TitlePolygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition.
Publication TypeJournal Article
Year of Publication2018
AuthorsTan CHong, Fan CChieh, Mormino EC, Sugrue LP, Broce IJ, Hess CP, Dillon WP, Bonham LW, Yokoyama JS, Karch CM, Brewer JB, Rabinovici GD, Miller BL, Schellenberg GD, Kauppi K, Feldman HA, Holland D, McEvoy LK, Hyman BT, Bennett DA, Andreassen OA, Dale AM, Desikan RS
Corporate AuthorsAlzheimer’s Disease Neuroimaging Initiative
JournalActa Neuropathol
Volume135
Issue1
Pagination85-93
Date Published2018 Jan
ISSN1432-0533
Abstract

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.

DOI10.1007/s00401-017-1789-4
Alternate JournalActa Neuropathol.
PubMed ID29177679
PubMed Central IDPMC5758038
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
R01AG15819 / / National Institutes of Health / United States
K01 AG049152 / AG / NIA NIH HHS / United States
P20AG10161 / / National Institutes of Health / United States
R01AG17917 / / National Institutes of Health / United States
R01 AG017917 / AG / NIA NIH HHS / United States
AG046374 / / National Institutes of Health / United States
K01AG049152 / / National Institutes of Health / United States
K01 AG046374 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
K01 AG051718 / AG / NIA NIH HHS / United States
R01 AG045611 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States