Usefulness of Plasma Amyloid as a Prescreener for the Earliest Alzheimer Pathological Changes Depends on the Study Population

Recently, Verberk et al showed that plasma Aβ42/Aβ40 ratio has potential to identify Alzheimer pathological changes in subjects with subjective memory decline. Furthermore, the inclusion of age and APOEε4 carriership in their multivariate model improved the likelihood of identification. Based on these results, Verberk and colleagues postulated that plasma Aβ42/Aβ40 ratio could be a potential prescreener to identify the earliest Alzheimer disease (AD) pathological changes in individuals with subjective memory decline. We aimed to extend the findings of Verberk et al, using the same statistical methods, but in a different population, namely healthy elderly subjects without memory complaints (N = 189). Subjects in this study were male and female, aged 72 years (mean; range = 65–86), with a mean Mini-Mental State Examination score of 28.8 (range = 25–30), and 15-item Geriatric Depression Scale score of 0.7 (mean; range = 0–5). Subjects were excluded if they had a cognitive or psychiatric disorder, or a history of drug and/or alcohol abuse. If a subject used medication that affected the central nervous system, or medication with a contraindication for a lumbar puncture, they would also be excluded. Self-reported memory performance and daily functioning were assessed with the Clinical Dementia Rating scale–sum of boxes (CDR) and the Instrumental Activities of Daily Living scale (IADL) in participating subjects only. Average CDR and IADL scores were 0 in all subjects. The sensitivity and specificity of the plasma Aβ42/Aβ40 ratio in our study were 30.8% and 71%, respectively, compared to 76% and 75% in Verberk et al. The results of our logistic regression and receiver operating characteristic (ROC) analyses showed that the plasma Aβ42/Aβ40 ratio did not significantly affect ROC curves discriminating between cerebrospinal fluid amyloid abnormal and amyloid normal individuals, in a multivariate model including age and APOEε4 carriership (Fig). Applying Verberk’s model to subjects in our sample would theoretically identify “preclinical” elderly, defined as elderly with biomarker evidence consistent with AD but without cognitive complaints. However, due to the low sensitivity (30.8%) of the model in our sample, we would miss a substantial number of healthy elderly with AD pathology, whom we need for participation in clinical trials on the prevention of AD. To build a model generalizable to an independent dataset, cross-validation of the regression model is crucial. Knowing that Verberk et al did not cross-validate their model, overfitting of the sampled data is a possible explanation for the discrepancy between Verberk’s and our findings. Although there is a maximum of 3 features included in Verberk’s multivariate model, if the model is trained on a homogenous population, overfitting can be a likely occurrence. We therefore think that the findings from the study of Verberk et al can only be limitedly extrapolated to a different population, and that their conclusion that plasma amyloid is a prescreener for the earliest AD pathological changes, as stated in the title of their article, seems as yet too strong. Another possible explanation for the divergent outcomes in the study by Verberk et al and ours may simply be the difference in populations. Past research has shown that subjects with subjective memory complaints are more likely to progress to dementia than healthy elderly without. Also, these subjects tend to have a higher chance of being Apoe4 carriers. Based on our findings, we can either conclude that Verberk’s regression model was overfitted and cannot be extrapolated to new data, or that plasma Aβ42/Aβ40 ratio is not a potential prescreener to identify elderly without memory complaints.