A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.

Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.

Anesthesia promotes acute expression of genes related to Alzheimer's disease and latent tau aggregation in transgenic mouse models of tauopathy.

BACKGROUND: Exposure to anesthesia in the elderly might increase the risk of dementia. Although the mechanism underlying the association is uncertain, anesthesia has been shown to induce acute tau hyperphosphorylation in preclinical models. We sought to investigate the impact of anesthesia on gene expression and on acute and long-term changes in tau biochemistry in transgenic models of tauopathy in order to better understand how anesthesia influences the pathophysiology of dementia. METHODS: We exposed mice with over-expressed human mutant tau (P301L and hyperdopaminergic COMTKO/P301L) to two hours of isoflurane and compared anesthetized mice to controls at several time points. We evaluated tau hyperphosphorylation with quantitative high-sensitivity enzyme-linked immunosorbent assay and performed differential expression and functional transcriptome analyses following bulk mRNA-sequencing. RESULTS: Anesthesia induced acute hyperphosphorylation of tau at epitopes related to Alzheimer's disease (AD) in both P301L-based models. Anesthesia was associated with differential expression of genes in the neurodegenerative pathways (e.g., AD-risk genes ApoE and Trem2) and thermogenesis pathway, which is related to both mammalian hibernation and tau phosphorylation. One and three months after anesthesia, hyperphosphorylated tau aggregates were increased in the anesthetized mice. CONCLUSIONS: Anesthesia may influence the expression of AD-risk genes and induce biochemical changes in tau that promote aggregation even after single exposure. Further preclinical and human studies are necessary to establish the relevance of our transcriptomic and biochemical findings in these preclinical models to the pathogenesis of dementia following anesthesia. TRIAL REGISTRATION: Not applicable.

Animal Models of Psychosis in Alzheimer Disease.

Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.

Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT-deleted (DM) tau mouse model.

In Alzheimer's disease, the phosphorylation of tau is a critical event preceding the formation of neurofibrillary tangles. Previous work exploring the impact of a dopamine blocking antipsychotic on tau phosphorylation in a tau transgenic model suggested that extracellular dopamine may play a regulatory role in the phosphorylation state of tau. In order to test this hypothesis, and in order to develop a mouse model of impaired dopamine metabolism and tauopathy, an extant P301L transgenic tau model of Alzheimer's disease and a novel P301L/catechol-O-methyltransferase deleted model (DM mouse) were treated with the norepinephrine reuptake inhibitor reboxetine, and prefrontal dopamine concentrations and the phosphorylated state of tau was quantified. In two experiments, male and female P301L+/+//COMT+/+ and P301L+/+//COMT-/- (DM) mice were treated with reboxetine 20 mg/kg IP. In one experiment, acutely following reboxetine injection, the prefrontal cortex of mice were microdialyzed for dopamine, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, utilizing the MetaQuant technique. In another experiment, acutely following reboxetine injections, tau phosphorylation was quantified in the frontal cortex, striatum, and hippocampus of the mice. Reboxetine injections were followed by significant increases from baseline in extracellular dopamine concentrations in P301L and DM mice, with significantly higher peak levels in the DM mice. Treatment was also followed by increases in tau phosphorylation spread throughout brain regions, with a larger impact on female mice. Extracellular dopamine concentrations exert an influence on the phosphorylation state of tau, with surges in dopamine associating with acute increases in tau phosphorylation.

CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes.

Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate afferent neural gustatory pathways. However, how ATP is released to fulfil this function is not fully understood. Here we show that calcium homeostasis modulator 1 (CALHM1), a voltage-gated ion channel, is indispensable for taste-stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells. Calhm1 knockout mice have severely impaired perceptions of sweet, bitter and umami compounds, whereas their recognition of sour and salty tastes remains mostly normal. Calhm1 deficiency affects taste perception without interfering with taste cell development or integrity. CALHM1 is expressed specifically in sweet/bitter/umami-sensing type II taste bud cells. Its heterologous expression induces a novel ATP permeability that releases ATP from cells in response to manipulations that activate the CALHM1 ion channel. Knockout of Calhm1 strongly reduces voltage-gated currents in type II cells and taste-evoked ATP release from taste buds without affecting the excitability of taste cells by taste stimuli. Thus, CALHM1 is a voltage-gated ATP-release channel required for sweet, bitter and umami taste perception.

Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians.

We compared coding region variants of 53 cognitively healthy centenarians and 45 patients with Alzheimer's disease (AD), all of Ashkenazi Jewish (AJ) ancestry. Despite the small sample size, the known AD risk variant APOE4 reached genome-wide significance, indicating the advantage of utilizing 'super-controls'. We restricted our subsequent analysis to rare variants observed at most once in the 1000 Genomes database and having a minor allele frequency below 2% in our AJ sample. We compared the burden of predicted protein altering variants between cases and controls as normalized by the level of rare synonymous variants. We observed an increased burden among AD subjects for predicted loss-of-function (LoFs) variants defined as stop-gain, frame shift, initiation codon (INIT) and splice site mutations (n = 930, OR = 1.3, P = 1.5×E-5). There was no enrichment across all rare protein altering variants defined as missense plus LoFs, in frame indels and stop-loss variants (n = 13 014, OR = 0.97, P = 0.47). Among LoFs, the strongest burden was observed for INIT (OR = 2.16, P = 0.0097) and premature stop variants predicted to cause non-sense-mediated decay in the majority of transcripts (NMD) (OR = 1.98, P = 0.02). Notably, this increased burden of NMD, INIT and splice variants was more pronounced in a set of 1397 innate immune genes (OR = 4.55, P = 0.0043). Further comparison to additional exomes indicates that the difference in LoF burden originated both from the AD and centenarian sample. In summary, we observed an overall increased burden of rare LoFs in AD subjects as compared to centenarians, and this enrichment is more pronounced for innate immune genes.

The Relational and Item-Specific Encoding Task in Mild Cognitive Impairment and Alzheimer Disease.

BACKGROUND: The Relational and Item-Specific Encoding task (RISE) measures episodic memory subcomponents, including item-specific and relational encoding of to-be-remembered stimuli. These memory components are neurobiologically relevant because they may engage distinct subregions of the medial temporal lobe, perirhinal and entorhinal cortices, parahippocampus, and hippocampus. METHODS: A total of 125 participants, including 84 healthy controls (HC), 22 mild cognitive impairment-diagnosed and 19 Alzheimer disease (AD)-diagnosed participants, were administered the RISE and neuropsychological measures. Stepwise linear regressions assessed prediction of functional ability from RISE d' measures. ANOVAs and logistic regressions determined the ability of the RISE to discriminate between the diagnostic groups. In addition, the psychometric properties of the RISE were examined. RESULTS: RISE measures predicted diagnosis with pseudo R2 values in the range of 0.25-0.30. Receiver operating characteristic curves demonstrated adequate sensitivity and specificity with areas under the curve in the range of 0.78-0.98. Memory following relational encoding was a significant predictor of everyday functional competence. The RISE had acceptable psychometric properties, with the exception of floor effects in the AD group. CONCLUSION: The RISE measures significantly predicted diagnosis and predicted everyday functional competence. The RISE offers unique advantages in the assessment of HC and individuals with preclinical AD.

Haloperidol and sudden cardiac death in dementia: autopsy findings in psychiatric inpatients.

OBJECTIVE: Treatment with haloperidol has been shown, in studies using death certificates and prescription files, to be associated with an excess of sudden cardiac deaths, and regulatory warnings highlight this risk in patients with dementia. We used autopsy findings to determine whether the rate of sudden cardiac death is greater in cases of unexpected deaths of patients with dementia treated with haloperidol. METHODS: From 1989 through 2013, 1219 patients with a primary diagnosis of dementia with behavioral disturbance were admitted to a psychiatric hospital, and 65 (5.3%) died suddenly. Sixty-five patients (5.3%) died unexpectedly. Complete post-mortem examinations after the sudden death were performed in 55 (84.6%) patients. Twenty-seven of the autopsied cases (49.1%) had been treated with haloperidol orally (2.2 mg ± 2.1 mg/day), the only antipsychotic used in this cohort. Univariable comparisons and multivariable regression analyses compared the groups of patients with or without sudden cardiac death. RESULTS: The leading causes of death were sudden cardiac death (32.7%), myocardial infarction (25.5% of patients), pneumonia (23.6%), and stroke (10.9%). Patients with sudden cardiac death and those with anatomically established cause of death were similar regarding the use of haloperidol (p = 0.5). Sudden cardiac death patients were more likely to suffer from Alzheimer's dementia (p = 0.027) and to have a past history of heart disease (p = 0.0094), and less likely to have been treated with a mood stabilizer (p = 0.024), but none of these variables were independent predictors of sudden cardiac death. CONCLUSION: Autopsy data suggest that oral haloperidol is not associated with increased risk of sudden cardiac death in psychiatric inpatients with dementia.

CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.

The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2(-/-) (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2(+/+) and J20 CNR2(-/-) mice. Seventeen J20 CNR2(+/+) mice (12 females, 5 males) and 16 J20 CNR2(-/-) mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aß production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aß42 and plaque deposition were significantly increased in J20 CNR2(-/-) mice relative to CNR2(+/+) mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2(-/-) mice. Total tau was significantly suppressed in J20 CNR2(-/-) mice relative to J20 CNR2(+/+) mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce Aß; however, the results suggest that interventions may have a divergent effect on tau pathology.

Psychosis in Alzheimer's disease is associated with frontal metabolic impairment and accelerated decline in working memory: findings from the Alzheimer's Disease Neuroimaging Initiative.

OBJECTIVE: An ascendant body of evidence suggests that Alzheimer disease with psychosis (AD+P) is a distinct variant of illness with its own genetic diathesis and a unique clinical course. Impaired frontal lobe function has been previously implicated in AD+P. The current exploratory study, presented in two parts, evaluates both the regional brain metabolic and psychometric correlates of psychosis in a longitudinal sample of subjects with AD, made available by the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: In Part 1 of the study, 21 ADNI participants with AD who developed psychotic symptoms during the study but were not psychotic at baseline were matched with 21 participants with AD who never became psychotic during the study period, and mean brain [F(18)]fluorodeoxyglucose positron emission tomography (FDG-PET) Cerebral metabolic rate for glucose (CMRgl) by regions of interest (ROIs) were compared Additionally, 39 participants with active psychosis at the time of image acquisition were matched with 39 participants who were never psychotic during the study period, and mean brain FDG-PET CMRgl by sROI were compared. In Part 2 of the study, 354 ADNI participants with AD who were followed for 24 months with serial psychometric testing were identified, and cognitive performance and decline were evaluated for correlation with psychotic symptoms. RESULTS: Part 1: There were no regional brain metabolic differences between those with AD destined to become psychotic and those who did not become psychotic. There was a significant reduction in mean orbitofrontal brain metabolism in those with active psychosis. Part 2: Over the course of study follow-up, psychosis was associated with accelerated decline in functional performance as measured by the Functional Assessment Questionnaire, the Mini-Mental State Examination, and Forward Digit Span. CONCLUSION: In a sample drawn from the ADNI dataset, our exploratory FDG-PET findings and longitudinal cognitive outcomes support the hypofrontality model of AD+P. Focal frontal vulnerability may mediate the accelerated decline seen in AD+P.

Psychosis in Alzheimer Disease and Elevations in Disease-Relevant Biomarkers.

