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Polygenic risk score for Alzheimer’s disease is related to amyloid positivity in subjective cognitive decline: The SCIENCe project
Author(s) -
van der Lee Sven J.,
Ebenau Jarith L.,
Jansen Iris E.,
Verberk Inge M.W.,
Scheltens Philip,
Teunissen Charlotte E.,
Barkhof Frederik,
Reinders Marcel J.T.,
Van Berckel Bart N.M.,
Holstege Henne,
van Der Flier Wiesje
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042116
Subject(s) - apolipoprotein e , cohort , dementia , medicine , cognitive decline , disease , memory clinic , alzheimer's disease neuroimaging initiative , cognition , logistic regression , oncology , psychology , psychiatry
Background The majority of individuals with subjective cognitive decline (SCD) is worried well, but in some the subjective experience of cognitive decline herald’s incipient neurodegenerative disease. Understanding the determinants of disease in SCD is important to separate wheat from chaff. Here we studied APOE and a polygenic risk score for Alzheimer’s disease (AD) in a cohort of SCD that was classified according to the ATN‐framework. Method We classified 542 participants with SCD (59.2±8.7 years, 38.9%Female, MMSE 28.3±1.5) from the Amsterdam Dementia Cohort and SCIENCe project according to the ATN‐framework, as determined by amyloid PET or CSF Abeta(A), CSF p‐tau(T) and MRI‐based medial temporal lobe atrophy(N). We reduced the number of categories to three: controls (A‐T‐N‐ or normal AD biomarkers, N=310(57%)), non‐AD pathologic change (A‐T‐N+, A‐T+N‐, A‐T+N+, N=142 (26%)) and the Alzheimer’s continuum (A+T‐N‐, A+T‐N+, A+T+N‐, A+T+N+, N=90(17%)). We determined APOE ɛ4 and 39 other genetic variants that were associated in previous studies with AD using array genotyping or imputation. A weighted AD polygenic risk score (AD‐PRS) was calculated based on 39 variants (excluding APOE ɛ4). Logistic regression models were fitted for the associations between AD‐PRS and APOE ɛ4 with Alzheimer’s continuum and non‐AD pathological changes. For 324 participants follow‐up for dementia was available (3.1±2.5 year) and progression could be studied. Cox proportional hazard models were used to analyse progression to all‐cause dementia (N=36, 6.6%) and AD‐dementia (N=22, 3.6%). Associations were corrected for 5 ancestry principal components. Result The APOE ɛ4 genotype was associated with Alzheimer’s continuum (OR=3.6, 95%CI 2.4‐5.3, P =3.0×10 ‐10 ) as well as non‐AD pathologic changes (OR=1.5, 95%CI 1.1‐2.2, P =1.6×10 ‐2 ). The AD‐PRS was associated with Alzheimer’s continuum (OR per 1‐SD =1.4, 95%CI 1.1‐1.8, P =3.5×10 ‐3 ), but not with non‐AD pathologic changes (OR=1.1, 95%CI 0.9‐1.3, P =0.64). In the progression analysis: APOE ɛ4 was associated with all‐cause dementia (HR=1.7, 95%CI 1.1‐2.7, P =2.3×10 ‐2 ) as well as AD‐dementia (HR=2.3, 95%CI 1.3‐4.2, P =4.5×10 ‐3 ). The AD‐PRS was not associated with progression to all‐cause dementia (HR=0.9, P =0.4) or AD‐dementia (HR=1.4, P =0.13). Conclusion In individuals with SCD APOE ɛ4 and an AD‐PRS are associated with the presence of amyloid biomarkers (Alzheimer’s continuum), showing that genetic factors can identify individuals at risk in individuals that are cognitively normal.