psychosis on the Mild Behavioral Impairment Checklist ('MBI‐psychosis' group) and those scoring 0 on all 5 items ('no symptoms' group). Survival until IQCODE >3.3 was assessed in a Cox proportional hazards model (adjusting for age, gender, education and mental health diagnoses). The frequency of other medical conditions and Instrumental Activities of Daily Living (IADL) impairment was also compared between the two groups. Result: There were 429 (8%) participants in the MBI‐psychosis group (72% men) and 4,656 in the no symptom group (72% men). The mean age was 63 (SD: 6.9). MBI‐psychosis was associated with a 3‐fold (95% CI: 2.4‐3.6, p<0.0001) higher risk of cognitive impairment relative to the no symptom group. There were modestly higher proportions of the following conditions in the MBI‐psychosis group compared with the no symptoms group (p<0.05): heart disease (9%, 6%), high blood pressure (33%, 27%), high cholesterol (30%, 25%), hypothyroidism (11%, 7%), arthritis (26%, 21%). There was no difference in IADL impairments. Conclusion: Relatively mild psychotic symptoms that emerge in later are associated with an increased risk of cognitive decline, suggesting that these symptoms in the cognitive normal population may be of clinical significance. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is a debilitating symptom in Parkinson's disease (PD), with high variability in onset and course of progression. This present study aimed to establish an accurate multivariate machine learning model to predict cognitive outcome in newly diagnosed PD. Method: Using baseline measures from the Parkinson's Progression Markers Initiative (PPMI) cohort we subset clinical, biofluid and genetic/epigenetic variables. Annual cognitive assessments over an eight‐year time span were used to define two outcomes of i) dementia conversion, and ii) cognitive impairment. Outcomes and variable subsets were tested using multiple machine learning (ML) algorithms (random forest, elasticnet, SVM‐linear and cforest) to predict prognosis of individual cognitive decline in PD. Prediction was assessed using multiple measures including Area under the Curve (AUC) and Mathews Correlation Coefficient (MCC). Result: For both cognitive outcomes, irrespective of the of ML algorithm, models consisting of clinical variables alone performed best, with high specificity and the largest AUC's (0.88 ‐ 0.92) and MCC's (0.57‐0.80). Notably, cognitive impairment outcome showed better sensitivity than dementia conversion outcome (0.72 – 0.81 vs 0.29 – 0.64, respectively). Addition of biological and genetic variables did not largely improve the model performance. However, a number of cerebrospinal fluid (CSF) proteins and epigenetic markers showed high predictive weighting in multiple models, when included alongside clinical variables. Conclusion: Machine learning algorithms can accurately predict cognitive impairment development in PD. Within the generated models, clinical predictors appear to play a more prominent role than biological predictors. We further present additional future study data, expanding epigenetic research into PD dementia. [ABSTRACT FROM AUTHOR]

Objective: To explore the current practices and challenges in night-time care for people with dementia living in care homes in the UK.Methods: Focus group discussions (FGD) were held with care staff and family carers from five care homes in South London. To supplement the FGD data, an online survey was circulated to family carers (n = 16), and informal interviews were conducted with night-time care staff and nurses (n = 19). The questions for the online survey were designed to specifically explore the themes that emerged from the FGD.Results: Thematic analysis revealed eight key themes in the management of sleep disturbance in people with dementia living in care homes: current night-time care practices, dissonance in perceived causes of sleep disturbances, inconsistencies in treatment options, insufficient staffing levels, working relationships between shifts, nurse burden and responsibility, communication as a critical challenge, connecting with residents and one overarching theme of balance.Conclusions: The findings of this study highlight the need for an evidence-based sleep disturbance management programme designed for use in care homes and informed by stakeholders. The key themes identified represent the major barriers to good quality care and areas which future programmes will need to address to improve the quality of night-time care in care homes. There are clearly opportunities for future examination of non-pharmacological night-time care management programmes for use in the population. