P3-103: Initial studies on the association between antemortem levels of cerebrospinal fluid β-secretase activity and post-mortem CERAD ratings of plaque densities in Alzheimer's disease

In Alzheimer's disease (AD) the brain shows high densities of plaques containing beta-amyloid (Aβ). Despite this, CSF levels of Aβ peptides are low in AD. The activity of β-amyloid converting enzyme (BACE) appears rate-limiting in the production of APP fragments (sAPPβ and Aβ). Although post-mortem BACE levels and activity in brain appear higher in AD, ante-mortem CSF BACE activity levels have been reported as elevated or unchanged in AD. We aimed to further examine the relationship between ante-mortem CSF BACE activity and APP processing with post mortem plaque and tangle densities. We obtained CSF by lumbar puncture from 17 AD patients, for whom post mortem plaque and tangle ratings showed CERAD ‘Probable' or ‘Definite' AD, and 27 cognitively healthy controls of similar age (post mortems in 6 confirmed ‘Normal brain'). Mean CSF BACE activity was significantly lower in AD patients (77% of control activity, p=0.01). CSF sAPPβ, Aβ1–40 and Aβ1–42 levels were also lower in AD patients (78%, 73% and 45% of control levels, p=0.01, p<0.001, p<0.001, respectively). CSF sAPPβ, Aβ1–40 and Aβ1–42 levels all related directly to CSF BACE activity (all p<0.005). The altered CSF Aβ levels in AD patients remained significant if we covaried BACE activity. CSF BACE activity, Aβ1–40 and Aβ1–42 levels all related inversely to CERAD ratings of plaques (p=0.015, p=0.04, p=0.007, respectively). The reduced CSF BACE activity in AD patients appears consistent with the lower CSF Aβ levels. However whether this directly reflects reduced APP catabolism remains uncertain. The inverse dependence of CERAD plaque ratings on both CSF BACE activity and Aβ levels raises the alternative possibility that a common mechanism, such as sequestration by plaques, lowers both.