Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition.

Autor: Tan CH; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. chinhong.tan@ucsf.edu., Fan CC; Department of Cognitive Science, University of California, La Jolla, San Diego, CA, USA., Mormino EC; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA., Sugrue LP; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA., Broce IJ; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA., Hess CP; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA., Dillon WP; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA., Bonham LW; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Yokoyama JS; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Karch CM; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA., Brewer JB; Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA.; Department of Radiology, University of California, La Jolla, San Diego, CA, USA.; Shiley-Marcos Alzheimer's Disease Research Center, University of California, La Jolla, San Diego, CA, USA., Rabinovici GD; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Miller BL; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Schellenberg GD; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA., Kauppi K; Department of Radiology, University of California, La Jolla, San Diego, CA, USA., Feldman HA; Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA., Holland D; Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA., McEvoy LK; Department of Radiology, University of California, La Jolla, San Diego, CA, USA., Hyman BT; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA., Andreassen OA; NORMENT Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway., Dale AM; Department of Cognitive Science, University of California, La Jolla, San Diego, CA, USA.; Department of Neurosciences, University of California, La Jolla, San Diego, CA, USA.; Department of Radiology, University of California, La Jolla, San Diego, CA, USA., Desikan RS; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. rahul.desikan@ucsf.edu.; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. rahul.desikan@ucsf.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2018 Jan; Vol. 135 (1), pp. 85-93. Date of Electronic Publication: 2017 Nov 24.
DOI: 10.1007/s00401-017-1789-4
Abstrakt: There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4-91.4, 98.83% white) individuals from the Alzheimer's Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3-108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.
Databáze: MEDLINE
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