4.7 Article

Progranulin mutations in clinical and neuropathological Alzheimer's disease

Journal

ALZHEIMERS & DEMENTIA
Volume 18, Issue 12, Pages 2458-2467

Publisher

WILEY
DOI: 10.1002/alz.12567

Keywords

Alzheimer's disease; neuropathology; progranulin; TDP43

Funding

  1. National Human Genome Research Institute
  2. Large Scale Sequencing and Analysis Centers (LSAC)
  3. National Heart, Lung, and Blood Institute (NHLBI)
  4. National Institute of Health (NIH)
  5. National Institute on Aging [P30AG10161, R01AG15819, R01AG17917, R01AG42210, U01AG46152, U01AG61356, R56AG063908, R01AG067501, RF1AG015473, U01 AG032984, UM1HG008901, R01 AG033193, U01AG006781, RF1AG054023, R01AG048927, RF1AG057519, R03AG054936, AG033193]

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This study found that pathogenic GRN mutations are common in FTLD and AD, often with TDP-43 pathology. Pathogenic GRN carriers have significantly higher PHFtau tangle density associated with AD. The rs5848 mutation is associated with increased frequency of hippocampal sclerosis and TDP-43 deposits in AD patients.
Introduction Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. Methods We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, beta-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers. Results Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE epsilon 4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort. Discussion GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with beta-amyloid load or AD.

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