Population-based blood screening for pre-clinical Alzheimers disease: a British birth cohort at age 70

In pre-clinical Alzheimer’s disease, cerebral amyloid-β (Aβ) deposition precedes symptoms; Aβ-targeted therapies may have maximum benefits at this stage. Existing Aβ status measurement techniques, including amyloid PET and CSF testing, are difficult to upscale. We therefore compared the concordance of three different blood-based techniques (liquid chromatography-mass spectrometry (LC¬-MS) measures of plasma Aβ, and single molecule array (Simoa) measures of plasma Aβ and phospho-tau181 (p-tau181)) with amyloid PET-positivity in dementia-free members of Insight 46, a sub-study of the British 1946 birth cohort.

Of 441 dementia-free individuals with complete data, 82 (18.6%) were amyloid PET-positive. The area under the receiver operating characteristics curve for amyloid PET status using a base model comprising age, sex and APOE 4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The best perform- ing Simoa biomarker was p-tau181 (0.707; 0.646–0.768). LC-MS Aβ1–42/1–40 performed significantly better (0.817; 0.770–0.864), with a Youden’s index cut-point of 0.095 detecting amyloid PET-positivity with 86.6% sensitivity and 71.9% specificity. Without screening, 543 individuals would need PET scans, to obtain 100 PET-positive individuals. Screening using the base model would require 940 individuals, with 266 proceeding to scan. Using LC-MS Aβ1–42/1–40 alone would reduce these numbers to 623 and 243 respectively. Across a theoretical range of amyloid PET-positivity prevalence of 10–50%, LC-MS Aβ1–42/1–40 would consistently reduce scan numbers, with greater cost savings at lower prevalence.