Late-life obesity is a protective factor for prodromal Alzheimer’s disease: a longitudinal study

Sun, Zhen; Wang, Zuo-Teng; Sun, Fu-Rong; Shen, Xue‐Ning; Xu, Wei; Ma, Ya‐Hui; Dong, Qiang; Tan, Lan; Yu, Jin‐Tai; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.18632/aging.102738

Cited by 60 publications

(44 citation statements)

References 42 publications

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“…Consistent evidences have proposed a higher risk of developing AD among middle-aged patients with raised body mass index (BMI) whereas overweight or obesity in late-life might have protective effects on cognition (46,47). Particularly the HR for AD was 0.89 (95% CI 0.81-0.98) among those with high late-life BMI, in contrast, there was 20% increased risk for AD (95% CI 1.09-1.33) among those with greater loss of BMI from midlife to late-life (46).…”

Section: Obesitymentioning

confidence: 99%

The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention

et al. 2021

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Mild Alzheimer’s disease is the leading cause of dementia, accounting for 50-70% of cases. Alzheimer’s disease is an irreversible neurodegenerative disease, which affects daily life activities and social functioning. As life expectancy increases and demographic ageing occurs, the global prevalence of Alzheimer’s disease is expected to continue to rise especially in developing countries, leading to a costly burden of disease. Alzheimer’s disease is a complex and multifactorial disorder that is determined by the interaction of genetic susceptibility and environmental factors across the life course. Epidemiological studies have identified potential modifiable risk and protective factors for Alzheimer’s disease prevention. Moreover, Alzheimer’s disease is considered to start decades earlier before clinical symptoms occur, thus interventions targeting several risk factors in non-demented elderly people even middle-aged population might prevent or delay Alzheimer’s disease onset. Here, we provide an overview of current epidemiological advances related to Alzheimer’s disease modifiable risk factors, highlighting the concept of early prevention.

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Section: Obesitymentioning

confidence: 99%

The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention

et al. 2021

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“…During the last years, studies incorporating AD biomarkers have shown that higher baseline levels of amyloid-β (Aβ) deposition, as measured by positron emission tomography (PET), and higher cerebrospinal fluid (CSF) levels of tau/Aβ42 ratio are associated with greater prospective body weight decline [ 15 , 16 ], and a recent study has reported a negative correlation between BMI change and amyloid-PET burden [ 17 ]. Other studies have found a negative correlation between BMI and Aβ and tau deposition in the brain of cognitively unimpaired elders [ 18 – 21 ]. While these studies have focused on associations with continuous measures of AD biomarkers, few studies have evaluated whether weight loss predicts AD biomarker positivity using categorical outcomes, such as amyloid-PET visual read results.…”

Section: Introductionmentioning

confidence: 98%

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer’s disease

et al. 2021

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Background Recognizing clinical manifestations heralding the development of Alzheimer’s disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. Methods This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. Results Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00–1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19–1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25–2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = − 0.141, p = 0.005), t-tau (β = − 0.147 p = 0.004) and neurogranin levels (β = − 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. Conclusions Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. Trial registration NCT01835717, NCT02485730, NCT02685969.

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“…Obesity is considered a risk factor for AD [ 1 , 2 , 3 ]. However, the relationship between body weight and dementia appears complex [ 4 , 5 , 6 ], and recent observations even pose a protective role of late-life excess weight in AD [ 7 ]. Taking into account the worrying worldwide prevalence of obesity and dementia [ 8 , 9 ], greater knowledge of possible links between the two conditions is imperative.…”

Section: Introductionmentioning

confidence: 99%

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance

Herrero-Labrador

Trueba-Saiz

Martinez-Rachadell

et al. 2020

IJMS

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Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation—ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.

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Late-life obesity is a protective factor for prodromal Alzheimer’s disease: a longitudinal study

Cited by 60 publications

References 42 publications

The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention

The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer’s disease

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance

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