Table 2.
Studies of polygenic risk on cognition and brain.
| Study | Participants | Study Design | SNP | APOE | Conversion Risk | Cognitive Impact | Neuroimaging Impact |
|---|---|---|---|---|---|---|---|
| Sabuncu et al., 2012 [168] | 104 CN (75.9 ± 5.1) and 100 AD (75.1 ± 7.8) | Cross-sectional study | 26 | N | The PGS was significantly associated with CDR-SB, MMSE, and AD diagnosis. | AD-specific cortical thickness was correlated with the PGS, even after controlling for APOE genotype and CSF levels of Aβ42. The association remained significant in CN subjects with levels of CSF Aβ42 in the normal range and in APOE ε3 homozygotes. | |
| Rodriguez-Rodriguez et al., 2013 [90] | 228 MCI | Longitudinal study (26.3 months) | 8 | N | PGS was not associated with risk of conversion from MCI to AD. MCI-converters to AD harboring six or more risk alleles progressed twofold more rapidly to AD when compared with those with less than six risk alleles. | ||
| Verhaaren et al., 2013 [91] | Non-demented 5171 (age range 45–99) | Cross-sectional study | 12 | Y | PGS was primarily associated with memory. | ||
| Marden et al., 2014 [92] | 10401 (memory score sample), 7690 (AD probability scores) non-Hispanic white and black | Cross-sectional study | 10 | Y | Each 0.10 unit change in PGS was associated with larger relative effects on dementia among aged 65+. | Each 0.10 unit change in the PGS was associated with a −0.07 standard deviation difference in memory score among aged 50+. | |
| Carrasquillo et al., 2015 [99] | CN 2674 | Longitudinal study | 10 | Y | PGS was associated with progression to MCI/LOAD. | PGS was associated with worse memory. | |
| Martiskainen et al., 2015 [164] | 890 AD (69.8 ± 8.2) and 701 CN (69.1 ± 6.2) | Cross-sectional study | 22 | Y/N | PGS associated with CSF Aβ42 levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. | ||
| Xiao et al., 2015 [94] | 459 AD (71.2 ± 9.6), 751 CN (72.7 ± 5.9) Chinese | Cross-sectional study | 3 | N | PGS significantly associated with AD risk. | ||
| Sleegers et al., 2015 [89] | 1162 AD (74.4 ± 8.9) and 1019 CN (76.2 ± 8.5) | Cross-sectional study | 22 | Y | Risk of AD increased with PGS; onset age decreased with increasing PGS. | CSF Aβ42 decreased with increasing PGS. | |
| Andrews et al., 2016 [98] | Non-demented 1689 (62.54 ± 1.51) | Longitudinal study | 12 | Y | PGS was associated with worse performance on episodic memory. | ||
| Harrison et al., 2016 [171] | 66 baseline participants (63.0 ± 10.4) and 45 follow-up participants (63.2±7.8) | Longitudinal study (2 years) | 21 | Y | Both unweighted risk score and weighted risk score correlated strongly with the percentage change in thickness across the whole hippocampal complex, driven by a strong relationship to entorhinal cortex thinning. By contrast, at baseline, the risk scores showed no relationship to thickness in any hippocampal complex subregion. | ||
| Louwersheimer et al., 2016 [97] | 1730 MCI from 4 independent datasets | Longitudinal study | 18 | N | PGS was modestly associated with cognitive decline over time. | PGS was modestly associated with CSF levels of tau and p-tau. | |
| Lupton et al., 2016 [173] | 1674 older (aged >53 years; 17% AD, 39% MCI) and 467 young (16–30 years) adults | Cross-sectional study | Different thresholds | N | PGS associated with reduced hippocampal volume in older CN and MCI. No associations were found in young adults. | ||
| Marden et al., 2016 [93] | 8253 non-Hispanic whites and blacks | Longitudinal study | 22 | Y/N | PGS can predict a more rapid decline in memory in whites and blacks; PGS without APOE ε4 only can predict memory decline in whites. | ||
| Darst et al., 2017 [167] | 1200 at baseline (53.6 ± 6.6) | Longitudinal study | 21 | Y | Non-significant for associations between the PGS and cognitive outcomes. | These additional variants did not add much predictive power over APOE alone on biomarkers of Aβ deposition, neurodegeneration and tau pathology. | |
