Journal
ACTA NEUROPATHOLOGICA
Volume 135, Issue 1, Pages 85-93Publisher
SPRINGER
DOI: 10.1007/s00401-017-1789-4
Keywords
Polygenic risk; Amyloid; Tau; Alzheimer's disease
Categories
Funding
- Radiological Society of North America Resident/Fellow Award
- American Society of Neuroradiology Foundation Alzheimer's Disease Imaging Award
- National Alzheimer's Coordinating Center Junior Investigator award
- National Institutes of Health [NIH-AG046374, K01AG049152, P20AG10161, R01AG15819, R01AG17917]
- Research Council of Norway [213837, 225989, 223273, 237250]
- South East Norway Health Authority [2013-123]
- Norwegian Health Association
- Kristian Gerhard Jebsen Foundation
- Alzheimer's Disease Neuroimaging Initiative
- National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site
- Alzheimer's Disease Genetics Consortium
- NATIONAL INSTITUTE ON AGING [K01AG049152, K01AG051718, R01AG045611, K01AG046374, P50AG023501, RF1AG015819, U24AG021886, R01AG017917, P30AG010161, R01AG015819, U01AG032984] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP1OD006849] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 epsilon 4 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 epsilon 4 noncarriers. Together, our results show that even after accounting for APOE epsilon 4 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available