F1‐03‐03: Mapping the progression of CSF and imaging biomarkers in “at‐risk” healthy subjects: The prevent‐ad program

Increasing evidence suggests that multiple cerebrospinal fluid (CSF) and imaging biomarkers may elucidate the pre-symptomatic phase of Alzheimer's disease (AD). Using a cohort of aging cognitively intact individuals with a first-degree family history of AD, we evaluated time course alterations in multiple AD biomarkers including “classic” CSF markers and lipid transport proteins in relation to brain resting-state network activity. We examined results across specific genotypes including APOE. Baseline, 3-, 12- and 24-months data were acquired for an ongoing prevention trial nested in the PREVENT-AD program. CSF was obtained by lumbar puncture, and protein concentrations were measured using Innotest technology for tau, P-tau and Aβ1-42. Luminex-based immunoassays (Millipore) were used to quantify CSF apolipoproteins A1, A2, B, C2, C3 and E. Genotypes for APOE and other polymorphisms were determined using standardized pyrosequencing techniques. Finally, a systematic analysis of different resting state functional MRI-derived indices was performed using standard machine learning algorithms. The resulting signal was then examined in relation to alteration in P-tau at 12 months vs. baseline. Time course analyses of tau, P-tau and Aβ1-42 over 2 years indicated strong APOE-e4 genotype-driven differences at baseline, with a clear exacerbation of pathological changes between 12 and 24 months. The latter elevation in tau/Aβ1-42 ratio (n=60) found among APOE-e4 carriers vs. non-carriers was inapparent, however, in subjects with the protective (G-negative) genotype at the HMGCR rs3866662 locus. Surprisingly, levels of CSF apoE protein correlated directly with age, a finding driven by results from e4-negative subjects only (p<0.002). Levels of CSF apoB (derived exclusively from blood) were significantly increased in e4 carriers vs. non-carriers at all timepoints (p<0.01). Resting state network activity connecting precuneus to anterior cingulate cortex correlated inversely with P-tau change between baseline and 12 months (p <0.01). Alterations over time in tau, Aβ1-42 and P-tau levels in the CSF in a cohort of high-risk cognitively intact subjects suggest ongoing “silent” neurodegeneration with consequences for at least one specific network function. Our findings with apoB suggest loss of blood-brain barrier integrity in persons with APOE e4 – a group with other signs of exaggerated pre-symptomatic AD pathology.

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