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a highly heterogeneous disorder, encompassing a complex spectrum of clinical presentation including motor, sleep, cognitive and neuropsychiatric symptoms. Together the cumulative effects of these symptoms have huge impacts on individual quality of life. Here we aim to investigate genome wide DNA‐methylation in post‐mortem PD brain samples and test for region specific association with common secondary symptoms of sleep disorder, visual hallucinations and dementia. Method: DNA methylation data was generated on the Illumina 450K microarray for a cohort of 142 individual post mortem brain samples from the Frontal Cortex (FC), Caudate Putamen (CP) and Substantia Nigra (SN). Data was quality controlled following standardized, previously published pipelines. Clinical records for each case were assessed for binary status of sleep disorder, visual hallucinations and dementia. Linear models were used to identify differentially methylated positions (DMPs) for each of these outcomes, controlling for age, sex, post‐mortem interval and inferred cell‐type proportions as covariates. Result: Thus far, results been only been generated for the dementia phenotype, with one genome wide significant loci passing multiple testing correction in the frontal cortex (p = 5.25e‐8). This DMP, found in the gene FAM175A / ABRAXAS‐1 (cg14699004), is hypomethylated in PD patients with preserved cognition, with comparable higher measures in PD‐Dementia and control samples. This effect appeared to be FC specific, with no DMPs passing genome wide significance in other brain regions tested. Conclusion: Preliminary evidence indicates potential sub‐phenotype associated DMPs, with methylation at one site specifically associated with dementia within the FC. Current analysis is focussing on generating reference results across each of the phenotypes and brain regions assessed. Future work will look at Weighted Gene Correlation Network Analysis to identify networks associated with these individual phenotypes. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is a common and debilitating symptom in Parkinson's disease (PD) with high variability in individual trajectory of decline. We sought to explore heterogeneity in the trajectory of individual cognitive change in a cohort of early stage PD patients and test association to cumulative genetic risk identified in large scale Genome Wide Association Studies (GWAS). Method: Using longitudinal measures of the Montreal Cognitive Assessment (MoCA) we employed latent class mixed modelling (LCMM) to identify and investigate unknown populations in the Parkinson's Progression Markers Inititative (PPMI) de‐novo PD cohort. Tranformed MoCA scores were modelled as a quadratic function of years from baseline, controlling for age, gender and motor symptom severity. Optimal group number was identified and determined using standardly advised model fit metrics. Polygenic risk scores (PRS) for five GWAS were calculated using PRSice‐2 applied to genotyping array data. Association of PRS with cognitive groups was tested using linear models and ANOVA tests. Result: LCMM showed optimal fit statistics for three classes (lowest BIC, high entropy) and these groups were retained for further analysis The largest identified class (n = 240) on average, presented at baseline with higher MoCA scores and remained stable over time. The second class (n = 132) presented with lower MoCA scores and showed a slow declining trajectory whilst the smallest class (n = 13) presented with lower MoCA scores but declined at a rapid rate. Educational attainment and Alzheimer's disease (AD) GWAS derived PRS were significantly associated with cognitive class and explained the highest amount of phenotypic variance. For PD case‐control status, only the PD PRS was significantly associated with Parkinson's status and explained a similar level of phenotypic variation. Conclusion: Latent class analysis may provide utility in subsetting longitudinal cognitive outcome groups for use in groupwise comparisons. Using this method we show evidence for association of educational attainment and AD cumulative genetic risk and worse cognitive outcomes in early PD. [ABSTRACT FROM AUTHOR]

