Sex-dependent cholinergic effects on amyloid pathology: A translational study.

INTRODUCTION: About two-thirds of Alzheimer's Disease (AD) patients are women, who exhibit more severe pathology and cognitive decline than men. Whether biological sex causally modulates the relationship between cholinergic signaling and amyloid pathology remains unknown. METHODS: We quantified amyloid beta (Aß) in male and female App-mutant mice with either decreased or increased cholinergic tone and examined the impact of ovariectomy and estradiol replacement in this relationship. We also investigated longitudinal changes in basal forebrain (cholinergic function) and Aß in elderly individuals. RESULTS: We show a causal relationship between cholinergic tone and amyloid pathology in males and ovariectomized female mice, which is decoupled in ovary-intact and ovariectomized females receiving estradiol. In elderly humans, cholinergic loss exacerbates Aß. DISCUSSION: Our findings emphasize the importance of reflecting human menopause in mouse models. They also support a role for therapies targeting estradiol and cholinergic signaling to reduce Aß. HIGHLIGHTS: Cholinergic tone regulates amyloid beta (Aß) pathology in males and ovariectomized female mice. Estradiol uncouples the relationship between cholinergic tone and Aß. In elderly humans, cholinergic loss correlates with increased Aß in both sexes.

Serum unsaturated phosphatidylcholines predict longitudinal basal forebrain degeneration in Alzheimer's disease.

Basal forebrain cholinergic neurons are among the first cell types affected by Alzheimer's disease pathology, but the cause of their early vulnerability is unknown. The lipid phosphatidylcholine is an essential component of the cell membrane, and phosphatidylcholine levels have been shown to be abnormal in the blood and brain of Alzheimer's disease patients. We hypothesized that disease-related changes in phosphatidylcholine metabolism may disproportionately affect basal forebrain cholinergic neurons due to their extremely large size, plasticity in adulthood and unique reliance on phosphatidylcholine for acetylcholine synthesis. To test this hypothesis, we examined whether serum phosphatidylcholine levels predicted longitudinal basal forebrain degeneration in Alzheimer's disease. All data were collected by the Alzheimer's Disease Neuroimaging Initiative. Participants were divided into a normal CSF group (controls; n = 77) and an abnormal CSF group (preclinical and clinical Alzheimer's disease; n = 236) based on their CSF ratios of phosphorylated tau and amyloid beta at baseline. Groups were age-matched (t = 0.89, P > 0.1). Serum lipidomics data collected at baseline were clustered by chemical similarity, and enrichment analyses were used to determine whether serum levels of any lipid clusters differed between the normal and abnormal CSF groups. In a subset of patients with longitudinal structural MRI (normal CSF n = 62, abnormal CSF n = 161), two timepoints of MRI data were used to calculate grey matter annual percent change for each participant. Multivariate partial least squares analyses tested for relationships between neuroimaging and lipidomics data which are moderated by CSF pathology. Our clustering analyses produced 23 serum lipid clusters. Of these clusters, six were altered in the abnormal CSF group, including a cluster of unsaturated phosphatidylcholines. In the subset of participants with longitudinal structural MRI data, a priori nucleus basalis of Meynert partial least squares analyses detected a relationship between unsaturated phosphatidylcholines and degeneration in the nucleus basalis which is moderated by Alzheimer's disease CSF pathology (P = 0.0008). Whole-brain grey matter partial least squares analyses of all 23 lipid clusters revealed that only unsaturated phosphatidylcholines and unsaturated acylcarnitines exhibited an Alzheimer's disease-dependent relationship with longitudinal degeneration (P = 0.0022 and P = 0.0018, respectively). Only the unsaturated phosphatidylcholines predicted basal forebrain degeneration in the whole-brain analyses. Overall, this study provides in vivo evidence for a selective relationship between phosphatidylcholine and basal forebrain degeneration in human Alzheimer's disease, highlighting the importance of phosphatidylcholine to basal forebrain grey matter integrity.

An inverse relationship between cortical plasticity and cognitive inhibition in late-life depression.

Executive dysfunction is a common and disabling component of late-life depression (LLD), yet its neural mechanisms remain unclear. In particular, it is not yet known how executive functioning in LLD relates to measures of cortical physiology that may change with age and illness, namely cortical inhibition/excitation and plasticity. Here, we used transcranial magnetic stimulation (TMS) to measure cortical inhibition/excitation (n = 51), and the potentiation of cortical activity following paired associative stimulation, which is thought to reflect long-term potentiation (LTP)-like cortical plasticity (n = 32). We assessed the correlation between these measures of cortical physiology and two measures of executive functioning: cognitive inhibition, assessed using the Delis-Kaplan Executive Function System Color-Word Interference ["Stroop"] Test, and cognitive flexibility, assessed using the Trail Making Test. Correlations with recall memory and processing speed were also performed to assess the specificity of any associations to executive functioning. A significant correlation was found between greater LTP-like cortical plasticity and poorer cognitive inhibition, a core executive function (rp = -0.56, p < 0.001). We did not observe significant associations between cortical inhibition/excitation and executive functioning, or between any neurophysiological measure and cognitive flexibility, memory, or processing speed. Our finding that elevated cortical plasticity is associated with diminished cognitive inhibition emphasizes the importance of balanced synaptic strengthening to healthy cognition. More specifically, our findings suggest that hyper-excitability of cortical circuits following repeated cortical activation may promote inappropriate prepotent responses in LLD. LTP-like cortical plasticity might therefore represent a neural mechanism underlying an inhibitory control cognitive endophenotype of LLD.