Genetic association between APOE*4 and neuropsychiatric symptoms in patients with probable Alzheimer's disease is dependent on the psychosis phenotype

Background: Neuropsychiatric symptoms such as psychosis are prevalent in patients with probable Alzheimer's disease (AD) and are associated with increased morbidity and mortality. Because these disabling symptoms are generally not well tolerated by caregivers, patients with these symptoms tend to be institutionalized earlier than patients without them. The identification of protective and risk factors for neuropsychiatric symptoms in AD would facilitate the development of more specific treatments for these symptoms and thereby decrease morbidity and mortality in AD. The E4 allele of the apolipoprotein E (APOE) gene is a well-documented risk factor for the development of AD. However, genetic association studies of the APOE 4 allele and BPS in AD have produced conflicting findings.Methods: This study investigates the association between APOE and neuropsychiatric symptoms in a large sample of clinically well-characterized subjects with probable AD (n=790) who were systematically evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Behavioral Rating Scale for Dementia (BRSD).Results: Our study found that hallucinations were significantly more likely to occur in subjects with no APOΕ4 alleles than in subjects with two Ε4 alleles (15% of subjects and 5% of subjects, respectively; p=.0066), whereas there was no association between the occurrence of delusions, aberrant motor behavior, or agitation and the number of Ε4 alleles. However, 94% of the subjects with hallucinations also had delusions (D+H).Conclusion: These findings suggest that in AD the Ε4 allele is differentially associated with D+H but not delusions alone. This is consistent with the hypothesis that distinct psychotic subphenotypes may be associated with the APOE allele. © 2012 Christie et al.; licensee BioMed Central Ltd

Trajectories of dementia-related cognitive decline in a large mental health records derived patient cohort

Background: Modeling trajectories of decline can help describe the variability in progression of cognitive impairment in dementia. Better characterisation of these trajectories has significant implications for understanding disease progression, trial design and care planning. Methods: Patients with at least three Mini-mental State Examination (MMSE) scores recorded in the South London and Maudsley NHS Foundation Trust Electronic Health Records, UK were selected (N = 3441) to form a retrospective cohort. Trajectories of cognitive decline were identified through latent class growth analysis of longitudinal MMSE scores. Demographics, Health of Nation Outcome Scales and medications were compared across trajectories identified. Results: Four of the six trajectories showed increased rate of decline with lower baseline MMSE. Two trajectories had similar initial MMSE scores but different rates of decline. In the faster declining trajectory of the two, a higher incidence of both behavioral problems and sertraline prescription were present. Conclusions: We find suggestive evidence for association of behavioral problems and sertraline prescription with rate of decline. Further work is needed to determine whether trajectories replicate in other datasets

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordPsychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD − P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10−8) and one spanning the 3′-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56–0.76), p = 3.24 × 10−8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.National Institute on Aging (NIA

Genome-wide association study of Alzheimer's disease with psychotic symptoms

International audiencePsychotic symptoms occur in approximately 40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD-P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 x 10-7; 'AD+PvControls' P=1.11 x 10-4). SNPs upstream of SLC2A9 (rs6834555, P=3.0x10-7) and within VSNL1 (rs4038131, P=5.9x10-7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised

Psychiatric Disorders in Dementia

Alzheimer’s disease (AD) is the most common form of dementia, a neurodegenerative disorder which is characterized not only by cognitive deterioration but also by a diversity of behavioral and psychological signs and symptoms of dementia (BPSD). BPSD in AD or other dementia subtypes such as frontotemporal dementia (FTD) or dementia with Lewy bodies (DLB) consist of delusions, hallucinations, activity disturbances, aggression/agitation, diurnal rhythm disturbances, mood disorders, apathy, and anxieties/phobias. Neuroimaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are very essential and useful imaging tools to differentially diagnose between AD and non-AD or healthy control subjects or between different dementia subtypes, such as AD and DLB or FTD. Besides their diagnostic utility, PET and SPECT are useful tools to investigate the cerebral pathophysiology of BPSD in dementia.Below, PET and SPECT neuroimaging research in dementia spanning the last three decades has been systematically reviewed. The most commonly used PET and SPECT radioligands, as well as new developments in the field, all targeting different and unique aspects of neurodegeneration, are described. Furthermore, PET and SPECT research in BPSD with a main focus on depression, apathy, and psychosis in AD, DLB, and FTD are discussed in detail. On the whole, both PET and SPECT have demonstrated that depending on the behavioral phenomenon and dementia subtype, BPSD are the fundamental expression of very regional cerebral pathological events rather than a diffuse brain illness