Background: Psychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer's disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving etiology. In this study we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 192 post‐mortem brain samples. Method: Brain samples with corresponding in life neuropsychiatric assessments were obtained from the University of Pittsburgh Alzheimer's disease Research Center (PITT‐ADRC). AD pathology was assessed and classified using CERAD neuritic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. The presence or absence of delusions and hallucinations was scored on the CERAD Behavioral Rating Scale. DNA was extracted, bisulfite treated and then profiled on the Illumina Methylation EPIC Array. Result: After data processing and quality control we used linear regression models to compare 152 AD+P samples to 40 AD samples without psychosis (AD‐P). A regional analysis of spatially correlated p‐values highlighted four differentially methylated regions (DMRs) associated with psychosis, which are being replicated in other data sets and validated for cell specificity using fluorescence activated nuclei sorting (FANS). Conclusion: The development of effective therapies for AD+P is an urgent priority. To address this we have collated a well powered study cohort to interrogate the epigenetic basis of AD+P, finding significant methylomic variation. This variation provides an insight into potential mechanisms and biomarkers which will help to identify drug targets and enable better treatment with existing medications. [ABSTRACT FROM AUTHOR]

Background: The Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Parkinson's disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different diseases from one another. Method: Bulk tissue from the cingulate gyrus and prefrontal cortex was analyzed on the Illumina Infinium Methylation EPIC array generating a quantitative measure of DNA methylation for over 850,000 CpG sites (n=∼100/disease group). Linear regression and pathway analyses were then used to identify loci that are significantly different or specific to each disease. Result: Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Age‐matched control cases have been selected that have similar levels of concomitant AD pathology to the disease groups. We have identified significant changes in methylation associated with both phenotype and neuropathology alongside the cellular pathways these changes correspond with. Conclusion: We have collated a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. We have completed DNA methylation analysis for two disease relevant brain regions and identified both phenotype neuropathology associated changes within these regions. Processing of samples for fluorescence activated nuclei sorting (FANS) and laser capture microdissection (LCM) has begun (n=15/group) to assess the cell type specificity of the methylation changes and the effect of Lewy bodies on neuronal methylation respectively. [ABSTRACT FROM AUTHOR]

Background: Evidence continues to build to support the value of regular physical exercise as an affordable dementia risk reduction intervention for cognitively healthy older adults. However, the types and intensities of exercise that yield the greatest benefits are yet to be established. This study uses the recently published FLAME cognitive analysis measure to explore the impact of exercise on cognition in older adults in an online cohort. Method: PROTECT is an innovative online study (www.protect.org.uk) in adults aged 50 and over in the UK, Participants complete annual cognitive assessment in addition to lifestyle and health measures. Participants were divided into three cohorts (Normal Cognition, Stage 2 Early AD and Stage 3 Early AD – based on the FDA framework) using baseline data from the cognitive assessment battery. Participants (n=8079) in these groups who completed the exercise questionnaire on two consecutive timepoints and within two weeks of cognitive assessment were included in this analysis. The analysis compared change in cognition from baseline using a one‐way ANOVA with physical activity type as a fixed factor and gender, age and education fitted as covariates. Result: Composite measures of Speed of Attention [p=0.0003, d=0.26], Accuracy of Attention [p=0.0008, d=0.21], Memory [p=0.0017, d=0.11] and Executive Function [p=0.0006, d=0.09], as well as the composite FLAME measure [p=0.006, d=0.24] all showed significant benefits in participants with Normal Cognition who performed brisk walking at least twice a week, compared to indiviudals with lower levels of exercise. These benefits were also evident in participants In the stage 2 and 3 Early AD groups [Stage 2: FLAME p=0.003, d=0.13; Stage 3: FLAME p=0.006, d=0.19]. Conclusion: These findings contribute further evidence that regular participation in exercise of at least moderate intensity offers benefit to major aspects of cognitive function in both healthy aging individuals and those at the pre‐clinical stages of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has presented an extraordinary and unprecedented challenge to individuals, society and