Psychological and neurobiological mechanisms involved in the relationship between loneliness and cognitive decline in older adults.

Loneliness, among older adults, is one of the risk factors for developing dementia. Still, little is known about the neurobiological and psychological conditions that link loneliness to cognitive decline. The current study investigated several research aims: First, it sought to identify neurobiological and psychological pathways that may account for the relationship between loneliness and decline across several cognitive domains. These pathways included depressive symptoms, total gray matter volume, and conditional analyses of pro-inflammatory cytokines and brain-derived neurotrophic factor (BDNF) expression. Second, it examined loneliness as a predictor of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Third, it sought to determine whether the relationship between loneliness and cognitive decline is sex-specific in older adults. Longitudinal data were collected from 2130 Rush Memory and Aging Project participants. Participants underwent annual cognitive and psychological assessments and neuroimaging procedures every year. BDNF gene expression was measured in the dorsolateral prefrontal cortex, cytokines were measured in serum, and the final consensus clinical diagnosis was identified at the time of death. All linear mixed and multinomial logistic regression models controlled for age at baseline, education, sex, and APOE genotype. Participants were largely women (73 %), and Caucasian (93 %). The average education was 14.93 (SD = 3.34). The average age at baseline was 80.05 (SD = 7.57). Results showed that gray matter volume and depressive symptoms partially mediated the relationship between loneliness and cognitive decline. There was a significant interaction between loneliness and BDNF expression in relation to cognitive decline. Higher levels of BDNF expression was associated with slower decline in semantic memory and visuospatial ability. Finally, the current study also established that higher levels of loneliness was positively associated with the incidence of AD and other dementias. The present findings support the growing literature, which tends to show that the consequence of loneliness goes beyond the feeling of being isolated. Loneliness may induce physiological changes in our brains, leading to cognitive decline. Future research can explore a wide range of biological and psychological expressions of loneliness to clarify how loneliness relates to dementia.

The Mediating Role of Inflammation in the Relationship Between α-Synuclein and Cognitive Functioning.

Accumulating evidence suggests that α-synuclein plays a role in the pathophysiology of Alzheimer's disease (AD). This study examined whether α-synuclein level in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also explored whether this relationship was mediated by proinflammatory cytokines TNF-α and IL-6, along with sIL-6R and vascular endothelial growth factor (VEGF). Using a cross-sectional Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 148) sample, we examined the relationship between α-synuclein and participants' performance on Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog 13) at baseline. Mediation analyses were utilized, adjusting for age, education, APOEe4, and Geriatric Depression Scale scores. All biological markers were measured in CSF. Participants in the current sample were 58.3% males, 41.7% females, and Caucasian (95.5%); their average education and age were 15.5 (standard deviation [SD] = 2.97) and 74.4 (SD = 7.51) years, respectively. Higher accumulation of α-synuclein was associated with poorer MMSE scores (ß = -0.41, standard error [SE] = 1.54, p < .001). This relationship appeared to be mediated by VEGF (ß = 0.27, SE = 2.15, p = .025) and IL-6r (ß = 0.22, SE = 1.66, p < .026). In addition, α-synuclein was associated with poorer performance on the ADAS-Cog 13 (ß = 0.34, p = .005) and mediated by VEGF (ß = -0.19, SE = 4.13, p = .025) after adjusting for age, education, APOEe4, and depressive symptoms. α-Synuclein may serve as an additional biomarker for determining poor cognitive functioning. VEGF and IL-6 soluble receptors were significant mediators of the relationship between α-synuclein and cognitive functioning. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.