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Background: Cumulative anticholinergic exposure, also known as anticholinergic burden, is associated with a variety of adverse outcomes. However, studies show that anticholinergic effects tend to be underestimated by prescribers, and anticholinergics are the most frequently prescribed potentially inappropriate medication in older patients. The grading systems and drugs included in existing scales to quantify anticholinergic burden differ considerably and do not adequately account for patients’ susceptibility to medications. Furthermore, their ability to link anticholinergic burden with adverse outcomes such as falls is unclear. This study aims to develop a prognostic model that predicts falls in older general practice patients, to assess the performance of several anticholinergic burden scales, and to quantify the added predictive value of anticholinergic symptoms in this context.Methods: Data from two cluster-randomized controlled trials investigating medication optimization in older general practice patients in Germany will be used. One trial (RIME, n = 1,197) will be used for the model development and the other trial (PRIMUM, n = 502) will be used to externally validate the model. A priori, candidate predictors will be selected based on a literature search, predictor availability, and clinical reasoning. Candidate predictors will include socio-demographics (e.g. age, sex), morbidity (e.g. single conditions), medication (e.g. polypharmacy, anticholinergic burden as defined by scales), and well-being (e.g. quality of life, physical function). A prognostic model including sociodemographic and lifestyle-related factors, as well as variables on morbidity, medication, health status, and well-being, will be developed, whereby the prognostic value of extending the model to include additional patient-reported symptoms will be also assessed. Logistic regression will be used for the binary outcome, which will be defined as “no falls” vs. “≥1 fall” within six months of baseline, as reported in patient interviews.Discussion: As the ability of different anticholinergic burden scales to predict falls in older patients is unclear, this study may provide insights into their relative importance as well as into the overall contribution of anticholinergic symptoms and other patient characteristics. The results may support general practitioners in their clinical decision-making and in prescribing fewer medications with anticholinergic properties.

Alzheimer’s disease (AD) is characterized by intracellular tau aggregates and extracellular deposition of amyloid-β (Aβ). The major genetic risk factor to develop AD is the Apolipoprotein E isoform 4 (ApoE4). ApoE4 may directly affect Aβ pathology, yet the exact role of ApoE4 in the progression of AD remains unclear. Although astrocytes are the main source of ApoE in brain tissue, other cell types might contribute to ApoE isotype-dependent effects. While ApoE expression does not play a relevant role in homeostatic microglia, we and others could recently show that ApoE expression is significant upregulated in disease-associated microglia including AD-mouse models and human AD. ApoE has been supposed to have an anti-inflammatory effect, with ApoE4 being less effective than ApoE3. However, ApoE-isotype specific effects on microglia function in disease have not been thoroughly investigated to date. In contrast to this, the role of ApoE2, the third most common major ApoE isoform, in neurodegeneration has not been characterized in detail, but it has been shown to delay the onset of disease in familial AD. To elucidate the differential roles of the three-major human ApoE isoforms on microglia function we each expressed the human ApoE isoforms in murine N9 microglia cells. We could show that ApoE4 specifically influences actin cytoskeleton rearrangement and morphology. In migration assays, ApoE4 significantly promotes cell motility. To quantify phagocytosis by microglia we established an uptake assay based on imaging flow cytometry. Although expression of ApoE4 led to significantly reduced uptake of Aβ in contrast to the other isoforms, we could show that ApoE4 specifically increased phagocytosis of apoptotic neuronal cells. Our findings show that ApoE4 intrinsically affects microglia physiology by upregulating motility and phagocytic behavior in vitro and may therefore specifically contribute to microglia dysregulation in AD.