Ge T, Sabuncu MR, Smoller JW, Sperling RA, Mormino EC, Alzheimer's Disease Neuroimaging Initiative. Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition. Neurology. 2018 May 1;90(18):e1605-e1612. Epub 2018 Mar 28 PubMed.
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Ge and colleagues add to the growing literature that AD polygenic risk has predictive utility on longitudinal cognitive decline and neurodegeneration, beyond APOE. This study extends our understanding of the differential effects of APOE and polygenic risk scores (PRS) on outcome variables of amyloid, cognitive decline, and neurodegeneration. In particular, the quantification of variance explained by PRS versus APOE in Aβ+ and Aβ- individuals on these outcome measures provides a compelling way to compare the predictive utility of PRS versus APOE.
Interestingly, while the current study only found weak association of PRS with baseline Aβ across the disease spectrum, we found that a polygenic hazard score (PHS) derived using a survival analysis approach predicted Aβ positivity, even in cognitively normal individuals (Tan et al., 2018). It would be of interest to investigate if there are differential effects of PHS versus PRS versus APOE on cognition and neurodegeneration to further understand how different methods of constructing polygenic scores influence disease prediction. Along with recent efforts looking closer at the effects of polygenic risk within and across APOE genotypes on AD dementia age of onset (van der Lee et al., 2018), the current study represents an important step toward understanding how genetic risk affects disease progression at an increasingly granular level.
References:
Tan CH, Fan CC, 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, Alzheimer’s Disease Neuroimaging Initiative. Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition. Acta Neuropathol. 2018 Jan;135(1):85-93. Epub 2017 Nov 24 PubMed.
van der Lee SJ, Wolters FJ, Ikram MK, Hofman A, Ikram MA, Amin N, van Duijn CM. The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study. Lancet Neurol. 2018 May;17(5):434-444. Epub 2018 Mar 16 PubMed.
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