Metabolic Syndrome and Amyloid Accumulation in the Aging Brain

Gómez, Gabriela; Beason‐Held, Lori L.; Bilgel, Murat; An, Yang; Wong, Dean F.; Studenski, Stephanie A.; Ferrucci, Luigi; Resnick, Susan M.

doi:10.3233/jad-180297

Cited by 53 publications

(26 citation statements)

References 64 publications

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“…Disparity of our results from previous studies could stem from our slightly modified definition of MetS, the cross-sectional study design, the surgical nature of our sample, and the high prevalence of MetS (35.6%) compared with those studies (12.9% [30]; 15.8% [29]; 22.4% [7]) but is in line with a recent systematic review of 25 studies which concluded that the evidence on associations of MetS with cognitive impairment in older age is insufficient at present [49]. A recent report of accumulation of beta amyloid in the brains of people with MetS [50] demonstrate the need for further research into the cognitive and neuropathological consequences of the syndrome.…”

Section: Discussionsupporting

confidence: 62%

Associations of the metabolic syndrome and its components with cognitive impairment in older adults

et al. 2019

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Background The metabolic syndrome (MetS) is an established cardiovascular risk factor. Here, we investigated its role in cognitive impairment. Methods Baseline data from 202 participants (aged 65 to 87 years) of the BioCog study were used. All were free of clinical dementia (MMSE≥24/30). Cognitive impairment was defined as the lowest tertile of a cognitive summary score. Multiple logistic regression analyses examined associations of body mass index (BMI), triglycerides (TG), high-density lipoprotein (HDL-C), glucose and glycated hemoglobin A1c (HbA1c) levels with the odds of cognitive impairment. MetS was defined as ≥3 of its 5 components obesity (BMI ≥ 30 kg/m 2 ), elevated TG (TG ≥1.7 mmol/L), reduced HDL-C (males: < 1.0 mmol/L; females: < 1.3 mmol/L), elevated glucose (glucose ≥5.5 mmol/L and/or diagnosed diabetes) and elevated blood pressure (history of hypertension). Analyses controlled for age, sex and smoking history. Results Lower HDL-C was significantly associated with a higher odds of cognitive impairment (OR 2.70 per 1 mmol/L reduction; 95% CI 1.25, 5.56; p = 0.011), whereas BMI, TG, glucose and HbA1c were not (all p > 0.05). Results for HDL-C were similar when HDL-C, glucose, BMI and TG were entered into a single model (OR 2.56 per 1 mmol/L reduction, 95% CI 1.09, 5.88, p = 0.031) and when cerebrovascular disease and coronary heart disease were additionally controlled for (OR 2.56 per 1 mmol/L reduction, 95% CI 1.06, 6.25, p = 0.036). Among the 5 MetS components, participants with elevated TG were at 2-fold increased odds of impairment (OR 2.09, 95% CI 1.08, 4.05, p = 0.028) including when the remaining 4 MetS components were entered (OR 2.23, 95% CI 1.07, 4.65, p = 0.033), but the finding was no longer statistically significant when cerebrovascular disease and coronary heart disease were additionally controlled for ( p = 0.11). Presence of MetS and of obesity, reduced HDL-C, elevated glucose or elevated blood pressure were not significantly associated with impairment (all p > 0.05). Conclusion Our findings support low HDL-C as an independent risk marker of cognitive impairment in older age. The need for research into mediatory and confounding factors, and re-evaluation of traditional cut-off points is highlighted. Trial registration The study was registered on 15th October 2014 at clinicaltrials.gov ( NCT02265263 ).

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Section: Discussionsupporting

confidence: 62%

Associations of the metabolic syndrome and its components with cognitive impairment in older adults

et al. 2019

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“…Our understanding of AD is evolving from a “brain-only disease” to a “metabolic-cognitive syndrome” 9 - 12 , 55 , 56 . AD is even referred to as “type 3 diabetes”, and a growing body of evidence suggests that abnormal brain energy metabolism is one of the main risk factors in the development of AD 12 , 33 .…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21

Sun¹,

Wang²,

Chen³

et al. 2020

Theranostics

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A viewpoint considering Alzheimer's disease (AD) as “type 3 diabetes” emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

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“…In this study, patients with metabolic syndrome had an 11.48 times more likeliness to develop AD compared to those without metabolic syndrome, and there was no association between metabolic syndrome and VD. In a previous study, metabolic syndrome was associated with accelerated amyloid beta accumulation in the elderly with amyloid deposition [42]. Therefore, the combination of amyloid deposition and vascular risk factors might have increased AD incidence in individuals with metabolic syndrome.…”

Section: Discussionmentioning

confidence: 87%

Associations between metabolic syndrome and type of dementia: Analysis based on the National Health Insurance Service database of Gangwon province in South Korea

Kim

Jeong

et al. 2021

Preprint

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Background Metabolic syndrome is a cluster of conditions that occur together, increasing the risk of cardiovascular disease. However, the relationship between metabolic syndrome and dementia has remained controversial. Using nationwide population cohort data, we investigated the association between metabolic syndrome and dementia, according to the dementia type. Methods We analyzed data of 84,144 individuals, in the aged group of more than 60 years, between January 1, 2009, to December 31, 2009, at Gangwon province by using the information of the (Korean) National Health Insurance Service. After eight years of gap, in 2017, we investigated the relationship between metabolic syndrome and dementia. We classified Dementia either as dementia of the Alzheimer type (AD) or vascular dementia (VD). AD and VD were defined as per the criteria of International Classification of Disease, Tenth Revision, Clinical Modification codes. Multiple logistic regression analyses examined the associations between metabolic syndrome or five metabolic syndrome components and dementia. Analyses included factors like age, sex, smoking, alcohol, physical inactivity, previous stroke, and previous cardiac disease. Results Metabolic syndrome was associated with AD (OR= 11.48, 95% CI 9.03-14.59), not with VD. Each of five components of metabolic syndrome were also associated with AD. (high serum triglycerides: OR= 1.87, 95% CI 1.60-2.19; high blood pressure: OR =1.85, 95% CI 1.55-2.21; high glucose: OR= 1.77, 95% CI 1.52-2.06; abdominal obesity: OR= 1.88, 95% CI 1.57-2.25; low serum high-density lipoprotein cholesterol: OR= 1.91, 95% CI 1.63-2.24) However, among components of metabolic syndrome, only the high glucose level was associated with VD. (OR= 1.26, 95% CI= 1.01-1.56) Body Mass Index (BMI), fasting glucose, and smoking were also associated with AD. (BMI: OR=0.951, 95% CI= 0.927-0.975; fasting glucose: OR=1.003, 95% CI=1.001-1.005; smoking: OR=1.020, 95% CI 1.003-1.039) A history of the previous stroke was associated with both AD and VD. (AD: OR=1.827, 95% CI 1.263-2.644; VD: OR 2.775, 95% CI 1.747-4.406) Conclusions Metabolic syndrome was associated with AD but not with VD. Patients with metabolic syndrome had an 11.48 times more likeliness to develop AD compared to those without metabolic syndrome. VD was associated only with several risk factors that could affect the vascular state rather than a metabolic syndrome. We suggested that the associations between metabolic syndrome and dementia would vary depending on the type of dementia.

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Metabolic Syndrome and Amyloid Accumulation in the Aging Brain

Cited by 53 publications

References 64 publications

Associations of the metabolic syndrome and its components with cognitive impairment in older adults

Associations of the metabolic syndrome and its components with cognitive impairment in older adults

Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21

Associations between metabolic syndrome and type of dementia: Analysis based on the National Health Insurance Service database of Gangwon province in South Korea

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