Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer’s Disease

Krivinko, Josh M.; Erickson, Susan; Ding, Ying; Sun, Zhe; Penzes, Peter; MacDonald, Matthew L.; Yates, Nathan A.; Ikonomović, Miloš D.; López, Oscar L.; Sweet, Robert A.; Kofler, Julia

doi:10.1176/appi.ajp.2018.17080858

Cited by 30 publications

(60 citation statements)

References 42 publications

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“…Recent studies have shown that reductions in kalirin are associated with improvements in psychosis-associated behaviours in AD mouse models, supporting earlier findings in postmortem tissue [63, 64•]. Notwithstanding the challenges and complexities of assessing the AD psychosis phenotype in animal models, these findings indicate novel pathways, such as synaptic resilience, which warrant further investigation [65]. They also highlight the value of preclinical testing in identifying such mechanisms.…”

Section: Kalirinsupporting

confidence: 78%

Psychosis in Alzheimer’s Disease

Ballard

Kales

Aarsland

et al. 2020

Curr Neurol Neurosci Rep

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Purpose of Review To review the incidence, treatment and genetics of psychosis in people with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Recent Findings Psychosis in Alzheimer’s disease (AD) has an incidence of ~ 10% per year. There is limited evidence regarding psychological interventions. Pharmacological management has focused on atypical antipsychotics, balancing modest benefits with evidence of long-term harms. The 5HT2A inverse agonist pimavanserin appears to confer benefit in PD psychosis with initial evidence of benefit in AD. Cholinesterase inhibitors give modest benefits in DLB psychosis. The utility of muscarinic agonists, lithium, glutamatergic and noradrenergic modulators needs further study. Summary Recent work has confirmed the importance of psychosis in MCI as well as AD. The lack of evidence regarding psychological therapies is an urgent knowledge gap, but there is encouraging evidence for emerging pharmacological treatments. Genetics will provide an opportunity for precision medicine and new treatment targets.

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Section: Kalirinsupporting

confidence: 78%

Psychosis in Alzheimer’s Disease

Ballard

Kales

Aarsland

et al. 2020

Curr Neurol Neurosci Rep

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“…99 We have previously reported that the presence of comorbid TDP43 pathology in AD is independently associated with psychosis risk. 100 We previously identified, and independently replicated, an inverse association between polygenic risk for schizophrenia, defined by a limited set of schizophrenia risk SNPs 69 , and risk for psychosis in AD. 28 It was thus somewhat surprising that we saw a non-significant genetic correlation between these two disorders when considering both a larger set of SNPs and a substantially enlarged cohort of AD subjects with and without psychosis.…”

Section: Discussionmentioning

confidence: 88%

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

DeMichele-Sweet

Klei

Creese

et al. 2020

Preprint

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Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P), affecting ~ 40% to 60% of individuals with AD. AD+P identifies a subgroup of AD patients with poor outcomes. The strongest clinical predictor of AD+P is a greater degree of cognitive impairment than in AD subjects without psychosis (AD-P). Other frequently replicated correlates of AD+P include elevated depressive symptoms. Although the estimated heritability of psychosis in AD is 61%, the underlying genetic sources of this risk are not known. We report a genome-wide meta-analysis of 12,317 AD subjects, with and without psychosis. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in the gene ENPP6 (best SNP rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26x10-8) and one spanning the 3-prime-UTR of an alternatively spliced transcript of SUMF1 (best SNP rs201109606, O.R. 0.65 (0.56-0.76), p=3.24x10-8), had genome-wide significant associations with the risk of psychosis in AD. Psychosis risk in AD demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We had previously observed a negative genetic correlation with schizophrenia, instead we now found a stronger negative correlation with the related phenotype of bipolar disorder. Psychosis risk in AD was not genetically correlated with AD or other neurodegenerative diseases. 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. Study of the genetic mechanisms underlying the associations of loci in ENPP6 and SUMF1 with psychosis in AD are warranted.

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“…Elevated total CSF tau levels have been reported in AD patients with psychosis versus AD patients without psychosis, although there were no differences in amyloid beta protein levels or phosphorylated tau levels [92]. Neuropathological studies additionally seem to support a role for phosphorylated tau in AD patients with psychosis, thus suggesting it may serve as a useful biomarker in future studies [93]. CSF biomarkers of amyloid and tau may also be useful in differentiating psychosis related to AD versus psychosis related to a psychiatric condition in older adults [94].…”

Section: Biomarker Studiesmentioning

confidence: 89%

“…CSF biomarkers of amyloid and tau may also be useful in differentiating psychosis related to AD versus psychosis related to a psychiatric condition in older adults [94]. No prior studies have used amyloid or tau PET tracers to investigate regionally specific neuropathological markers of psychosis in dementia, though evidence linking psychosis in AD to phosphorylated tau suggests this may be a useful approach [61,92,93]. There is a suggested link of psychosis with vascular and Lewy body pathology based on postmortem data though replication with in vivo samples is required [95].…”

Section: Biomarker Studiesmentioning

confidence: 99%

Revisiting Criteria for Psychosis in Alzheimer’s Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research

Fischer

Ismail

Youakim

et al. 2020

JAD

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Background: Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

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Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer’s Disease

Cited by 30 publications

References 42 publications

Psychosis in Alzheimer’s Disease

Psychosis in Alzheimer’s Disease

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

Revisiting Criteria for Psychosis in Alzheimer’s Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research

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