| Desikan et al., 2017 [172] | More than 80,000 people from two projects | Longitudinal study | 31 | N | ADGC Phase 1: highest PGS quartile, lower age onset and the highest yearly AD incidence rate. APOE ε3/3 individuals: PGS modified expected age of AD onset by more than 10 years between the lowest and highest deciles. Independent cohorts: PGS strongly predicted empirical age of AD onset and longitudinal progression. | PGS was associated with neuropathology (Braak stage of neurofibrillary tangles and Consortium to Establish a Registry for Alzheimer’s Disease score for neurotic plaques) and in vivo markers of AD neurodegeneration (volume loss within the entorhinal cortex and hippocampus) | |
| Foley et al., 2017 [175] | 272 T1 (24.8 ± 6.9), 197 DTI (23.9 ± 5.1), 87 Hopkins Verbal Learning Task (23.9 ± 4.4) | Cross-sectional study | 7 thresholds | Y/N | A significant association between PGS and left hippocampal volume; this effect remained when the APOE gene was excluded. The fractional anisotropy of the right cingulum was inversely correlated with PGS. | ||
| Lacour et al., 2017 [96] | 4 MCI groups 853/812/1245/306 | Longitudinal study | 9 | N | PGS predicted a small effect on the risk of MCI to AD progression in APOE ε4 carriers. | ||
| Voyle et al., 2017 [165] | About 250 people with normal and abnormal CSF Aβ from ADNI | Cross-sectional study | − | N | A case/control PGS is marginally more predictive of Aβ and tau pathology than the basic models (with age, gender and APOE genotype). | ||
| Xiao et al., 2017 [174] | 231 CN (age range 19–55) | Cross-sectional study | 6 thresholds | N | Almost no significant association of PGS with cognition. | There was a significant negative relationship between PGS and hippocampal function. | |
| Ge et al., 2018 [104] | 702 participants (221 CN, 367 MCI, and 114 AD) and a subset of 669 participants | Longitudinal study | Different thresholds | N | Only weak associations between PGS and baseline Aβ were present. PGSs were associated with hippocampal atrophy in Aβ− and weakly associated with baseline hippocampal volume in Aβ+. | ||
| Kauppi et al., 2018 [193] | 336 MCI (baseline age range 55–89) | Longitudinal study (3 year) | 31 | Y | PGS significantly predicted time to progression from MCI to AD over 120 months, and PGS was significantly more predictive than APOE alone. | PGS improved the prediction of change in the CDR-SB score and MMSE over 36 months in MCI at baseline, beyond both APOE and baseline levels of brain atrophy. | |
| Li et al., 2018 [170] | 360 CN (19.4 ± 1.1) in discovery dataset and 323 CN (22.7 ± 2.5) in replication dataset | Cross-sectional study | − | Y/N | No correlation between PGS and any cognitive measure in either sample. | In both cohorts, an elevated PGS was associated with a smaller precuneal volume, and the effect remained after excluding the APOE genotype. | |
| Lin et al., 2019 [194] | 2907 stroke-free individuals (76.73 ± 5.83) | Cross-sectional study | 3 thresholds | Y/N | PGSs were associated with lobar cerebral microbleeds, white-matter lesion load, and coronary artery calcification, mostly explained by single-nucleotide polymorphism in the APOE region. The effect of PGS on cognition was partially but significantly mediated by cerebral microbleeds, white-matter lesions, and coronary artery calcification. | ||
| Tan et al., 2018 [166] | 347 CN (baseline age range 59.7–90.1), 599 MCI (baseline age range 54.4–91.4), and 485 (age at death range = 71.3–108.3) in another cohort | Longitudinal study | 31 | N | Even after accounting for APOE ε4 effects, PGS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression. |
CN, cognitive normal; MCI, mild cognitive impairment; AD, Alzheimer’s disease; PGS: polygenic risk score; Y, APOE included in PGS; N, APOE not included in PGS; Y/N, Both situations of APOE included and not in PGS; CDR-SB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini-Mental State Examination; CSF, cerebrospinal fluid; ADGC, Alzheimer’s Disease Genetics Consortium.