Aβ42/Aβ40 Ratios of Presenilin 1 Mutations Correlate with Clinical Onset of Alzheimer's Disease.

Missense mutations in presenilin 1 cause early onset familial Alzheimer's disease in a way that is not understood. Increased Aβ42/Aβ40 ratios are the most consistent biochemical phenotype of such mutations in cultured cells and in vivo, and are thus considered central to the amyloid hypothesis. Previously, an inverse relation has been observed between the Aβ42/Aβ40 ratio of such mutants and the clinical age of symptom onset in patients carrying the mutation. However, a recent extensive study by Sun et al. of assayed presenilin 1 mutants concluded that such a relationship is not evident. To reconcile the disagreement, three different clinical datasets were compared directly with the data by Sun et al. After considering data noise and measurement uncertainty, we find a clear and highly significant inverse correlation between the Aβ42/Aβ40 ratio and the clinical age of onset in all three datasets even without removing noisy single- and double-patient data. With these data removed, the correlation coefficients increase further. The probability that these relationships are coincidental are approximately 0.1%.