Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe

Kwangsik Nho, Andrew J. Saykin, Peter T. Nelson

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848-T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180-A) was associated with multifocal atrophy whereas a SNP (rs7488080-A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622-T), KCNMB2 (rs9637454-A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

Original languageEnglish
Pages (from-to)373-383
Number of pages11
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - Apr 26 2016

Bibliographical note

Publisher Copyright:
© 2016 IOS Press and the authors. All rights reserved.


  • Arteriolosclerosis
  • KATP
  • SUR2
  • TDP-43
  • dementia
  • progranulin
  • rs1990622
  • rs5848
  • rs704180
  • rs9637454

ASJC Scopus subject areas

  • Neuroscience (all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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