Abstract
BackgroundRecognizing 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.MethodsThis 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.ResultsWeight 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.ConclusionsWeight 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 registrationNCT01835717, NCT02485730, NCT02685969.
Highlights
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
Weight loss predicted a higher likelihood of positive FTM-positron emission tomography (PET) visual read, abnormal cerebrospinal fluid (CSF) p-tau levels, and an Aβ positivity (A+)T+ profile and was greater among participants with an A+T+ profile (p < 0.01) at follow-up
Prediction of biomarker status by weight loss Weight loss predicted a higher likelihood of having a positive FTM-PET visual read [odds ratio (OR) 1.27, 95% confidence interval (CI) 1.00–1.61, p = 0.049], displaying abnormal CSF p-tau levels, and having an A+T+ CSF biomarker profile (Figs. 1 and 2)
Summary
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. Weight decline from midlife to late-life has been linked with increased risk of incident mild cognitive impairment [12], and there is neuropathological evidence that links lower body mass index (BMI) with a higher level of AD pathology, but not with other common causes of dementia, such as vascular pathology and Lewy body pathology [13]. Regarding mechanisms underlying these associations, it has been suggested that hypothalamic dysfunction and olfactory function impairment due to AD-related neurodegeneration (or in the context of other neurodegenerative conditions) may cause weight decline [14]. Cognitive, behavioral and mood changes arising throughout the course of the disease may contribute to weight loss
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