Association between the CSF Aβ1- 42/Aβ1-40 ratio and amyloid PET

Most studies have found a strong association between CSF Aβ1-42 and amyloid PET measurements. However, in these studies, 10–20% of healthy individuals and MCI patients show a mismatch in CSF Aβ1-42 alone and amyloid PET status⁶. A study published by Janelidze et al. in 2016 demonstrated that the CSF Aβ1-42/Aβ1-40 (and Aβ1-42/Aβ1-38) ratio better predicts abnormal cortical amyloid deposition (visualized with PET) compared to Aβ1-42 alone. The ratios increased the classification performance both for people who were falsely classified as positive (by low CSF Aβ1-42) and for people who were falsely classified as negative (by high CSF Aβ1-42).⁷

Janelidze et al. show that in patients with mild cognitive complaints, low CSF Aβ1-42, Aβ1-40, and Aβ38 are linked to subcortical injury. They hypothesize that underlying mechanisms are likely related to dysregulation in amyloid precursor protein (APP) pathways with a general decline in the 

production of Aβ. However, in accordance with earlier investigations, they found that low CSF levels of Aβ1-42, but not Aβ1-40 and Aβ38, were associated with more AD-specific neurodegeneration (i.e., hippocampal atrophy). They partially attribute the 23–36% increase in accuracy of the Aβ1-42/Aβ1-40 ratio compared to Aβ42 alone when differentiating AD from Parkinson’s Disease/DLB and Vascular Dementia (or from non‐AD dementias as a whole group) to this phenomenon.⁷

Furthermore, significantly higher concordance with 18F- flutemetamol PET was observed when using the Aβ1-42/Aβ1-40 ratio compared to Aβ1-42 alone in a study by Pannee et al.  These results showed that the CSF Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38 ratios are strongly associated with cortical Aβ fibrils measured by 18F- flutemetamol PET.⁸

Interestingly, the Aβ1-42/Aβ1- 40 ratio may reflect altered Aβ kinetics potentially detecting changes in amyloid deposition before these changes are detectable by PET. These altered kinetics may account for the minor discordances observed between PET and CSF results most frequent in MCI and healthy individuals.⁹

Altogether, these results suggest that an isolated drop in CSF Aβ1-42 may be more specific for AD-type pathology, whereas lower CSF levels of all three Aβ isoforms might be associated with subcortical damage in general. This assumption fits findings that reduced levels of all three Aβ species can be found in Parkinson Dementia, Dementia with Lewey bodies and Vascular Dementia, several disorders that are accompanied by subcortical changes.⁷