Obesity as a risk factor for Alzheimer's disease: weighing the evidence

Abstract

Alzheimer's disease (AD) is the sixth leading cause of death in the USA today; therefore, it is imperative that public health initiatives and clinical strategies are developed to prevent and effectively treat AD. Despite the enormous impact that AD has on individuals, families, society, and the health care system, there are no biomarkers to clearly identify those at risk for AD, public health prevention strategies in place, or treatments to address the underlying pathology or stop the progression of AD. There is ample scientific as well as empirical evidence that obesity and its metabolic and vascular comorbidities are related to AD and likely in the causative pathway. Obesity prevention and treatment could prove to be an efficacious and safe approach to preventing AD, a serious and daunting epidemic disease. In this review, we present the current pathophysiological and clinical evidence linking obesity and obesity-related comorbidities (eg, insulin resistance, hyperglycaemia, and type 2 diabetes) with AD. Additionally, we discuss which population to target and when to consider treatment for AD. Finally, we summarize the current evidence regarding the efficacy of anti-obesity and anti-diabetic pharmacotherapeutic agents for the treatment of AD.

Fecal Microbiota Transplantation Decreases Amyloid Load and Improves Cognition in Alzheimer’s

“…Furthermore, FMT may allow for increased clearance or renewal of clearance mechanisms of Ab from the amygdala which could result in reduced anxiety. The overall results of the EPM show a trend towards normalization of 10 anxiety to levels similar to that observed in age-matched wildtype mice.…”

“…Evidence suggests that these two 5 pathological deposits are potentially involved in feedback loops where each causes further deposition of the other (3,4) leading to synaptic degeneration (5,6). Although genetic risk factors have been well-established in early-onset AD (6)(7)(8)(9), various other causal mechanisms have been associated with the development of the more prevalent, sporadic form of AD, including obesity (10), increased plasma cholesterol and type 2 diabetes mellitus (11,12). 10 The human microbiome has been described to have a distinct, complex role in the pathophysiology of multiple diseases (13).…”

“…Although genetic risk factors have been well-established in early-onset AD (6)(7)(8)(9), various other causal mechanisms have been associated with the development of the more prevalent, sporadic form of AD, including obesity (10), increased plasma cholesterol and type 2 diabetes mellitus (11,12). 10 The human microbiome has been described to have a distinct, complex role in the pathophysiology of multiple diseases (13). Inter-individual variation (14) as well as age-dependent changes (15) in the human gut microbiome have been described, with Firmicutes and Bacteroidetes identified as the predominant phyla while gut microbial involvement has been suggested in neurodevelopmental (16,17), autoimmune (18), movement (19,20) and neurodegenerative (20, 15 21) disorders.…”

“…To understand the impact of FMT in a murine model of AD, we performed the procedure via oral gavage in twenty-three 5xFAD (30-32 weeks) recipient mice using fecal matter from healthy B6SJL wildtype donor mice (10-12 and 30-32 week-old) over a period of seven days. Eight of the 10 old recipient mice received oral gavage of fecal slurry obtained from healthy, wild-type donor mice of the same age (Old Tg-fed old; Old Tg-FO) and eight received oral gavage of fecal slurry from healthy, younger wild-type donors (Old Tg-fed young; Old Tg-FY). The control 5xFAD recipient mice (30-32 weeks old; n = 7) were gavaged with normal saline (Old Tg-Control).…”

“…The percentage area can be interpreted as the size of cortical Ab plaques and the decrease in area indicates shrinkage of cortical amyloid plaques. This could be attributed10 to increased clearance and reduced deposition of Ab, possibly by FMT-induced renewal of immune-mediated clearance mechanisms or inflammatory regulation (39). To reflect the correlation of Ab plaque loading and cognitive performance, a Cognition Score (CS) was calculated for each animal in each group as a compounded score of the behavioral studies results and plotted against the mean percentage area of amyloid plaque, or amyloid plaque loading (AP) 15.…”