governments. Aside from the direct clinical impacts of COVID‐19, the social restrictions are likely to have had considerable impacts on cognitive and mental health. Understanding these trends will be critical to improve future responses to outbreaks and to improve the treatment and care provided to individuals affected. Method: PROTECT is an innovative online study (www.protect.org.uk) in adults aged 50 and over in the UK, Participants complete annual cognitive assessment and health measures including the PHQ‐9 and GAD‐7. Participants were divided into three cohorts (Normal Cognition, Stage 2 Early AD and Stage 3 Early AD, based on the FDA framework) using baseline data from the cognitive assessment battery. This analysis utilised data from a total of 5301 participants followed annually over the last 5 years, including the year of the COVID‐19 pandemic. It also utilises the newly published FLAME composite cognitive measure that has shown sensitivity to cognitive decline. Result: In the participants with worsening PHQ‐9 and GAD‐7 scores between 2019 and 2020 (63%), composite measures of Speed [Stage 2: p=0.008, d=0.27; Stage 3: p=0.0006, d=0.17], and accuracy of Attention [Stage 2: p=0.004, d=0.11; Stage 3: p=0.0016, d=0.21], Memory [Stage 2: p=0.0011, d=0.3; Stage 3: p=0.0009, d=0.22] and Executive Function [p=0.08], as well as the composite FLAME measure [p=0.0014, d=0.28], showed a larger decline over the last 12 months compared to the prior assessment period. Whilst no significant increase in the rate of decline was seen in people without worsening of depression or anxiety. Conclusion: The pandemic has had a detectable and significant detrimental impact on key aspects of cognitive health in adults over 50, including adults with early cognitive impairment (stage 2 and 3 pre‐clinical AD in the FDA framework) mediated predominantly through worsening of mental health. [ABSTRACT FROM AUTHOR]

Background: Late‐life onset neuropsychiatric symptoms (NPS) have received increasing attention in recent years because of their prognostic potential for neurodegenerative disease. As focus intensifies, appropriate measurement will be critical. The emergence of Mild Behavioral Impairment ‐ which describes late‐life onset apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness, and psychosis ‐ and the MBI‐Checklist (MBI‐C), developed to capture these symptoms in accordance with the ISTAART‐AA MBI criteria, has been a step forward. Previous work has demonstrated only modest correlation between proxy informant and self‐rated MBI‐C responses, but the significance of these differences in responses is not yet understood. Moreover, there is relatively less work examining non‐affective late‐life NPS. To explore both of these factors, we examined the relationship between genetic risk for Alzheimer's disease and the five MBI domains in a sample of cognitively normal older adults. Method: Genetic and clinical data from 2,529 cognitively normal participants aged ≥65 in the PROTECT study were analysed. MBI was evaluated using the MBI‐C; individual domain scores were calculated, and participants dichotomised into domain 'present' or 'absent'. Polygenic risk scores (PRS) for Alzheimer's disease were used as predictors in binary logistic regression models with the MBI domains, each rated by self and by proxy, as separate outcomes. To evaluate whether AD PRS was associated with depression, the most commonly considered NPS in older adults, we also tested the association between AD PRS and PHQ‐9 score (>=5 or <5). Result: AD PRS was associated with a greater risk of apathy and impulse dyscontrol in proxy MBI‐C ratings but not in self‐report MBI‐C ratings (OR: 1.2 [95% CI: 1.06‐1.40], p=0.004; OR: 1.12 [95% CI: 1.01‐1.24], p=0.03, respectively). There was no association between AD PRS and PHQ‐9 symptoms. Conclusion: Proxy informant and self‐reported MBI‐C elicit different associations in analysis of AD genetic risk. These findings suggest that even in cognitively normal older adults, proxy informant ratings are important to consider in the evaluation of NPS and risk of dementia. There was no association between PHQ‐9 symptoms and AD PRS, highlighting the importance of the multi‐domain MBI‐C as a specific tool to capture late‐life NPS as risk factors for dementia. [ABSTRACT FROM AUTHOR]

