Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

Abstract

OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid b-protein 42 (Ab42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI.METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent b-cell function (HOMA-b) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS:Obese adolescents had values of Ab42 higher than overweight and normal-weight peers (190.2 6 9.16 vs 125.9 6 7.38 vs 129.5 6 7.65 pg/mL; P , .0001) as well as higher levels of PSEN1 (2.34 6 0.20 vs 1.95 6 0.20 vs 1.65 6 0.26 ng/mL; P , .0001). Concentrations of Ab42 were significantly correlated with BMI (r = 0.262; P , .0001), HOMA-IR (r = 0.261; P , .0001) and QUICKI (r = 20.220; P , .0001). PSEN1 levels were correlated with BMI (r = 0.248; P , .0001), HOMA-IR (r = 0.242; P , .0001), and QUICKI (r = 20.256; P , .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein.CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD. WHAT'S KNOWN ON THIS SUBJECT:Insulin resistance plays a role in obesity. Recently it has been associated with increased risk of AD. Ab42 and PSEN1 are molecules associated with increased risk of later AD. Patients affected by AD show elevated levels of plasma Ab42.WHAT THIS STUDY ADDS: Levels of Ab42 and PSEN1 are significantly elevated in obese adolescents and correlated with the degree of both adiposity and systemic insulin resistance. Dr Manco conceptualized and designed the study, performed assays, analyzed data and interpreted results, contributed to the discussion, and critically revised the manuscript; Ms Luciano and Ms Barraco conceptualized and designed the study, performed assays, analyzed data and interpreted results, and drafted the manuscript; Drs Muraca, Ottino, Sforza, Rustico, and Morino and Ms Spreghini enrolled patients, collected growth data, and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This condition has been termed as "brain insulin resistance" and seems to be a constant trait that precedes clinical symptoms of dementia and AD even for decades. Researchers refer to AD also as "type 3 diabetes" by virtue of the analogous brain glucose hypometabolism that characterizes both conditions and the high rate of their co-occurrence. 1,4,5 Patients with T2D exhibit an increased risk of developing cognitive impairment and dementia and, vice versa, impaired fasting glucose and diabetes are highly prevalent among patients...

Early Life Epidemiology of Alzheimer's Disease - A Critical Review

“…Interestingly, in a small study of 20 adults diagnosed with AD and 20 controls, digit ratio - a marker of prenatal testosterone and estrogen exposure - was associated with AD risk, with opposite patterns for males vs. females (higher digit ratios in AD males and lower digit ratios in AD females) 45 . Finally, high childhood BMI and concomitant insulin resistance increases circulating levels of the AD-associated proteins amyloid-beta 42 and presenilin-1, suggesting a molecular link between childhood metabolism, body measurements, and later AD 46 .…”

Percentiles of serum uric acid and cardiometabolic abnormalities in obese Italian children and adolescents

“…The study population includes 1364 Caucasian overweight/obese children and adolescents (age range 4.18–17.93 years), referred by general practitioners to the Unit of Clinical Nutrition at the Bambino Gesù Children’s Hospital between July 2012 and 2013 [16]. Patients underwent anthropometric measurements, laboratory evaluation of uric acid, fasting glucose and insulin, lipid profile, liver function tests, white blood cell count (WBC); and a standard oral glucose tolerance test (OGTT).…”

Circadian Rhythms, Sleep, and Disorders of Aging

“…Clinically, insulin resistance is associated with increased risk of developing AD [116], and childhood obesity is not only a risk factor for diabetes, it may also increase the risk of developing cognitive impairment at later life stages [117]. Further evidence comes from studies of apolipoprotein E (APOE), an important regulator of lipid metabolism expressed mainly in brain astrocytes and liver.…”