Importance: The emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology. Objective: To investigate the longitudinal dynamics of plasma tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) levels in association with the emergence of psychotic symptoms (delusions and hallucinations) in the context of AD. Design, Setting, and Participants: This cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Baseline analyses compared patients with mild cognitive impairment (MCI) and AD (both with psychosis [AD+P] and without psychosis [AD-P]) and participants who were cognitively unimpaired (CU). For the longitudinal analysis, participants with MCI and AD were subdivided into patients with evidence of psychosis at baseline (AD+P baseline) and patients free of psychosis at baseline who showed incidence of psychosis over the course of the study (AD+P incident). Study data were analyzed between June and November 2023. Exposures: Plasma p-tau181 and NfL measures in individuals with MCI and AD, both with and without psychosis. Main Outcomes and Measures: Plasma p-tau181 and NfL quantifications up to 48 months and concurrent assessments of presence or absence of delusions and hallucinations via the Neuropsychiatric Inventory (NPI) questionnaire. Results: The cohort included 752 participants with AD (mean [SD] age, 74.2 [7.7] years; 434 male [57.7%]). A total of 424 CU participants had a mean (SD) age of 75.4 (6.6) years of whom 222 were female (52.4%). In the longitudinal analysis of p-tau181 trajectories of the AD+P group, the group of patients who showed incidence of psychosis over the course of follow-up (AD+P incident) demonstrated an associated increase in plasma p-tau181 levels compared with the group of patients who had psychosis at baseline (AD+P baseline) and showed an associated decrease in plasma p-tau181 levels (F4, 117 = 3.24; P = .01). The mean slope of p-tau181 change was significantly different in AD+P incident and AD+P baseline groups (F5,746 = 86.76, P < .0001) and when only individuals with amyloid-ß positivity (Aß+), which was determined using positron emission tomography, were compared (F5,455 = 84.60, P < .001). Patients who experienced psychosis at any time had increased levels of NfL relative to those who never experienced psychosis. Conclusions and Relevance: Results of this cohort study suggest that the emergence of psychosis in AD was associated with elevations in plasma levels of p-tau181, highlighting the potential utility of plasma p-tau181 as a biomarker of neuropsychiatric illness in AD, which could have implications for predictive and treatment response strategies.

Association between pre-dementia psychiatric diagnoses and all-cause dementia is independent from polygenic dementia risks in the UK Biobank.

BACKGROUND: Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention. METHODS: In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models. FINDINGS: Among 502,408 participants, 9352 had dementia. As expected, AD PRS was associated with greater risk for dementia (odds ratio (OR) 1.62, 95% confidence interval (CI), 1.59-1.65). A total of 94,237 participants had PDPD, of whom 2.6% (n = 2519) developed subsequent dementia, compared to 1.7% (n = 6833) of 407,871 participants without PDPD. Accordingly, PDPD were associated with 73% greater risk of incident dementia (OR 1.73, 1.65-1.83). Among dementia subtypes, the risk increase was 1.5-fold for AD (n = 3365) (OR 1.46, 1.34-1.59) and 2-fold for vascular dementia (VaD, n = 1823) (OR 2.08, 1.87-2.32). Our data indicated that PDPD were neither a dementia prodrome nor a mediator for AD PRS. Shared factors for both PDPD and dementia likely substantially account for the observed association, while a causal role of PDPD in dementia could not be excluded. AUD could be one of the shared causes for PDPD and dementia. INTERPRETATION: Psychiatric diagnoses were associated with subsequent dementia in UKB participants, and the association is orthogonal to established dementia genetic risks. Investigating shared causes for psychiatric disorders and dementia would shed light on this dementia pathway. FUNDING: US NIH (K08AG054727).

CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.

The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2⁻/⁻ (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2⁺/⁺ and J20 CNR2⁻/⁻ mice. Seventeen J20 CNR2⁺/⁺ mice (12 females, 5 males) and 16 J20 CNR2⁻/⁻ mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aß production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aß42 and plaque deposition were significantly increased in J20 CNR2⁻/⁻ mice relative to CNR2⁺/⁺ mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2⁻/⁻ mice. Total tau was significantly suppressed in J20 CNR2⁻/⁻ mice relative to J20 CNR2⁺/⁺ mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce Aß; however, the results suggest that interventions may have a divergent effect on tau pathology.

The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [11C] Raclopride Binding in Tau Mouse Models of Alzheimer's Disease.

Psychosis that occurs over the course of Alzheimer's disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human-mutant-tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [11C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment-on both tau and behavior-that may have relevance to AD and other tauopathies.

Relationships between behavioral syndromes and cognitive domains in Alzheimer disease: the impact of mood and psychosis.