Background: Apathy is one of the most common Neuropsychiatric Symptom (NPS) and is associated with poor clinical outcomes. Apathy remains under‐researched and its medical classification remains unclear, potentially associated with the fact that apathy is commonly a comorbidity with depression. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. Method: Using latent class analysis (LCA) we analysed data from the KCL Care Home Research Network study with 349 participants (an observational study of people living with dementia in care homes). The aim was to understand how apathy and depression phenotypes cluster together. Apathy and depression were defined on the basis of item G (Apathy) and D (Depression) of the NPI‐NH scale, combining the 7 apathy subquestions with the 8 depression subquestions, rated as yes or no. Predictors of class membership were then analysed, including other NPS, demographics, medication and Clinical Dementia Rating (CDR). Result: The LCA analysis showed a 4‐cluster group which was considered the best model: No symptoms, predominantly depression, apathy/depression, and a predominantly apathy group. Those in the apathy/depression class were more likely to experience psychosis symptoms compared to the no symptoms class, whilst those in the predominantly apathy class were more likely to have a higher CDR score compared to the no symptoms class. Conclusion: Using a data driven method, we show distinct clustering of apathy and depression symptoms in this cohort. There was evidence that these clusters have different clinical associations which may help inform diagnostic categories for research studies and clinical practice. Potentially, the four subtypes may be used in future studies to further evaluate their utility in biomarker studies in dementia. [ABSTRACT FROM AUTHOR]

Background: Mild Behavioral Impairment describes a spectrum of later‐life onset sustained neuropsychiatric symptoms which are a risk state for dementia. Symptoms which constitute MBI can be grouped into apathy, mood, impulse dyscontrol, social inappropriateness and psychosis. While previous studies have shown the presence of any MBI symptoms (i.e. a global measure) to be associated with worse cognitive performance over one‐year, little is known about the individual constituent domains. In this study we examined the cognitive correlates of each of the five MBI domains over two years in a cognitively normal sample. Method: Data from 8,001 participants aged 50 or over taking part in the PROTECT study were analysed. Cognitive performance was assessed at baseline and after two years via completion of a battery of four tests broadly assessing working memory and elements of executive function (paired associates learning, digit span, self‐ordered search and verbal reasoning). MBI status was ascertained at baseline using the MBI‐C at the same time as performance on the first cognitive test. Change in cognitive performance was calculated was a difference score (year 2‐baseline) and analysed in a regression model with MBI domain score as the predictor and controlling for relevant medical and demographics covariates. Result: The mean age of the sample was 62 and ∼75% were women. Apathy, mood and impulse dyscontrol were associated with worse cognitive performance across all four cognitive tests, the largest effects were observed for impulse dyscontrol on self‐ordered search and verbal reasoning (β= ‐0.05, p=<0.001; β= ‐0.12, p=0.005 respectively). Social inappropriateness was only associated with worse performance on digit span and self‐ordered search (β= ‐0.08, p=0.005; β= ‐0.11, p=0.018) while there were no cognitive changes associated with psychotic symptoms. Conclusion: We present the first longitudinal analysis of the relationship between individual MBI domains and cognition. The worse cognitive performance over two years associated with impulse dyscontrol and social inappropriateness highlight the importance of non‐affective symptomology in later life. [ABSTRACT FROM AUTHOR]

Background: The Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Parkinson's disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different LB diseases from one another. Method: Bulk tissue from the cingulate gyrus and prefrontal cortex will be as analysed for DNA methylation levels using the Illumina Infinium Methylation EPIC array to generate quantitative methylation data for over 850,000 CpG sites across the genome (n=∼100/disease group). Linear regression and pathway analyses will be used to identify loci that are significantly different or specific to each disease. Following this we will validate loci and determine their cellular specificity using a subset of samples (15 DLB, 15 PDD, 15 PD only, 15 controls) using fluorescence activated cell sorting (FACS). In each sample we will isolate various different cellular populations, including neurons, microglia, oligodendrocytes and astrocytes before profiling these using the EPIC array. Result: Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Control cases have been selected for matched age and levels of concomitant AD pathology. Cases for FACS (n=15/group) have been selected to allow where possible a high base RIN, pH and minimal post‐mortem interval. Conclusion: We are collating a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. Follow up FACS sorting and analysis will allow for the cell specific methylation changes occurring in each of the LB diseases. [ABSTRACT FROM AUTHOR]

