Differential regulation of MAP2 by phosphorylation events in proline-rich versus C-terminal domains.

MAP2 is a critical cytoskeletal regulator in neurons. The phosphorylation of MAP2 (MAP2-P) is well known to regulate core functions of MAP2, including microtubule (MT)/actin binding and facilitation of tubulin polymerization. However, site-specific studies of MAP2-P function in regions outside of the MT-binding domain (MTBD) are lacking. We previously identified a set of MAP2 phosphopeptides which are differentially expressed and predominantly increased in the cortex of individuals with schizophrenia relative to nonpsychiatric comparison subjects. The phosphopeptides originated not from the MTBD, but from the flanking proline-rich and C-terminal domains of MAP2. We sought to understand the contribution of MAP2-P at these sites on MAP2 function. To this end, we isolated a series of phosphomimetic MAP2C constructs and subjected them to cell-free tubulin polymerization, MT-binding, actin-binding, and actin polymerization assays. A subset of MAP2-P events significantly impaired these functions, with the two domains displaying different patterns of MAP2 regulation: proline-rich domain mutants T293E and T300E impaired MT assembly and actin-binding affinity but did not affect MT-binding, while C-terminal domain mutants S426E and S439D impaired all three functions. S443D also impaired MT assembly with minimal effects on MT- or actin-binding. Using heterologous cells, we also found that S426E but not T293E had a lower capability for process formation than the wild-type protein. These findings demonstrate the functional utility of MAP2-P in the proline-rich and C-terminal domains and point to distinct, domain-dependent regulations of MAP2 function, which can go on to affect cellular morphology.

Targeting the post-synaptic proteome has therapeutic potential for psychosis in Alzheimer Disease.

Individuals with Alzheimer Disease who develop psychotic symptoms (AD + P) experience more rapid cognitive decline and have reduced indices of synaptic integrity relative to those without psychosis (AD-P). We sought to determine whether the postsynaptic density (PSD) proteome is altered in AD + P relative to AD-P, analyzing PSDs from dorsolateral prefrontal cortex of AD + P, AD-P, and a reference group of cognitively normal elderly subjects. The PSD proteome of AD + P showed a global shift towards lower levels of all proteins relative to AD-P, enriched for kinases, proteins regulating Rho GTPases, and other regulators of the actin cytoskeleton. We computationally identified potential novel therapies predicted to reverse the PSD protein signature of AD + P. Five days of administration of one of these drugs, the C-C Motif Chemokine Receptor 5 inhibitor, maraviroc, led to a net reversal of the PSD protein signature in adult mice, nominating it as a novel potential treatment for AD + P.

Trio and Kalirin as unique enactors of Rho/Rac spatiotemporal precision.

Rac1 and RhoA are among the most widely studied small GTPases. The classic dogma surrounding their biology has largely focused on their activity as an "on/off switch" of sorts. However, the advent of more sophisticated techniques, such as genetically-encoded FRET-based sensors, has afforded the ability to delineate the spatiotemporal regulation of Rac1 and RhoA. As a result, there has been a shift from this simplistic global view to one incorporating the precision of spatiotemporal modularity. This review summarizes emerging data surrounding the roles of Rac1 and RhoA as cytoskeletal regulators and examines how these new data have led to a revision of the traditional dogma which placed Rac1 and RhoA in antagonistic pathways. This more recent evidence suggests that rather than absolute activity levels, it is the tight spatiotemporal regulation of Rac1 and RhoA across multiple roles, from oppositional to complementary, that is necessary to execute coordinated cytoskeletal processes affecting cell structure, function, and migration. We focus on how Kalirin and Trio, as dual GEFs that target Rac1 and RhoA, are uniquely designed to provide the spatiotemporally-precise shifts in Rac/Rho balance which mediate changes in neuronal structure and function, particularly by way of cytoskeletal rearrangements. Finally, we review how alterations in Trio and/or Kalirin function are associated with cellular abnormalities and neuropsychiatric disease.

MAP2 is differentially phosphorylated in schizophrenia, altering its function.

Schizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of microtubule-associated protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach, we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into three modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wild type and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz-that a large proportion of individuals have a "MAP2opathy"-in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia.

