A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation

Background: In the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (A beta) levels consistent with the presence of Alzheimer's disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs. Methods: Healthy elderly subjects (n = 200; age 65-70 (N = 100) and age > 70 (N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF A beta 1-42 concentrations, plasma A beta 1-40, A beta 1-42, neurofilament light, and total Tau concentrations were measured. A beta 1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE epsilon 4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier. Results: Two hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65-86) years. Twenty-four (27.3%) were A beta positive for AD (age 65-83). The results of the logistic regression classifier showed that predictive features for A beta positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (+/- 4.35) and a specificity of 89.25% (+/- 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (+/- 0.10). Conclusion: This algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF A beta levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs.

Automated summary

The study aimed to develop an algorithm using biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects at risk of Alzheimer's disease pathology. The algorithm led to a significant reduction in the need for lumbar punctures, decreasing burden and costs for study subjects.