Metformin, age-related cognitive decline, and brain pathology.

The objective of this study was to evaluate the relation of metformin with change in cognition and brain pathology. During a mean of 8 years (SD = 5.5) of annual follow-up visits, 262/3029 participants were using metformin at any time during the study. Using a linear-mixed effect model adjusted for age, sex, and education, metformin users had slower decline on a score of global cognition compared to non-users (estimate = 0.017, SE = 0.007, p = 0.027). Analyses of cognitive domains showed a slower decline in episodic memory and semantic memory specifically. In sensitivity analysis, when examining any diabetes medication use vs none, no association was observed of any diabetes medication use with cognitive function. In the autopsy subset of 1584 participants, there was no difference in the level of Alzheimer's disease (AD) pathology or the presence of infarcts (of any size or location) between groups of metformin users vs non-users. However, in additional analyses, metformin users had higher odds of subcortical infarcts, and lower odds of atherosclerosis and arteriosclerosis.

Locus coeruleus pathology is associated with cerebral microangiopathy at autopsy.

INTRODUCTION: We investigated the link between locus coeruleus (LC) pathology and cerebral microangiopathy in two large neuropathology datasets. METHODS: We included data from the National Alzheimer's Coordinating Center (NACC) database (n = 2197) and Religious Orders Study and Rush Memory and Aging Project (ROSMAP; n = 1637). Generalized estimating equations and logistic regression were used to examine associations between LC hypopigmentation and presence of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, correcting for age at death, sex, cortical Alzheimer's disease (AD) pathology, ante mortem cognitive status, and presence of vascular and genetic risk factors. RESULTS: LC hypopigmentation was associated with higher odds of overall CAA in the NACC dataset, leptomeningeal CAA in the ROSMAP dataset, and arteriolosclerosis in both datasets. DISCUSSION: LC pathology is associated with cerebral microangiopathy, independent of cortical AD pathology. LC degeneration could potentially contribute to the pathways relating vascular pathology to AD. Future studies of the LC-norepinephrine system on cerebrovascular health are warranted. HIGHLIGHTS: We associated locus coeruleus (LC) pathology and cerebral microangiopathy in two large autopsy datasets. LC hypopigmentation was consistently related to arteriolosclerosis in both datasets. LC hypopigmentation was related to cerebral amyloid angiopathy (CAA) presence in the National Alzheimer's Coordinating Center dataset. LC hypopigmentation was related to leptomeningeal CAA in the Religious Orders Study and Rush Memory and Aging Project dataset. LC degeneration may play a role in the pathways relating vascular pathology to Alzheimer's disease.

DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKMζ.

Protein kinase M zeta, PKMζ, is a brain enriched kinase with a well characterized role in Long-Term Potentiation (LTP), the activity-dependent strengthening of synapses involved in long-term memory formation. However, little is known about the molecular mechanisms that maintain the tissue specificity of this kinase. Here, we characterized the epigenetic factors, mainly DNA methylation, regulating PKMζ expression in the human brain. The PRKCZ gene has an upstream promoter regulating Protein kinase C ζ (PKCζ), and an internal promoter driving PKMζ expression. A demethylated region, including a canonical CREB binding site, situated at the internal promoter was only observed in human CNS tissues. The induction of site-specific hypermethylation of this region resulted in decreased CREB1 binding and downregulation of PKMζ expression. Noteworthy, CREB binding sites were absent in the upstream promoter of PRKCZ locus, suggesting a specific mechanism for regulating PKMζ expression. These observations were validated using a system of human neuronal differentiation from induced pluripotent stem cells (iPSCs). CREB1 binding at the internal promoter was detected only in differentiated neurons, where PKMζ is expressed. The same epigenetic mechanism in the context of CREB binding site was identified in other genes involved in neuronal differentiation and LTP. Additionally, aberrant DNA hypermethylation at the internal promoter was observed in cases of Alzheimer's disease, correlating with decreased expression of PKMζ in patient brains. Altogether, we present a conserved epigenetic mechanism regulating PKMζ expression and other genes enhanced in the CNS with possible implications in neuronal differentiation and Alzheimer's disease.

Diabetes and function in different cognitive systems in older individuals without dementia.

OBJECTIVE: To examine the relation of type 2 diabetes to the level of function in five different cognitive systems in older individuals without dementia. RESEARCH DESIGN AND METHODS: Participants were 882 older men and women without dementia participating in the Rush Memory and Aging Project, a longitudinal clinical-pathological study of aging and dementia. They underwent uniform evaluations, which included clinical classification of dementia, and detailed cognitive function testing from which previously established summary measures of episodic memory, semantic memory, working memory, perceptual speed, visuospatial ability, and global cognition were derived. Diabetes was identified by history and direct medication inspection. RESULTS: Diabetes was present in 116 (13%) participants. In separate linear regression models controlling for age, sex, and education, diabetes was associated with lower levels of semantic memory (P < 0.001) and perceptual speed (P = 0.005), but not with episodic memory, working memory, or visuospatial ability or with a measure of global cognition. The associations of diabetes with cognition were reduced when controlling for several vascular variables, and the associations were substantially stronger in current smokers than in individuals who never smoked or formerly smoked. CONCLUSIONS: These results suggest that type 2 diabetes is associated with cognitive impairment, especially in semantic memory and perceptual speed and that these effects may be modified by smoking status.