BackgroundEvidence on preventing Alzheimer’s disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention.MethodsElectronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised.ResultsA total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B).InterpretationEvidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

A large number of physiological processes in the adult liver are regulated by nuclear receptors that require heterodimerization with retinoid X receptors (RXRs). In this study, we have used cre-mediated recombination to disrupt the mouse RXR␣ gene specifically in hepatocytes. Although such mice are viable, molecular and biochemical parameters indicate that every one of the examined metabolic pathways in the liver (mediated by RXR heterodimerization with PPAR␣, CAR␤, PXR, LXR, and FXR) is compromised in the absence of RXR␣. These data demonstrate the presence of a complex circuitry in which RXR␣ is integrated into a number of diverse physiological pathways as a common regulatory component of cholesterol, fatty acid, bile acid, steroid, and xenobiotic metabolism and homeostasis.Members of the nuclear receptor family regulate a broad range of developmental and physiological processes by binding to DNA response elements and regulating transcriptional activation (7). The retinoid X receptors (RXRs) are unique among the nuclear receptors in that they bind DNA as a homodimer and are required as a heterodimeric partner for a number of additional nuclear receptors to bind DNA (19). The latter receptors, termed the class II nuclear receptor subfamily, include many which are established or implicated as important regulators of gene expression in the liver (reviewed below). There are three RXR genes (18), coding for RXR␣, -␤, and -␥, all of which are able to heterodimerize with any of the class II receptors, although there appear to be preferences for distinct RXR subtypes by partner receptors in vivo (6).The physiological processes that are regulated by the class II receptors in the liver are diverse. LXR␣ is activated by oxycholesterol and promotes cholesterol metabolism (22). FXR (also known as RIP14) is part of an interrelated process, in that FXR is activated by bile acids (the end product of cholesterol metabolism) (17,21,34), which serve to inhibit cholesterol catabolism. CAR␤ is involved in phenobarbital induction of the cytochrome P450 2B10 (Cyp2B10) gene (9), which encodes a drug-and xenobiotic-metabolic enzyme. Interestingly, CAR␤ has constitutively activity, but becomes inactive in response to the steroid androstane (8). PXR is activated by a wide spectrum of steroids, and induces the Cyp3A gene (Cyp3A1 in mice; Cyp3A4 in humans) which encodes a broad-spectrum oxidase that is responsible for steroid degradation and for the catabolism of numerous pharmaceutical compounds (2, 11). PPAR␣ is activated by leukotriene B4 and by synthetic peroxisome proliferators, such as fibrates, and controls the expression of several genes which are related to fatty acid metabolism and processing (28). Although not discussed further in the context of this study, other class II nuclear receptors, including the retinoic acid and thyroid hormone receptors, are also likely to be important regulators of liver metabolism.In the adult liver, RXR␣ is the most abundant of the three RXRs (18), suggesting that it might have a prominent role in...

It is widely believed that light-to-moderate alcohol intake may protect against dementia while excessive drinking may instead increase the risk. Nonetheless, these findings need cautious interpretations due to varying methodologies and lack of standard definition, which hindered our transferring into preventative practice. The objective of this study is to investigate the potential dose-response association between alcohol consumption and risk of dementia. A systematic search was conducted in electronic databases to identify relevant studies. Risk estimates were combined using a random-effect model. Eleven studies with 73,330 participants and 4586 cases for all-cause dementia (ACD), five studies with 52,715 participants and 1267 cases for Alzheimer's dementia (AD) and four studies with 49,535 participants and 542 cases for vascular dementia were included. We observed a nonlinear association between alcohol consumption and ACD risk (p < 0.05). The alcohol dose associated with lower risk of dementia was confined to at most 12.5 g/day, with the risk hitting bottom (RR ≈ 0.9) at roughly 6 g/day. Of note, the ACD risk seemed to be elevated (≈10%) when the dose surpasses certain levels: 23 drinks/week or 38 g/day. For the alcohol type, recommendation for wine is prioritized. The subgroup analysis further indicated that the effect of alcohol may be greater in younger adults (<60 years old) with regard to fighting against dementia. Modest alcohol consumption (≤12.5 g/day) is associated with a reduced risk of dementia with 6 g/day of alcohol conferring a lower risk than other levels while excessive drinking (≥38 g/day) may instead elevate the risk.