Reduced dendritic spine density (DSD) in cortical layer 3 of the superior temporal gyrus (STG), and multiple other brain regions, is consistently observed in postmortem studies of schizophrenia (SZ). Elucidating the molecular mechanisms of this intermediate phenotype holds promise for understanding SZ pathophysiology, identifying SZ treatment targets and developing animal models. DNA methylation (DNAm), the addition of a methyl group to a cytosine nucleotide, regulates gene transcription and is a strong candidate for such a mechanism. We tested the hypothesis that DNAm correlates with DSD in the human STG and that this relationship is disrupted in SZ. We used the Illumina Infinium HumanMethylation450 Beadchip Array to quantify DNAm on a genome-wide scale in the postmortem STG from 22 SZ subjects and matched non-psychiatric control (NPC) subjects; DSD measures were available for 17 of the 22 subject pairs. We found DNAm to correlate with DSD at more sites than expected by chance in NPC, but not SZ, subjects. In addition, we show that the slopes of the linear DNAm-DSD correlations differed between SZ and NPC subjects at more sites than expected by chance. From these data, we identified 2 candidate genes for mediating DSD abnormalities in SZ: brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) and discs large, Drosophila, homolog of, 1 (DLG1). Together, these data suggest that altered DNAm in SZ may be a mechanism for SZ-related DSD reductions.

Genome-wide copy-number variation study of psychosis in Alzheimer's disease.

About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.

Genome-wide association study of Alzheimer's disease.

In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD). However, the genetic effect attributable to known loci is about 50%, indicating that additional risk genes for LOAD remain to be identified. In this study, we have used a new GWAS data set from the University of Pittsburgh (1291 cases and 938 controls) to examine in detail the recently implicated nine new regions with Alzheimer's disease (AD) risk, and also performed a meta-analysis utilizing the top 1% GWAS single-nucleotide polymorphisms (SNPs) with P<0.01 along with four independent data sets (2727 cases and 3336 controls) for these SNPs in an effort to identify new AD loci. The new GWAS data were generated on the Illumina Omni1-Quad chip and imputed at ~2.5 million markers. As expected, several markers in the APOE regions showed genome-wide significant associations in the Pittsburg sample. While we observed nominal significant associations (P<0.05) either within or adjacent to five genes (PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1), significant signals were observed 69-180 kb outside of the remaining four genes (CD33, CLU, CD2AP and CR1). Meta-analysis on the top 1% SNPs revealed a suggestive novel association in the PPP1R3B gene (top SNP rs3848140 with P = 3.05E-07). The association of this SNP with AD risk was consistent in all five samples with a meta-analysis odds ratio of 2.43. This is a potential candidate gene for AD as this is expressed in the brain and is involved in lipid metabolism. These findings need to be confirmed in additional samples.

Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory.

OBJECTIVE: Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. METHODS: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. RESULTS: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (ß = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (ß = -0.44, SE = 0.09, p = 0.009 and ß = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (ß = 0.26, SE = 0.10, p = 0.010). CONCLUSIONS: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.

Genome-wide association analysis of age-at-onset in Alzheimer's disease.

The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ~2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.

Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease.

BACKGROUND: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission. METHODS: Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (41%) [corrected] used only ChEIs, and 416 (44.1%) [corrected] used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications). RESULTS: Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death. CONCLUSIONS: This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.

Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study.

OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study. METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts. RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD. CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.

Lewy bodies in the amygdala increase risk for major depression in subjects with Alzheimer disease.

OBJECTIVE: To determine the relationship between major depression and the presence of Lewy bodies (LBs) in patients with Alzheimer disease (AD). METHODS: The authors examined the presence of major depression in 267 pathologically diagnosed AD cases with Mini-Mental State Examination (MMSE) scores >9. LBs were identified in 142 (53%) patients using alpha-synuclein immunohistochemistry. Subjects were classified according to the Consensus Guidelines for the Clinical and Pathologic Diagnosis of Dementia with LB: 1 to 2 (n = 21), 3 to 6 (n = 26), and 7 to 10 (n = 69). Twenty-six patients had LB only in the amygdala. All cases with LB scores 7 to 10 (or cortical) had amygdala LBs. The association between LBs and major depression was examined with logistic regression analyses, controlled for age at study entry, education level, MMSE scores, antidepressant use, follow-up time, and the presence of cerebrovascular disease. RESULTS: Major depression was present in 11 (9%) AD alone cases, and in 25 (18%) of the AD + LBs cases; amygdala: 8 (31%), scores 1 to 2: 1 (5%), scores 3 to 6: 3 (11.5%), and scores 7 to 10: 13 (14%). Major depression was associated with LBs, in general (relative risk [RR] = 3.06, 95% CI: 1.25 to 7.46), with amygdala only LBs (RR = 8.56 (95% CI: 1.83 to 40.3), and with LB scores 7 to 10 (RR = 3.83, 95% CI: 1.33 to 11.0). There was an association between all amygdala LBs cases (amygdala only LBs + LB scores 7 to 10) and major depression (RR = 4.77, 95% CI: 1.78 to 12.7), but no association was noted between LBs and depression in the absence of amygdala LBs (RR = 0.96, 95% CI: 0.46 to 1.06). CONCLUSION: Lewy bodies (LBs) in the amygdala and in cortical areas increase the risk for major depression in Alzheimer disease. What is common in these two groups is the presence of LBs in the amygdala. That is, all of the cases with cortical LBs also had LBs in the amygdala, making this region the critical area for the development of depression.

