Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, and a lack of disease‐modifying therapeutics. While the abnormal accumulation of lipids was described in the very first report of AD neuropathology, it was not until recent decades that lipid dyshomeostasis became a focus of AD research. Clinically, lipidomic and metabolomic studies have consistently shown alterations in the levels of various lipid classes emerging in early stages of AD brains. Mechanistically, decades of discovery research have revealed multifaceted interactions between lipid metabolism and key AD pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. In the present review, converging evidence defining lipid dyshomeostasis in AD is summarized, followed by discussions on mechanisms by which lipid metabolism contributes to pathogenesis and modifies disease risk. Furthermore, lipid‐targeting therapeutic strategies, and the modification of their efficacy by disease stage, ApoE status, and metabolic and vascular profiles, are reviewed.

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer’s disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.

/pdf/cholesterol-and-alzheimer-s-disease-from-risk-genes-to-16tpy4p3q3.pdf

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Alzheimer's disease (AD), the most common cause of dementia, results in a sustained decline in cognition. There are currently few effective disease modifying therapies for AD, but insights into the mechanisms that mediate the onset and progression of disease may lead to new, effective therapeutic strategies. Amyloid beta oligomers and plaques, tau aggregates, and neuroinflammation play a critical role in neurodegeneration and impact clinical AD progression. The upstream modulators of these pathological features have not been fully clarified, but recent evidence indicates that the gut microbiome (GMB) may have an influence on these features and therefore may influence AD progression in human patients. In this review, we summarize studies that have identified alterations in the GMB that correlate with pathophysiology in AD patients and AD mouse models. Additionally, we discuss findings with GMB manipulations in AD models and potential GMB-targeted therapeutics for AD. Lastly, we discuss diet, sleep, and exercise as potential modifiers of the relationship between the GMB and AD and conclude with future directions and recommendations for further studies of this topic. 

https://molecularneurodegeneration.biomedcentral.com/counter/pdf/10.1186/s13024-023-00595-7

The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored

A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.

Promoting Successful Cognitive Aging: A Ten-Year Update.

Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward. This Review summarizes adaptive immune cell dysregulation in obesity and type 2 diabetes mellitus (T2DM). Under-appreciated comorbidities of obesity and T2DM (oral cavity inflammation, neuroinflammation and dysbiosis) are considered, and previous clinical trials of anti-inflammatory therapies for T2DM are discussed.

Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities

Background:
Several risk factors contribute to dementia, but the role of obesity remains unclear This study investigated whether increased body weight or central obesity were associated with a higher risk of developing dementia in a representative sample of older English adults
/
Methods:
We studied 6582 participants from the English Longitudinal Study of Ageing (ELSA) who were aged ≥50 years and were dementia-free at baseline, that being either wave 1 (2002–2003) for study members who started at wave 1, or at either wave 2 (2004–2005) or 4 (2008–2009) for those who began the study as refreshment samples Body mass index (BMI) was measured at baseline and categorized into normal weight (185–249 kg/m2), overweight (25–299 kg/m2) and obese (≥30 kg/m2) Central obesity was defined as a waist circumference (WC) >88 cm for women and >102 cm for men Cumulative incidence of dementia was ascertained based on physician-diagnosed dementia, an overall score >338 on the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and Hospital Episodes Statistics (HES) data at every ELSA wave from baseline until wave 8 (2016–2017) Cox proportional hazards models were used to assess the association between baseline BMI levels or abdominal obesity in relation to dementia incidence during the mean follow-up period of 11 years
/
Results:
From the overall sample, 69% (n = 453) of participants developed dementia during the follow-up period of maximum 15 years (2002–2017) Compared with participants with normal weight, those who were obese at baseline had an elevated risk of dementia incidence [hazard ratio (HR) = 134, 95% confidence interval (CI) 107–161] independent of sex, baseline age, apolipoprotein E-e4 (APOE-e4), education, physical activity, smoking and marital status The relationship was slightly accentuated after additionally controlling for hypertension and diabetes (HR = 131, 95% CI 103–159) Women with central obesity had a 39% greater risk of dementia compared with non-central obese women (HR = 139, 95% CI 112–166) When compared with a normal BMI and WC group, the obese and high WC group had 28% (HR = 128, 95% CI 103–153) higher risk of dementia
/
Conclusions:
Our results suggest that having an increased body weight or abdominal obesity are associated with increased dementia incidence These findings have significant implications for dementia prevention and overall public health

Higher risk of dementia in English older individuals who are overweight or obese

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Higher risk of dementia in English older individuals who are overweight or obese

Authors' response to comments on: Higher risk of dementia in English older individuals who are overweight or obese.