OBJECTIVES: Behavioral disturbances occur in nearly all Alzheimer disease (AD) patients together with an array of cognitive impairments. Prior investigations have failed to demonstrate specific associations between them, suggesting an independent, rather than shared, pathophysiology. The objective of this study was to reexamine this issue using an extensive cognitive battery together with a sensitive neurobehavioral and functional rating scale to correlate behavioral syndromes and cognitive domains across the spectrum of impairment in dementia. DESIGN: Cross-sectional study of comprehensive cognitive and behavioral ratings in subjects with AD and mild cognitive impairment. SETTING: Memory disorders research center. PARTICIPANTS: Fifty subjects with AD and 26 subjects with mild cognitive impairment; and their caregivers. MEASUREMENTS: Cognitive rating scales administered included the Mini-Mental State Examination; the Modified Mini-Mental State Examination; the Boston Naming Test; the Benton Visual Retention Test; the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychology Assessment; the Controlled Oral Word Test; the Wechsler Memory Scale logical memory I and logical memory II task; the Wechsler Memory Scale-Revised digit span; the Wechsler Adult Intelligence Scale-Revised digit symbol task; and the Clock Drawing Task together with the Clinical Dementia Rating Scale and the Neuropsychiatric Inventory. RESULTS: Stepwise regression of cognitive domains with symptom domains revealed significant associations of mood with impaired executive function/speed of processing (Δr = 0.22); impaired working memory (Δr = 0.05); impaired visual memory (Δr = 0.07); and worsened Clinical Dementia Rating Scale (Δr = 0.08). Psychosis was significantly associated with impaired working memory (Δr = 0.13). CONCLUSIONS: Mood symptoms appear to impact diverse cognitive realms and to compromise functional performance. Among neuropsychological indices, the unique relationship between working memory and psychosis suggests a possible common underlying neurobiology.

The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT- and rTg(P301L)4510 mouse models of Alzheimer's disease.

INTRODUCTION: Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive decline and increased mortality; preclinical models that would develop new therapeutic approaches are desperately needed. The current report evaluates the ability of the neoteric antipsychotic, pimavanserin, to normalize hyperkinesis and sensorimotor gating in the novel catechol-O-methyltransferase (COMT) deleted P301L/COMT- and rTg(P301L)4510 models of psychotic AD, and the impact of pimavanserin on tau pathology. METHODS: Female P301L/COMT- mice were behaviorally characterized for abnormalities of locomotion and sensorimotor gating, and biochemically characterized for patterns of tau phosphorylation relative to relevant controls utilizing high-sensitivity tau enzyme-linked immunosorbent assay (ELISA). Female P301L/COMT- and rTg(P301L)4510 mice were randomized to pimavanserin or vehicle treatment to study the ability of pimavanserin to normalize locomotion and rescue sensorimotor gating. Additionally, high-sensitivity tau ELISA was used to investigate the impact of treatment on tau phosphorylation. RESULTS: P301L/COMT- mice evidenced a hyperlocomotive phenotype and deficits of sensorimotor gating relative to wild-type mice on the same background, and increased tau phosphorylation relative to COMT-competent P301L mice. Pimavanserin normalized the hyperkinetic phenotype in both the P301L/COMT- and rTg(P301L)4510 mice but had no impact on sensorimotor gating in either model. Pimavanserin treatment had little impact on tau phosphorylation patterns. DISCUSSION: These data suggest that pimavanserin ameliorates tau-driven excessive locomotion. Given the morbidity associated with aberrant motor behaviors such as pacing in AD and lack of effective treatments, future studies of the impact of pimavanserin on actigraphy in patients with this syndrome may be warranted.

Psychotropic Medication Use Is Associated With Greater 1-Year Incidence of Dementia After COVID-19 Hospitalization.

