Effects of cerebrospinal fluid proteins on brain atrophy rates in cognitively healthy older adults

Biomarkers associated with Alzheimer's disease (AD)-like brain atrophy in healthy individuals may identify mechanisms involved in early stage AD. Aside from cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and tau, no studies have tested associations between CSF proteins and AD-like brain atrophy. We studied 90 healthy elders, who underwent lumbar puncture at baseline, and serial magnetic resonance imaging scans for up to 4 years. We tested statistical effects of baseline CSF proteins (N = 70 proteins related to Aβ42-metabolism, microglial activity, and synaptic/neuronal function) on atrophy rates in 7 AD-related regions. Besides the effects of Aβ42 and phosphorylated tau (P-tau) that were seen in several regions, novel CSF proteins were found to have effects in inferior and middle temporal cortex (including apolipoprotein CIII, apolipoprotein D, and apolipoprotein H). Several proteins (including S100β and matrix metalloproteinase-3) had effects that depended on the presence of brain Aβ pathology, as measured by CSF Aβ42. Other proteins (including P-tau and apolipoprotein D) had effects even after adjusting for CSF Aβ42. The statistical effects in this exploratory study were mild and not significant after correction for multiple comparisons, but some of the identified proteins may be associated with brain atrophy in healthy persons. Proteins interacting with CSF Aβ42 may be related to Aβ brain pathology, whereas proteins associated with atrophy even after adjusting for CSF Aβ42 may be related to Aβ-independent mechanisms.