Regional specificity of chandelier neuron axon terminal alterations in schizophrenia.

BACKGROUND: The axon terminals of GABAergic chandelier cells form linear arrays, termed cartridges, that synapse on the axon initial segment of neocortical pyramidal cells. These cartridges are immunoreactive for the GABA membrane transporter-1, and the density of GABA membrane transporter-1-immunoreactive cartridges in the prefrontal cortex has been reported to be reduced in schizophrenia. The goal of this study was to determine if reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in schizophrenia are restricted to the prefrontal cortex. METHODS: Relative GABA membrane transporter-1-immunoreactive cartridge density was determined in auditory association area 42, a region previously implicated in the pathophysiology of schizophrenia, in 14 matched pairs of subjects with schizophrenia and normal comparison subjects. The results were compared with similar data from prefrontal area 46 in the same subjects. RESULTS: Mean GABA membrane transporter-1-immunoreactive cartridge density in area 42 was decreased by 9.8% in layers II-IIIa, and by 11.9% in layer VI in subjects with schizophrenia, although these differences did not achieve statistical significance. However, the magnitude of the reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in area 42 of the subjects with schizophrenia was not significantly smaller than those in area 46. CONCLUSIONS: In subjects with schizophrenia, alterations in chandelier neuron axon cartridges appear to be more marked in the prefrontal cortex than in another cortical region implicated in the illness, although such changes might not be restricted to the prefrontal cortex.

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease.

Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-->A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype.

Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40-60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses.

Linkage analysis of Alzheimer disease with psychosis.

Although a portion of risk for late-onset AD (LOAD) is attributable to APOE, the search for other loci is ongoing. The authors hypothesize that psychotic symptoms with LOAD (LOAD+P) identify a potentially more etiologically homogeneous form of AD. Linkage analysis of families with LOAD+P identified one significant and several suggestive novel linkage signals, which bolsters the conjecture of greater etiologic homogeneity.

Increased familial risk of the psychotic phenotype of Alzheimer disease.

BACKGROUND: Psychotic symptoms in patients with AD (AD with psychosis [AD+P]) define a phenotype characterized by more rapid cognitive and functional decline and a liability to aggressive behaviors. OBJECTIVE: To determine if AD+P aggregates within families. METHODS: Case-control study of AD+P frequency in 461 siblings of 371 probands diagnosed with AD. All siblings were ascertained as part of a genetic investigation and also were diagnosed with AD. Statistical analysis used Generalized Estimating Equations to adjust for clustering within families. RESULTS: AD+P in probands was associated with a significantly increased risk for AD+P in family members (OR, 2.41; 95% CI 1.46-4.0; p = 0.0006). The correlation among siblings for AD+P status was modest: 0.16. CONCLUSION: AD+P demonstrates familial aggregation. Further studies are required to investigate a possible genetic basis of AD+P.

The establishment of a brain bank for the study of late-life depression: a feasibility study of factors facilitating consent.

BACKGROUND: Studies of postmortem brain tissue are advancing the understanding of the pathophysiology of major depressive disorder (MDD). The nature and quality of subject samples, however, limit their applicability to late-life MDD. OBJECTIVE: To examine the feasibility of establishing a brain bank for late-life MDD, and identify clinical, demographic, and procedural factors that might facilitate subject enrollment. METHODS: Elderly subjects participating in clinical trials associated with the Mental Health Intervention Research Center for Late-Life Mood Disorders (MHIRC/LLMD) at the University of Pittsburgh were approached by clinical research staff for consent to future brain-only autopsy. Subjects who consented to participation were compared with those who refused participation on demographic and clinical variables. MHIRC/LLMD clinical research staff were interviewed to determine factors that may have facilitated or hindered the consent process and reasons for subject consent or refusal. RESULTS: Eighty out of 242 subjects (33%) subjects approached for participation in the brain bank provided consent. Consent to participate was associated with higher level of education and with lower Mini-Mental State Examination score. Several factors facilitating and hindering the consent process were identified. CONCLUSION: We provide preliminary evidence for the feasibility of establishing a brain bank for the study of late-life MDD. Future efforts may be guided by the factors identified as facilitating the consent process, especially the inclusion of family in the consent process.