Background: COVID-19 has been associated with an increased risk of incident dementia (post-COVID dementia). Establishing additional risk markers may help identify at-risk individuals and guide clinical decision-making. Methods: We investigated pre-COVID psychotropic medication use (exposure) and 1-year incidence of dementia (outcome) in 1,755 patients (≥65 years) hospitalized with COVID-19. Logistic regression models were used to examine the association, adjusting for demographic and clinical variables. For further confirmation, we applied the Least Absolute Shrinkage and Selection Operator (LASSO) regression and a machine learning (Random Forest) algorithm. Results: One-year incidence rate of post-COVID dementia was 12.7% (N = 223). Pre-COVID psychotropic medications (OR = 2.7, 95% CI: 1.8-4.0, P < 0.001) and delirium (OR = 3.0, 95% CI: 1.9-4.6, P < 0.001) were significantly associated with greater 1-year incidence of post-COVID dementia. The association between psychotropic medications and incident dementia remained robust when the analysis was restricted to the 423 patients with at least one documented neurological or psychiatric diagnosis at the time of COVID-19 admission (OR = 3.09, 95% CI: 1.5-6.6, P = 0.002). Across different drug classes, antipsychotics (OR = 2.8, 95% CI: 1.7-4.4, P < 0.001) and mood stabilizers/anticonvulsants (OR = 2.4, 95% CI: 1.39-4.02, P = 0.001) displayed the greatest association with post-COVID dementia. The association of psychotropic medication with dementia was further confirmed with Random Forest and LASSO analysis. Conclusion: Confirming prior studies we observed a high dementia incidence in older patients after COVID-19 hospitalization. Pre-COVID psychotropic medications were associated with higher risk of incident dementia. Psychotropic medications may be risk markers that signify neuropsychiatric symptoms during prodromal dementia, and not mutually exclusive, contribute to post-COVID dementia.

CALHM1 P86L polymorphism modulates CSF Aß levels in cognitively healthy individuals at risk for Alzheimer's disease.

The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling intracellular calcium homeostasis and amyloid-ß (Aß) peptide metabolism, a key event in the etiology of Alzheimer's disease (AD). The P86L polymorphism in CALHM1 (rs2986017) initially was proposed to impair CALHM1 functionally and to lead to an increase in Aß accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence Aß metabolism in vivo by increasing Aß levels in human cerebrospinal fluid (CSF). Although the role of CALHM1 in AD risk remains uncertain, concordant data have now emerged showing that CALHM1 P86L is associated with an earlier age at onset of AD. Here, we have analyzed the association of CALHM1 P86L with CSF Aß in samples from 203 AD cases and 46 young cognitively healthy individuals with a positive family history of AD. We failed to detect an association between the CALHM1 polymorphism and CSF Aß levels in AD patients. Our data, however, revealed a significant association of CALHM1 P86L with elevated CSF Aß42 and Aß40 in the normal cohort at risk for AD. This work shows that CALHM1 modulates CSF Aß levels in presymptomatic individuals, strengthening the notion that CALHM1 is involved in AD pathogenesis. These data further demonstrate the utility of endophenotype-based approaches focusing on CSF biomarkers for the identification or validation of risk factors for AD.

Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers.

To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRSnon-APOE), we estimated PRSnon-APOE in superagers (age ≥ 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRSnon-APOE decile to the lowest decile (OR = 4.82, p = 2.5 × 10-6), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 × 10-9). Thus PRSnon-APOE is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRSnon-APOE modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRSnon-APOE in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 × 10-5) among APOE4 carriers. This disproportionally large PRSnon-APOE among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (ß = -0.02, p = 4.8 × 10-3) as a predictor of PRSnon-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.

A pilot study of the prevalence of psychiatric disorders in PLS and ALS.

The prevalence of psychiatric disorders in primary lateral sclerosis (PLS) is currently unknown. In the present study, we compared the prevalence of psychiatric illness in patients with PLS and amyotrophic lateral sclerosis (ALS). We hypothesized that if the psychosocial stress of motor neuron disease predisposes patients to depressive disorders, patients with ALS (with a poorer prognosis and more disability than patients with PLS) should have a higher prevalence of depressive disorders than patients with PLS. We administered the gold standard of psychiatric assessment, the SCID, to 19 PLS and 13 ALS patients. We found a prevalence of current depressive disorders in PLS patients that was, by a non-significant trend, lower than that of ALS patients. The prevalence of current depressive disorders in the ALS patients was higher than previously reported and similar to that observed in non-neurological medical disorders. Other psychiatric disorders were rare. In conclusion, depressive disorders were the most commonly observed psychiatric disorders in both PLS and ALS. By a non-significant trend, the PLS patients had a lower current prevalence of depressive disorders than the ALS patients. These data are consistent with the hypothesis that the psychosocial stress of MND is a risk factor for depression.