The sex-specific impact of anxiety on Alzheimer's disease progression

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. However, until recently, much of the research narrowly targeted co-morbid depression. Clinical reports have provided evidence that anxiety symptoms predict the conversion to AD, over and beyond the effects of depression, memory loss, and even atrophy. Similarly, epidemiological studies show that neurodegeneration and clinical symptoms occur more rapidly in females once diagnosed. Although most AD studies have been performed using male mice, females represent two-thirds of the AD population and are more susceptible to depression and anxiety. To study how anatomical sex and anxiety impact AD progression, I used our activity-dependent tagging system, the ArcCreERT2 x channelrhodopsin (ChR2)-EYFP x AD (APP/PS1) mice. These mice allow for brain-wide indelible labeling of neurons activated during learning, which then can be compared with secondary neuronal ensembles activated during memory retrieval. The neurons activated at both time points represent a memory trace or 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, and 4) Unlike their male counterparts, female AD mice showed a decline in memory traces in the CA3 of the hippocampus. We are currently working to translate these findings to humans using the Alzheimer’s disease neuroimaging initiative (ADNI) dataset. We have found that in humans, anxiety predicts transition to dementia and that anxiety has a sex-specific effect on brain atrophy. 
ADNI: Females with anxiety exhibit smaller brain volumes compared to males.
Long-term implications: 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.