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

Oriol Grau-Rivera, Irene Navalpotro-Gomez, Gonzalo Sánchez-Benavides, Marc Suárez-Calvet, Marta Milà-Alomà, Eider M Arenaza-Urquijo, Gemma Salvadó, Aleix Sala-Vila, Mahnaz Shekari, José Maria González-de-Echávarri, Carolina Minguillón, Aida Niñerola-Baizán, Andrés Perissinotti, Maryline Simon, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, José Luis Molinuevo, ALFA Study, Annabella Beteta, Raffaele Cacciaglia, Alba Cañas, Carme Deulofeu, Irene Cumplido, Ruth Dominguez, Maria Emilio, Carles Falcon, Sherezade Fuentes, Laura Hernandez, Gema Huesa, Jordi Huguet, Karine Fauria, Paula Marne, Tania Menchón, Grégory Operto, Albina Polo, Sandra Pradas, Anna Soteras, Marc Vilanova, Natàlia Vilor-Tejedor, Oriol Grau-Rivera, Irene Navalpotro-Gomez, Gonzalo Sánchez-Benavides, Marc Suárez-Calvet, Marta Milà-Alomà, Eider M Arenaza-Urquijo, Gemma Salvadó, Aleix Sala-Vila, Mahnaz Shekari, José Maria González-de-Echávarri, Carolina Minguillón, Aida Niñerola-Baizán, Andrés Perissinotti, Maryline Simon, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, José Luis Molinuevo, ALFA Study, Annabella Beteta, Raffaele Cacciaglia, Alba Cañas, Carme Deulofeu, Irene Cumplido, Ruth Dominguez, Maria Emilio, Carles Falcon, Sherezade Fuentes, Laura Hernandez, Gema Huesa, Jordi Huguet, Karine Fauria, Paula Marne, Tania Menchón, Grégory Operto, Albina Polo, Sandra Pradas, Anna Soteras, Marc Vilanova, Natàlia Vilor-Tejedor

Abstract

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 .

Keywords: Alzheimer’s disease; Biomarkers; Cognitively unimpaired; Preclinical; Risk factors; Weight loss.

Conflict of interest statement

IN-G received honoraria for travel and accommodation to attend scientific meetings from Zambon, Teva, Bial, AbbVie, and Krka. MS and GK are full-time employees of Roche Diagnostics. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. JLM is currently a full- time employee of H. Lundbeck A/S and priory has served as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. The remaining authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Odds ratios (in logarithmic scale) and 95% confidence intervals for the association between weight loss (% weight loss during follow-up) and core-AD biomarker results. Weight loss refers to reversed values of the annualized weight change rate (i.e., positive values of weight change expressed weight loss)
Fig. 2
Fig. 2
Odds ratios (in logarithmic scale) and 95% confidence intervals for the association between weight loss (% weight loss during follow-up) and being A+T+ compared with A-T-. Weight loss refers to reversed values of the annualized weight change rate (i.e., positive values of weight change expressed weight loss)
Fig. 3
Fig. 3
Differences in the annualized rate of weight change across AT groups. Brackets and numbers above them indicate between-group statically significant differences and Bonferroni-adjusted P values
Fig. 4
Fig. 4
Interaction between amyloid status and the annualized rate of weight change on cognitive performance change, CSF biomarkers and Centiloids. std. Beta: standardized beta coefficients

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