Anxiety throughout Alzheimer’s disease progression: In mice and (wo)men

Abstract

Neuropsychiatric disturbances, such as depression and anxiety, are observed in 90% of Alzheimer's disease (AD) patients and are frequent in those at risk for AD (Lyketsos CG, et al. 2012). Similarly, epidemiological studies show that neurodegeneration and clinical symptoms occur more rapidly in females once diagnosed. In addition to cognitive decline and daily anxiety, AD patients (∼50%) become confused, agitated, and anxious in the evening, often referred to as "sundowning"(Canevelli M, et al. 2016). This circadian disruption can also greatly impact AD pathology. Restlessness before and during sleep has been shown to inhibit Ab clearance, increase neurofibrillary tangles, and dysregulate synaptic activity, all of which are characteristic hallmarks of AD (Cordone S, et al. 2019). Using our activity-dependent tagging system, the ArcCreERT2 x (ChR2)-EYFP x AD (APP/PS1), we labeled neurons activated during learning. These neurons can then can be compared with secondary neuronal ensembles activated during memory retrieval. The neurons activated at both time points represent an engram. Here, we aimed to identify the neural ensembles linking anxiety and memory loss following AD progression by utilizing behavioral studies, calcium imaging and whole-brain microscopy, in female and male mice. We found: 1) Female AD mice exhibited anxiety-like behavior at an earlier age compared to controls and male mice, 2) AD female mice displayed memory deficits as early as 2 months of age, 3) Anxiety-like behavior correlated with memory impairment only in AD female mice, 4) Unlike their male counterparts, female AD mice showed a decline in memory traces in the CA3 of the hippocampus, and 5) Male AD mice exhibit sundowning behavior at 2 months which correlates to increased calcium transients in the vCA1. We have also translated these findings to humans using the ADNI dataset. In humans, anxiety predicts transition to dementia and that anxiety has a sex-specific effect on brain atrophy. To use anxiety as a neuropsychiatric biomarker of AD in the human population in combination with current imaging and cognitive testing and to find novel brain areas associated with increased anxiety and memory loss. This could provide new therapeutic targets for those at risk for AD.