Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels

Abstract

Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD–P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD–P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD–P [Mean (SD) AD+P 0.295 (0.061); AD–P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD–P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.

Targeting the Post-Synaptic Proteome in Alzheimer Disease with Psychosis

“…There was a signi cant shift of almost all proteins to lower levels in AD+P in comparison to AD-P (t = -90.6, df=1612, p<2x10 -307 ). Additional analyses con rmed the robustness of this downregulation: analysis of the larger set of proteins resulting when using peptides quanti ed in at least 50% of samples; analysis of the 51 individuals included in our prior report of a targeted panel of 190 synaptic proteins [16], or the remaining 55 AD subjects who were newly evaluated; and; analysis covarying for excitatory neuron proportion which we previously reported is reduced in AD+P relative to AD-P [17] (Figure S4A-F).…”

“…Most recently, we examined gray matter levels of a limited panel of 190 synaptic proteins in individuals with AD+P and found reductions in canonical postsynaptic density (PSD) proteins relative to AD-P subjects [16]. These differences exceeded those which could be accounted for by any differences in neuropathology burden between the groups [16], or by reduction in the corresponding mRNA transcripts due to greater excitatory neuron loss in AD+P [17].…”

Unique Transcriptional Signatures Correlate with Behavioral and Psychological Symptom Domains in Alzheimer’s Disease

“…The data presented here represents the first exploration of affective, apathy, and agitation symptoms on the transcriptome-wide level and establishes unique patterns of mRNA expression in one of the most consistently implicated brain regions to BPSD, the ACC [49][50][51]. In addition, we add to the growing knowledge base about transcriptional changes in AD with psychosis [28] (discussed in greater detail along with the affective and apathy domain in supplementary materials). We confirmed that commonly co-occurring BPSD symptoms cluster into domains in our cohort and that these domains are typified by unique transcriptional signatures in the ACC, even when individual samples are used in an overlapping design.…”

“…The main novelty of our study is that it is the first, to our knowledge, to study the affective, apathy, and agitation domains on the transcriptome-wide level, which is comparable to the many studies of cognition in AD [73,75,77], dating back at least as early as 2008 [72], and the recent study of AD with psychosis [28].…”

“…This could implicate similar molecular mechanisms underlying each cluster. Despite the ubiquity and burden of BPSD clinically, very few molecular studies exist to elucidate the molecular mechanisms underlying BPSD [25][26][27], with the exception of AD with psychosis [28][29][30]. To begin to identify the molecular mechanisms of BPSD, in this study, we first verified the occurrence of BPSD domains in a sample of older adults based on the use of a structured clinical interview administered within two years of death.…”