Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease

Neurobiol Aging. 2017 Jan:49:216.e7-216.e13. doi: 10.1016/j.neurobiolaging.2016.09.020. Epub 2016 Oct 3.


We present 2 cases of early-onset Alzheimer's disease due to a novel N135Y mutation in PSEN1. The proband presented with memory and other cognitive symptoms at age 32. Detailed clinical characterization revealed initial deficits in memory with associated dysarthria, progressing to involve executive dysfunction, spastic gait, and episodic confusion with polyspike discharges on long-term electroencephalography. Amyloid- and FDG-PET scans showed typical results of Alzheimer's disease. By history, the proband's father had developed cognitive symptoms at age 42 and died at age 48. Neuropathological evaluation confirmed Alzheimer's disease, with moderate to severe amyloid angiopathy. Skeletal muscle showed type 2 fiber-predominant atrophy with pale central clearing. Genetic testing of the proband revealed an N135Y missense mutation in PSEN1. This mutation was predicted to be pathogenic by in silico analysis. Biochemical analysis confirmed that the mutation caused an increased Aβ42/Aβ40 ratio, consistent with other PSEN1 mutations and with a loss of presenilin function.

Keywords: Alzheimer's disease; Elecrtoencephalography; PET scan; Presenilin 1.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Brain / pathology
  • Electroencephalography
  • Female
  • Genetic Association Studies*
  • Genetic Testing
  • Humans
  • Magnetic Resonance Imaging
  • Middle Aged
  • Mutation / genetics*
  • Neuroimaging*
  • Neuropsychological Tests
  • Positron-Emission Tomography
  • Presenilin-1 / genetics*


  • Amyloid beta-Peptides
  • PSEN1 protein, human
  • Presenilin-1