110 Chapter 5 Amyloid PET was available for 72 individuals within 1 year of baseline diagnosis ([18F] florbetapir n=13, [18F]florbetaben n=43, [18F]flutemetamol n=10 and [11C]-PIB (Pittsburgh compound-B) n=6). The following systems were used to acquire PET scans: Gemini TF PET-CT, Ingenuity TF PET-CT, and Ingenuity PET/MRI (Philips Healthcare, Best, The Netherlands). For [18F]florbetapir (30) and [11C]PIB imaging(31), a dynamic scanning protocol was used, for [18F]florbetaben (32) and [18F]flutemetamol (33) imaging, a static scanning protocol. A trained nuclear medicine physician (BvB) visually rated scans as ‘positive’ or ‘negative’. CSF was available in 644 individuals. A lumbar puncture was performed using a 25-gauge needle and syringe. Concentrations of abeta1-42 were measured using an Innotest ELISA (n=636) or Elecsys assay (n=8). The Innotest abeta levels were corrected for the upward drift in CSF biomarker analyses that occurred over the years (34). We transformed the abeta values obtained by Elecsys to the Innotest equivalent values using the following formula: Elecsys Abeta (pg/ml) = -365 + 1.87 * Innotest Abeta (pg/ml) (35). Adjusted concentrations <813 pg/mL were considered abnormal. Tau phosphorylated threonine 181 (p-tau) was measured using Innotest ELISAs (hTAUAg and PhosphoTAU-181p); concentrations > 52 pg/mL were considered abnormal. An MRI scan of the brain was available for 703 individuals (Siemens Avanto, n=6; GE Discovery MR750, n=14; Impact, n=97; 3T Philips Ingenuity TF PET/MR system, n=141; 1.5T GE Signa HDxt, n=22; 3.0T GE Signa HDxt, n=264; 1.5T Siemens Sonata, n=25; 3T Toshiba Vantage Titan, n=134). All scans were reviewed by an experienced neuroradiologist. Coronal T1-weighted images were used for visual assessment of MTA (range 0-4). The left and right MTA scores were averaged, and age dependent cut-off values were used. For individuals <65 years of age, an MTA score ≥1 was considered abnormal, for individuals ≥65 years, an MTA score ≥1.5 was considered abnormal (36). Genotyping and imputation procedures We selected 39 genetic variants for which there was evidence of a significant association with AD from previous genome-wide association studies (GWAS) and candidate-gene studies (Supplementary Table 1) (8, 9, 37). All genetic variants in our cohort were determined by standard genotyping or imputation methods and we applied established quality control methods (38). All individuals were genotyped using Illumina Global Screening Array (GSAsharedCUSTOM_20018389_A2). We used high-quality genotyping in all individuals (individual call rate >98%, variant call rate >98%). All individuals’ reported sex matched with their genetic sex. Variants that departed from Hardy–Weinberg equilibrium were excluded at p<1×10-6. Genotypes
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