Obesity and Alzheimer's disease dementia: Examining inflammatory links to cognitive decline and neuropsychiatric symptoms

Abstract

Obesity is recognized as a risk factor for cardiovascular disease, vascular dementia, and Alzheimer's disease dementia (AD dementia). Emerging evidence indicates that obesity in AD patients is associated with heightened neuropsychiatric symptoms, as reflected by inflammatory biomarkers such as C-reactive protein and complement C3. Neuroinflammation, particularly through certain aspects of microglial activation, plays a significant role in AD development and cognitive decline. While further research is warranted to explore these neuroinflammatory pathways as potential therapeutic targets, proactive weight management starting in middle age may help mitigate both cognitive decline and neuropsychiatric symptoms.

Obesity is a well-established risk factor for cardiovascular disease, vascular dementia, and Alzheimer's disease dementia (AD dementia). ¹ Recent findings by Wang et al. ² have revealed that obesity is associated with increased neuropsychiatric symptoms (NPS) among AD patients from the ADNI cohort. Notably, biomarkers such as C-reactive protein (CRP) and complement C3 closely track these symptoms, highlighting the complex interplay between cognitive decline, immune function, and obesity. NPS are common in dementia patients, ³ and inflammatory processes are increasingly recognized as key drivers in the progression of neurodegenerative disorders. Evidence suggests that body weight exerts a reverse J-curved influence on both NPS and cognitive functioning over the lifespan. In younger and middle-aged adults, obesity is linked to an elevated risk of dementia, primarily due to harmful vascular changes and inflammatory processes that cause neurological damage.^4,5 Conversely, in later life, unintentional weight loss, particularly when occurring as a component of geriatric frailty, has been identified as a marker of undernutrition, which independently contributes to accelerated cognitive decline and increased mortality risk.^6,7

Managing dementia becomes even more challenging with the emergence of NPS, as treatment options for these symptoms remain limited. ⁸ The difficult behaviors associated with obesity, as noted by Wang et al., ² can undermine the vital emotional bond between caregivers and recipients, intensifying the struggle with everyday activities. ⁹ In addition, many psychotropic medications are known to contribute to weight gain and are often contraindicated in older adults due to safety concerns,^10,11 further complicating treatment strategies.

At this point, it is imperative to stress the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD, which underlie many of the cognitive and neuropsychiatric symptoms in AD. ¹² Indeed, microglial activation has been shown to distribute preferentially along highly connected brain regions, similar to tau pathology,^13,14 while microglia response, synaptic integrity, and cerebrovascular endothelial function trend with rates of cognitive decline. ¹⁵ Amyloid-β accumulation and tau phosphorylation, which are central to AD pathology, both contribute to neuroinflammation through distinct yet interconnected mechanisms. While amyloid-β triggers a microglial response, particularly influenced by factors like sex and obesity, ¹⁶ tau pathology appears to drive spatially specific microglial activation across functionally connected brain regions ¹⁷ —suggesting a synergistic relationship that may accelerate neurodegenerative progression.

Wang et al. ² found raised complement C3; however other studies found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline, ¹⁵ underscoring the importance of further research into the disease processes underlying neuroinflammation and obesity.

Understanding these intricate processes demonstrates the importance of proactive obesity management as a condition with significant immunological implications, not merely as a lifestyle choice. Initiating such management in middle age is critical for prevention. This justifies adopting a more pro-active treatment approach in mid-life, possibly using established agents like metformin—already used to counteract weight gain induced by psychotropic medications ¹⁰ —or newer drugs like GLP-1 receptor antagonists to mitigate both cognitive decline and neuropsychiatric symptoms. While weight loss drugs are overall well-tolerated, ¹⁸ and their effectiveness, especially as part of programs combining them with exercise, has been demonstrated, ¹⁹ they have also been linked to a loss of muscle mass and sarcopenia. ²⁰ In later life, especially among dementia patients, focus should therefore shift toward preventing frailty and ensuring optimal nutrition to support cognitive health. ²¹ The ESPEN guidelines already provide guidance on supporting individuals living with dementia in meeting their nutritional needs. ²² In the future, initiatives like PROMED-COG ²³ may help refine our understanding of optimal dietary practices and weight management strategies for older adults, both with and without dementia.

Given the global rise in both obesity and dementia, these issues are poised to significantly impact healthcare systems worldwide. There is a pressing need for comprehensive research into how obesity, neuroinflammation, exercise, and muscle mass interrelate with apathy, cognitive decline, and overall disease progression. While Wang et al. ² have clearly established the link between obesity and NPS in AD, further exploration of hitherto underexplored neuroinflammatory pathways as therapeutic targets remains a promising avenue for future investigation, potentially leading to more effective prevention strategies and targeted interventions that could alleviate the future burden on global healthcare infrastructures.