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

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.

Preclinical trials in Alzheimer’s disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice

“…For analysis of body weight, we combined our groups (Young and Aged cohorts) and as such it is possible that these large group sizes enabled a significant difference between genotypes from an earlier age than previously reported [ 37 , 56 ]. Nevertheless, weight loss in AD mice is not unexpected as weight loss is well known to progress with disease progression in human patients with AD [ 83 , 84 ] and in individuals at risk for AD (A+T+), potentially downstream of Abeta deposition [ 85 ]. With respect to activity, it is possible that circadian rhythm alteration played a role in the hyperactivity that we observed in Aged TG mice.…”

Relationship between eating problems and the risk of dementia: A retrospective study

“…The amyloid‐β build up in the brain can damage neurons in the hypothalamus, resulting in weight loss and a pathologically low leptin level 48 . Another paper detected weight loss as a predictor of brain amyloid deposition and worsening cerebrospinal fluid AD biomarkers in preclinical AD 30 . Moreover, emotional changes, such as apathy and depressive symptoms, in the prodromal stage of dementia could also explain this phenomenon 49,50 .…”

“…As weight changes can result in cognitive decline, 28–31 changes in appetite could result in dementia. Saha et al .…”

Obesidade como fator de risco para Doença de Alzheimer

“…Há evidências acumuladas de estudos epidemiológicos de que as alterações no peso corporal estão associadas à doença de Alzheimer (DA) desde a obesidade na meia-idade, aumentando o risco de desenvolver DA até a perda de peso que ocorre nos estágios iniciais da DA (GRAU-RIVERA et al, 2021).…”