In a recent study published in eBioMedicine, researchers investigate the effects of anxiety on cognitive degeneration in non-dementia elderly. To this end, a multi-omics approach was used to elucidate the biological mechanisms contributing to cognitive impairment.
The current study found that anxiety accelerates cognitive impairment in non-dementia elderly. More specifically, anxiety contributed to mitochondrial energy imbalances and destructively altered axon/synapse pathways, thereby leading to late-life cognitive progression.
Study: Anxiety adds the risk of cognitive progression and is associated with axon/synapse degeneration among cognitively unimpaired older adults. Image Credit: Perfect Wave / Shutterstock.com
Anxiety and dementia
Dementia is an umbrella term used to describe cognitive conditions that impair at least two brain functions, especially memory, and judgment. As of 2020, almost 55 million people worldwide had dementia, with that number expected to double every 20 years. Alzheimer's disease (AD) is the most common form of dementia in the elderly, as it affects 60-70% of dementia patients over the age of 65.
AD is identified by hyperphosphorylated tau (p-tau) protein upregulation and increased extracellular amyloid beta (Aβ) deposition. To date, there is no cure for AD.
The link between mental health and preclinical AD has been increasingly investigated, as previous studies have shown that depression increases the risk of dementia. Depression and anxiety often co-occur; however, the independent association of anxiety with dementia has not been fully evaluated.
Previous studies indicate certain associations that exist between anxiety and mild cognitive impairment (MCI). For example, anxiety has been shown to upregulate Aβ deposition and alter cerebrospinal fluid (CSF) total tau (t-tau) in non-dementia elderly.
While previous literature has been restricted to meta-analyses or small, low-sample-sized cross-sectional studies, the present large longitudinal cohort study utilized a multi-omics approach to elucidate the association between anxiety and AD, as well as the biological mechanisms responsible for these processes.
About the study
In the present study, researchers selected individuals from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Shanghai Mental Health Center (SMHC) cohorts as participants in the study.
ADNI participation initially comprised 2,272 individuals between the ages of 55 and 90, 1,070 of whom were selected for the study after cognitive screening. The cohort was divided into two groups, 260 of whom reported anxiety symptoms and 810 individuals without anxiety symptoms, who were denoted as the anxiety and normal groups, respectively.
All participants underwent a Functional Activities Questionnaire (FAQ), Mini-Mental State Examination (MMSE), ADNI Memory test (ADNI-MEM), and Alzheimer's Disease Assessment Scale-cognitive test (ADAS-cog). This long-term test involved follow-up visits with cohort members for up to 168 months, during which periodic CSF and blood collections were obtained for multi-omics investigations.
The CLHLS cohort comprised the validation dataset of this study. Of the 6,389 participants in this cohort, 737 reported chronic anxiety and formed the 'anxiety' group, whereas the remaining 5,652 individuals were placed in the 'normal' group.
For cognitive validation, 732 anxious and 1,464 normal elderly were administered the Chinese Mini-Mental State Examination (CMMSE). Similar to the ADNI study, follow-up visits with were conducted for up to 204 months.
SMHC participants formed the neuroimaging dataset and comprised 99 participants. Of these, 37 individuals were placed in the anxiety group, with 62 in the normal group.
The present study elucidated the association between anxiety and cognitive progression among the elderly. Male participants were more susceptible to anxiety and exhibited more significant cognitive impairment and reduced quality of life than females. In both test and validation cohorts, individuals in the ADNI and CLHLS anxiety groups were at a 158% and 123% greater risk, respectively, than participants in the normal group.
Proteomics analyses revealed that anxiety activates synapse pathways associated with signaling, organization, transport regulation, and axon development. Anxiety also triggered biological mechanisms that have been associated with various degenerative diseases, including amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and schizophrenia.
Transcriptomics results were identical to proteomics results, thus emphasizing the correlation between anxiety and an increased risk of cognitive decline in non-dementia elderly.
The joint analysis of transcriptomics and proteomics identified the most influential variables, including the ATP6V1G2 gene, CYP1A2 and APOB proteins involved in the energy metabolism, and the MYNN, WARS2, and CAMP genes, BASP1 and NGF proteins involved in brain function."
Energy metabolism results from the ADNI group showed that anxiety can cause significant imbalances in the normal functioning of the mitochondrial machinery. Anxiety was found to suppress oxidative phosphorylation, mitochondrial respiratory chain complex assembly, aerobic respiration, and mitochondrial ribosome activity, including biogenesis, ribonucleic acid (RNA) processing, and translation.
In the present long-term, multi-cohort study, researchers investigated the association between anxiety and cognitive progression, especially in aged non-dementia-positive individuals. Multi-omics analyses revealed that anxiety significantly increases the risk of mental degeneration through biological pathways that damage or suppress normal axon/synapse functioning.
Treating anxiety and targeting mitochondrial dysfunction may be an effective way to prevent dementia."