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Alzheimers Dement. 2016 Aug;12(8):862-71. doi: 10.1016/j.jalz.2016.01.010. Epub 2016 Mar 15.

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

Author information

1
Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK. Electronic address: j.schott@ucl.ac.uk.
2
Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
3
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
4
Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
5
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
6
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
7
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
8
UCSF, San Francisco, CA, USA.
9
Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Memory Disorders Unit, Department of Neurology, University Hospital Virgen del Rocio, Seville, Spain.
10
Memory Disorders Unit, Department of Neurology, University Hospital Virgen del Rocio, Seville, Spain.
11
Institute of Brain, Behaviour and Mental Health, University of Manchester, UK.
12
Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus, Amsterdam, Netherlands.
13
Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands; UC San Diego/VA San Diego Healthcare System, San Diego, CA, USA.
14
INSERM U610, Hôpital de la Salpêtrière, Paris, France.
15
Centre des Maladies Cognitives et Comportementales, IM2A, ICM, Paris 6 University, France.
16
Regional Memory Centre (CMRR), CHU Besançon, Besançon, France.
17
University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Italy.
18
Vita-Salute San Raffaele University, Milan, Italy.
19
University of New South Wales, Sydney, Australia.
20
Alzheimer's Association, Chicago, IL, USA.
21
Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK.

Abstract

INTRODUCTION:

The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.

METHODS:

We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.

RESULTS:

We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]).

DISCUSSION:

We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

KEYWORDS:

APOE; Alzheimer's disease; GWAS; Genetics; Posterior cortical atrophy; Selective vulnerability

PMID:
26993346
PMCID:
PMC4982482
DOI:
10.1016/j.jalz.2016.01.010
[Indexed for MEDLINE]
Free PMC Article

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