Background: Risks of stroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in people with dementia but specific mechanisms are unclear. In a novel application of a drug repurposing paradigm, we aimed to identify candidate underlying mechanisms in‐silico by leveraging publicly available transcriptomic data. Methods: Whole transcriptome signatures were first generated for three antipsychotics (amisulpride, risperidone and volinanserin) using RNA‐sequencing in SHSY‐5Y cell lines. These compounds were chosen to represent a range of mechanisms of action relevant to clinically used compounds and novel compounds in development. An unbiased high throughput screen generated correlations between each compound and a public repository of over 100,000 human disease samples. From a long list of statistically significant hits, correlations between each antipsychotic and conditions/diseases related to known side effects of antipsychotic use in dementia were identified and gene set enrichment analysis performed. Results: Statistically significant associations were found between antipsychotic transcriptional signatures and atherosclerosis (amisulpride p=0.002; risperidone p=6.98x10‐6; volinanserin p=5.5x10‐8), venous thromboembolism (risperidone p=8.13x10‐7; volinanserin p=0.002) and influenza (amisulpride p=0.002). Pathways enriched in antipsychotic signatures were linked to the cardiovascular system, the immune system and inflammation (including brain derived neurotrophic factor, platelet derived growth factor receptor beta, tumor necrosis factor alpha signalling). Conclusion: Using a novel, high throughput approach, these findings implicate cardiovascular disease and the immune system in the mechanisms of action of atypical antipsychotics, providing a list of priority candidate mechanisms of harm relevant to dementia research. This approach could have implications for drug safety screening of psychotropic drugs in dementia. [ABSTRACT FROM AUTHOR]

Background: With the evolution of technologies to extract DNA and undertake analysis from saliva samples, it is now feasible to collect postal samples for genetic analysis as part of cohort studies run on digital platforms. Ethics and engagement will be discussed and Mild Behavioral Impairment (MBI) is presented as an example of where this approach has delivered a substantial and cost‐effective study. MBI, a late‐life neuropsychiatric syndrome, is associated with faster progression to dementia and Aβ deposition even in healthy adults. MBI screening may enrich samples with individuals at risk for dementia, with benefits to clinical studies and possibly trials. Method: 25,000 participants from the PROTECT digital platform were invited to provide a saliva sample by post. Ethics approval was underpinned by an on‐line consent process, genotypes were not disclosed to participants. Polygenic scores (PRS) for Alzheimer's disease (AD) were calculated and split by tertile (representing low, medium and high AD genetic risk). Data were analysed as a whole sample then stratified by the presence of MBI. Result: 87% of PROTECT participants agreed to provide genetic samples by post. 10,000 of these have been genotyped. 75% of the sample were women and the mean age was 62 (range: 50‐100). At the time of data freeze, genetic, MBI and cognitive data were available for 3,126. AD genetic risk was associated with a lower cognitive score (F(2,3119)=3.93, p=0.02; mean difference between low and high genetic risk: ‐15, p=0.02, Cohen's d=0.13). In stratified analysis, genetic risk for AD was associated with worse cognition but only in the MBI group (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). There was a significant difference between the high and low genetic risk groups (mean difference: ‐0.22, p=0.005); the effect size was stronger than in the whole sample analysis (Cohen's d increase from 0.13 to 0.19). Conclusion: High degrees of engagement can be achieved to obtain DNA samples from participants in online cohort studies. With respect to MBI, these findings demonstrate that neuropsychiatric symptoms may modify the relationship between genetic risk for AD and cognitive impairment. MBI screening may represent a useful sample enrichment strategy for clinical studies and trials. [ABSTRACT FROM AUTHOR]