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Brain. 2019 Feb 1;142(2):460-470. doi: 10.1093/brain/awy327.

Polygenic hazard score, amyloid deposition and Alzheimer's neurodegeneration.

Author information

1
Division of Psychology, Nanyang Technological University, 48 Nanyang Avenue, Singapore.
2
Department of Radiology and Biomedical Imaging, University of California, San Francisco, 500 Parnassus Avenue, San Francisco, CA, USA.
3
Department of Neurology, University of California, San Francisco, 400 Parnassus Ave, San Francisco, CA, USA.
4
Department of Cognitive Science, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, USA.
5
Department of Neurology and Neurological Sciences, Stanford University, 300 Pasteur Dr, Palo Alto, CA, USA.
6
Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA, USA.
7
Department of Psychiatry, University of California, San Francisco, 982 Mission St, San Francisco, CA, USA.
8
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 204 N Broad St, Philadelphia, PA, USA.
9
Department of Radiology, University of California, San Diego, 8929 University Center, La Jolla, CA, USA.
10
Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, USA.
11
National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, 1959 NE Pacific St, Seattle, WA, USA.
12
Department of Neurology, Massachusetts General Hospital, 15 Parkman St, Boston, MA, USA.
13
Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, USA.
14
NORMENT Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Boks 1072 Blindern, Oslo, Norway.

Abstract

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-β protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.

PMID:
30689776
PMCID:
PMC6351776
[Available on 2020-02-01]
DOI:
10.1093/brain/awy327

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