GWAS of longitudinal amyloid accumulation on¹⁸F-florbetapir PET in Alzheimer’s disease implicates microglial activation geneIL1RAP

Abstract

Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

Solanezumab—prospects for meaningful interventions in AD?

“…8 This finding supports the notion that AD can be divided into an amyloid accumulation phase that might be silent, and an immune-inflammatory phase that drives cognitive decline. In the largest genome-wide association study of sporadic AD to date, 9 involving over 74,000 participants, immune–inflammatory genes were overrepresented, reinforcing the importance of these pathways, and raising the possibility that some forms of AD are driven by ‘hyperinflammation’ that begins and/or propagates independently of fibrillar amyloidosis.…”

The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

“…Beginning with AD candidate genes nominated by large genome wide association studies (GWAS) [73] sequencing studies (e.g., TREM2 [56–59], PLD3 [60]), prior studies of AD endophenotypes in ADNI [74, 75] and other studies, followed by GWA (e.g., [76, 77]), we expect to identify variants that improve prediction of disease trajectory (i.e., onset, course, and outcome). We also predict that variants associated with biomarkers may yield clues to biological mechanisms and serve as potential targets for enrichment or therapeutic development.…”

A variant in PPP4R3A protects against alzheimer‐related metabolic decline

“…Previous GWAS studies using imaging markers including hippocampal atrophy, beta-amyloid, and CSF tau have provided insight into the mechanisms underlying genetic vulnerability to AD, implicating a number of genes associated with these AD endophenotypes 8,9,21,31 . The significant advantage of using PCC metabolic decline as an endophenotype in the present study, is that it is a consistent early biomarker for AD that has been shown to correlate well with disease progression, to a greater extent than beta-amyloid deposition 10,11 .…”