Alzheimer Disease and Associated Comorbidities: Investigating Modifiable Risk Factors

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It is anticipated that 30% to 50% of adults will develop Alzheimer disease or dementia by age 85 to 90 years.
It is anticipated that 30% to 50% of adults will develop Alzheimer disease or dementia by age 85 to 90 years.

Alzheimer disease (AD) affects an estimated 5.5 million people in the United States, and it is anticipated that 30% to 50% of adults will develop AD or another form of dementia by age 85 to 90 years.1 The increasing rates of the disease underscore the urgent need for biomarkers that can identify patients with a high risk of developing AD, and for prevention strategies and treatment approaches that can slow its progression.

Research increasingly points to obesity and associated comorbidities as potential contributors to AD pathophysiology, suggesting that conditions such as prediabetes and diabetes, poor-quality diet, and a sedentary lifestyle may be modifiable risk factors. A recently published study in Obesity Reviews examined possible mechanisms in the AD-obesity connection, as well as relevant treatment strategies that may influence the development and progression of AD.2

Findings from numerous human and animal studies suggest an association between obesity and AD. Throughout the life course, higher body mass index (BMI) and obesity are linked to cognitive decline, brain atrophy, reduced white matter and integrity of the blood-brain barrier, and elevated risk for late-onset AD. In pooled results from longitudinal epidemiological studies,3 the calculated effect size of obesity for AD was 1.54.

There is particularly strong evidence for midlife obesity as a risk factor for AD. A cross-sectional study published in Obesity found an inverse relationship between BMI and cognitive function among healthy late middle-aged adults, and various observational studies have reported that obesity in midlife increased the risk for late-life dementia.4 In research recently published in JAMA, high BMI in midlife was the only midlife vascular risk factor that demonstrated a significant association with increased late-life brain amyloid deposition (odds ratio, 2.06).5

Despite the potential connection between midlife obesity and subsequent AD, this relationship appears to shift in later life. "Weight loss has been described in 20% to 45% of patients with AD although the aetiology for weight loss is not fully understood," wrote the investigators of the Obesity Reviews study.2 "The decline in BMI that precedes the diagnosis of AD may be related to neurodegeneration in areas of the brain involved in homeostatic weight regulation although data are limited."2

Potential Mechanisms

Obesity is characterized by an inflammatory response in adipose tissue that involves the increased secretion of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and the chemokine (C-C motif) ligand 2. This response leads to chronic systemic inflammation that, together with the local inflammation in adipose tissue, promotes cellular insulin resistance, and ultimately hyperinsulinemia and hyperglycemia.

Brain inflammation may lead to reduced synaptic plasticity and neurogenesis. Elevated levels of microglial-derived tumor necrosis factor-α can block intracellular insulin signaling through its effects on insulin receptor substrate 1.5

"Altered insulin action in the brain appears to contribute to Aβ accumulation and lack of degradation of misfolded and hyper-phosphorylated tau protein," according to the paper.2 "Attenuated expression of the insulin receptor, the insulin-like growth factor 1 receptor, and [insulin receptor substrate 1] in the hippocampus and hypothalamus has been identified in subjects with AD." Additional findings revealed a lower ratio of cerebrospinal fluid to peripheral insulin in individuals with AD, which suggests decreased insulin action in the central nervous system.6,7

Insulin Resistance

Obesity is the main driver of insulin resistance, and data "strongly suggest that insulin resistance in middle age increases the risk for AD probably through multiple pathways including decreased brain glucose metabolism and dysfunctional brain insulin [signaling], resulting in increased amyloid deposition and reduced brain volume," the investigators wrote.2

Evidence from animal and human studies shows increased brain insulin resistance in subjects with AD. In addition, a prospective cohort study linked fasting insulin and homeostasis model assessment of insulin resistance with an increased risk for AD during the 3-year follow-up period, and postmortem research linked these variables to a higher risk for neuritic plaques.9,10 Other results revealed associations between insulin resistance and progressive medial temporal lobe atrophy, decreased hippocampal volume and cognitive performance, and reduced glucose metabolism in the left medial temporal lobe. Participants of the latter study are currently being followed to evaluate the correlation between insulin resistance and AD.

Hyperglycemia and Type 2 Diabetes

A substantial amount of research indicates that type 2 diabetes increases AD risk, with 1 meta-analysis showing a relative risk of 1.53 for AD among individuals with diabetes.3 The degree of hyperglycemia may be the key factor rather than presence or absence of type 2 diabetes. For example, HbA1c levels ≥6.5% have been found to increase AD risk 2.8-fold in elderly patients, whereas levels ≥7% increased the risk 4.7-fold.11

Impaired Leptin Activity

The hormone leptin, produced mostly by adipose cells, helps regulate appetite by inhibiting hunger. Results from in vitro and rodent studies demonstrated that leptin reduces tau phosphorylation in several brain regions and attenuates Aβ-induced neurodegeneration. Other findings indicate that leptin transport across the blood-brain barrier may be impaired in obesity.8

Treatment Possibilities and Future Directions

The most promising potential treatment in this realm thus far is intranasal insulin, which improved verbal memory in patients with mild cognitive impairment who were APOE ε4 noncarriers and worsened it in those who were APOE ε4 carriers.12 In other research, a 21-day course of intranasal insulin led to improved attention, cognitive functioning, and verbal memory in patients with early AD.13 A randomized controlled trial noted improvements in delayed memory and functional ability after 4 months of intranasal insulin in patients with AD or MCI.14 Similar effects were observed with administration of the insulin analog detemir.

Multiple randomized trials exploring the effects of intranasal insulin on AD are currently in progress.15 Limited findings indicate that the type 2 diabetes agents, glucagon-like peptide-1 receptor agonists, and sodium-glucose transporter 2 inhibitors may also be worth further investigation as AD treatments.

"No longitudinal studies to date have shown that weight loss in those with midlife obesity will reduce incident AD, although metabolic corrections following weight loss have been clearly demonstrated, making this an intriguing approach," the authors stated.15 Ongoing research is needed to explore the many facets of the AD-obesity connection and potential treatment strategies. "Even a small reduction in incident AD could significantly reduce the human and economic burden of this epidemic disease."


  1. Alzheimer's Association. 2017 Alzheimer's disease facts and figures. Accessed November 25, 2017.
  2. Alford S, Patel D, Perakakis N, Mantzoros CS. Obesity as a risk factor for Alzheimer's disease: weighing the evidence [published online October 10, 2017]. Obes Rev. doi:10.1111/obr.12629
  3. Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry. 2010;67(6):505–512.
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  12. Ramirez A, Wolfsgruber S, Lange C, et al. Elevated HbA1c is associated with increased risk of incident dementia in primary care patients. J Alzheimers Dis. 2015;44(4):1203-1212.
  13. Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323-331.
  14. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70(6):440-448.
  15. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29-38.
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