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

Article type: Research Article

Authors: Nho, Kwangsik^{a; c; d; *} | Saykin, Andrew J.^{a; b; c; d} | Alzheimer’s Disease Neuroimaging Initiative¹ | Nelson, Peter T.^{e; *}

Affiliations: [a] Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA | [b] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA | [c] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA | [e] University of Kentucky, Sanders-Brown Center on Aging and Pathology Department, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Correspondence to: Peter T. Nelson, MD, PhD, Department of Pathology, Division of Neuropathology, University of Kentucky, Rm 311, Sanders-Brown Center on Aging, 800 S. Limestone Avenue, Lexington, KY 40536, USA. Tel.: +1 859 218 3862; E-mail: [email protected] and Kwangsik Nho PhD, Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Tel.: +1 317 963 7503; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: 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.

Keywords: Arteriolosclerosis, dementia, KATP, progranulin, rs5848, rs704180, rs1990622, rs9637454, SUR2, TDP-43

DOI: 10.3233/JAD-160077

Journal: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 373-383, 2016