In a recent study published in The American Journal of Geriatric Psychiatry, researchers review the neuroinflammation mechanisms related to depression, Alzheimer’s disease, and obesity, the therapeutic options for decreasing neuroinflammation, and radiological initiatives for assessing neuroinflammation.

Study: Neuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer’s Disease, and Depression. Image Credit: Kateryna Kon / Shutterstock.com

Background

Alzheimer’s disease, obesity, and depression are the three most prevalent global health crises. Recent estimates suggest that by 2050, over 150 million individuals might be diagnosed with Alzheimer’s disease.

Depression affects over 300 million individuals and is the foremost reason for lack of productive life years and disability. Obesity can also be rapidly becoming a worldwide health epidemic, with near 36% and 38% of men and girls worldwide, respectively, considered obese or obese.

These three diseases are also interconnected, with depression in early- or mid-life being a risk factor for Alzheimer’s disease and within the later years being a prodrome or early manifestation of Alzheimer’s disease. The connection between depression and obesity can also be complex, with obesity resulting in comorbid depression and depression increasing the danger of obesity.

Mid-life obesity can also be an independent risk factor for Alzheimer’s disease. Actually, the inflammatory state of obesity is linked to the pathophysiology of depression and Alzheimer’s disease.

Mechanisms of neuroinflammation

Chronic inflammation can also contribute to the immune dysregulation linked to gut microbiome dysbiosis, metabolic changes, or amyloid pathology interactions resulting in neuroinflammation. Obesity-associated chronic inflammation is believed to affect the central nervous system, subsequently resulting in cognitive decline and neurodegeneration.

Neuroinflammation driven by obesity may occur through various mechanisms. For instance, proinflammatory cytokines akin to interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) may lead to the secretion of adrenocorticotropic hormone and activate the hypothalamic-pituitary-adrenal axis, subsequently resulting in hypercortisolemia, dendritic atrophy, neuronal apoptosis, and reactive gliosis.

Diets high in fats have also been linked to activation of the renin-angiotensin-aldosterone system and gut microbiome dysbiosis. Previous in vivo studies have shown that high-fat diets obstruct neurogenesis by reducing the expression of non-coding ribonucleic acid (RNA) and messenger RNA (mRNA) needed for neurogenesis.

High-fat diets also lower calcium signaling, decrease the degrees of brain-derived neurotrophic factor, and increase the hippocampal adenosine monophosphate-activated protein kinase signaling levels, thereby resulting in decreased neurogenesis.

Animal models of obesity have also demonstrated a rise within the permeability of the blood-brain barrier (BBB). This enables proinflammatory cytokines to enter the hypothalamus, thereby increasing leptin and insulin levels to ultimately cause chronic activation of microglia.

Oxidative stress mediated by obesity is a trademark of depression and Alzheimer’s disease. Obesity-induced production of reactive oxygen species (ROS) resulting from mitochondrial dysfunction may alter synaptic function and axonal transport, which is exacerbated by ROS produced by the beta-amyloid plaques.

Obesity-related neuroinflammation and insulin resistance can also contribute to the pathophysiology of depression and Alzheimer’s disease. Possible mechanisms for this association include the activation of astrocytes and microglia into neurotoxic subtypes and disruption of the glycogen synthase kinase-3 pathway that is important for synaptic plasticity and neurogenesis.

The association between obesity and the danger of Alzheimer’s disease is complex, as mid-life obesity is linked to the next risk of developing Alzheimer’s disease. Comparatively, healthy adiposity doesn’t appear to affect metabolic dysregulation in older adults and has been shown to have neuroprotective effects.

Weight reduction amongst older adults has also been linked to cognitive decline in older adults and is recognized as a possible indicator of cognitive decline in Alzheimer’s disease.

Interventions

A few of the most important interventions that could be used to cut back inflammation related to obesity, Alzheimer’s disease, and depression include lifestyle changes akin to increased physical activity, dietary and calorific restrictions, and bariatric surgery.

Pharmacological interventions include anti-depressants to cut back neuroinflammation, statins to diminish hyperlipidemia and subsequently lower proinflammatory mediators, in addition to non-steroidal anti-inflammatory drugs (NSAIDs) to lower the danger of Alzheimer’s disease.

Imaging initiatives are essential for understanding the pathophysiology of the disease, in addition to for monitoring disease progression and intervention outcomes. Positron emission tomography (PET) using biomarkers akin to translocator protein 18 kilo Dalton (kD) has been used to watch neuroinflammation in depression and Alzheimer’s disease. Other markers of neuroinflammation may include type 2 cannabinoid receptors, cyclooxygenase-2, and arterial spin labeling.

Conclusions

Neuroinflammation resulting in neurodegeneration is a cumulative effect of assorted events; subsequently, it is important to detect and address inflammation and pathology in its early stages. These findings indicate that therapeutic strategies have to shift their focus to the metabolic imbalances and systemic inflammation signs that occur in mid-life.

The present review also addresses socioeconomic and racial disparities that contribute to the occurrence of Alzheimer’s disease, depression, and obesity. Moreover, advancements in imaging initiatives may improve disease monitoring and the understanding of neuroinflammation and disease progression.