TABLE 3.
MEGALIN SNP associations with predicted annual rates of cognitive change between age 50 y and the mean age at follow-up: multiple OLS regression analysis—HANDLS study1
| Predicted annual rate of cognitive change between age 50 y and mean age at follow-up2 |
|||
| n | β ± SE3 | P-trend | |
| MMSE | |||
| MEGALIN: rs3755166: G/A | 788 | −0.002 ± 0.001 | 0.0184 |
| Men | 349 | −0.001 ± 0.002 | 0.35 |
| Women | 439 | −0.002 ± 0.001 | 0.0244 |
| MEGALIN: rs2075252: C/T | 788 | +0.0005 ± 0.0014 | 0.74 |
| Men | 349 | +0.0001 ± 0.003 | 0.99 |
| Women | 439 | +0.0008 ± 0.016 | 0.56 |
| MEGALIN: rs2228171: C/T | 788 | +0.0003 ± 0.0011 | 0.76 |
| Men | 349 | −0.0001 ± 0.0020 | 0.97 |
| Women | 439 | −0.0006 ± 0.0129 | 0.63 |
| BVRT | |||
| MEGALIN: rs3755166: G/A | 782 | +0.000 ± 0.002 | 0.985 |
| Men | 350 | +0.004 ± 0.003 | 0.12 |
| Women | 432 | −0.003 ± 0.002 | 0.25 |
| MEGALIN: rs2075252: C/T | 782 | −0.0046 ± 0.0028 | 0.09 |
| Men | 350 | −0.0010 ± 0.0043 | 0.82 |
| Women | 432 | −0.007 ± 0.004 | 0.06 |
| MEGALIN: rs2228171: C/T | 782 | +0.002 ± 0.002 | 0.40 |
| Men | 350 | +0.0048 ± 0.0034 | 0.16 |
| Women | 432 | +0.001 ± 0.003 | 0.81 |
| CVLT-List A | |||
| MEGALIN: rs3755166: G/A | 680 | −0.0001 ± 0.0002 | 0.74 |
| Men | 295 | +0.0001 ± 0.0003 | 0.73 |
| Women | 385 | −0.0002 ± 0.0003 | 0.56 |
| MEGALIN: rs2075252: C/T | 680 | −0.0003 ± 0.004 | 0.33 |
| Men | 295 | +0.0003 ± 0.0005 | 0.62 |
| Women | 385 | −0.0007 ± 0.0005 | 0.12 |
| MEGALIN: rs2228171: C/T | 680 | −0.0000 ± 0.003 | 0.97 |
| Men | 295 | +0.0000 ± 0.0004 | 0.97 |
| Women | 385 | −0.0000 ± 0.0004 | 0.94 |
| CVLT-DFR | |||
| MEGALIN: rs3755166: G/A | 660 | +0.0001 ± 0.0004 | 0.73 |
| Men | 284 | −0.0004 ± 0.0010 | 0.51 |
| Women | 376 | +0.0003 ± 0.0005 | 0.56 |
| MEGALIN: rs2075252: C/T | 660 | +0.0008 ± 0.0006 | 0.20 |
| Men | 284 | +0.0004 ± 0.0009 | 0.65 |
| Women | 376 | +0.0011 ± 0.0009 | 0.21 |
| MEGALIN: rs2228171: C/T | 660 | +0.0001 ± 0.005 | 0.79 |
| Men | 284 | −0.0006 ± 0.008 | 0.44 |
| Women | 376 | +0.0007 ± 0.0007 | 0.32 |
| VFT-C | |||
| MEGALIN: rs3755166: G/A | 797 | +0.0004 ± 0.0114 | 0.74 |
| Men | 356 | −0.0002 ± 0.0020 | 0.89 |
| Women | 441 | +0.0011 ± 0.0014 | 0.45 |
| MEGALIN: rs2075252: C/T | 797 | +0.002 ± 0.002 | 0.25 |
| Men | 356 | +0.0024 ± 0.0031 | 0.42 |
| Women | 441 | +0.0019 ± 0.0023 | 0.43 |
| MEGALIN: rs2228171: C/T | 797 | +0.0009 ± 0.0019 | 0.55 |
| Men | 356 | +0.004 ± 0.002 | 0.14 |
| Women | 441 | −0.0012 ± 0.019 | 0.49 |
| Trails A | |||
| MEGALIN: rs3755166: G/A | 745 | −0.056 ± 0.067 | 0.41 |
| Men | 326 | +0.111 ± 0.160 | 0.49 |
| Women | 419 | −0.140 ± 0.097 | 0.15 |
| MEGALIN: rs2075252: C/T | 745 | −0.015 ± 0.112 | 0.89 |
| Men | 326 | −0.111 ± 0.160 | 0.49 |
| Women | 419 | +0.032 ± 0.155 | 0.83 |
| MEGALIN: rs2228171: C/T | 745 | −0.049 ± 0.088 | 0.58 |
| Men | 326 | +0.058 ± 0.125 | 0.65 |
| Women | 419 | +0.090 ± 0.125 | 0.47 |
| Trails B | |||
| MEGALIN: rs3755166: G/A | 745 | −0.012 ± 0.124 | 0.92 |
| Men | 326 | +0.209 ± 0.195 | 0.66 |
| Women | 419 | −0.142 ± 0.166 | 0.39 |
| MEGALIN: rs2075252: C/T | 745 | −0.141 ± 0.206 | 0.49 |
| Men | 326 | −0.144 ± 0.328 | 0.66 |
| Women | 419 | −0.159 ± 0.267 | 0.55 |
| MEGALIN: rs2228171: C/T | 745 | +0.155 ± 0.164 | 0.34 |
| Men | 326 | +0.065 ± 0.257 | 0.80 |
| Women | 419 | +0.296 ± 0.217 | 0.17 |
| DS-F | |||
| MEGALIN: rs3755166: G/A | 773 | −0.0002 ± 0.0005 | 0.66 |
| Men | 349 | +0.0001 ± 0.0008 | 0.86 |
| Women | 424 | −0.0002 ± 0.0007 | 0.73 |
| MEGALIN: rs2075252: C/T | 773 | −0.0001 ± 0.0008 | 0.905 |
| Men | 349 | +0.0013 ± 0.0013 | 0.33 |
| Women | 424 | −0.0012 ± 0.0011 | 0.28 |
| MEGALIN: rs2228171: C/T | 773 | +0.0006 ± 0.0007 | 0.40 |
| Men | 349 | +0.0010 ± 0.0010 | 0.34 |
| Women | 424 | +0.0005 ± 0.0009 | 0.56 |
| DS-B | |||
| MEGALIN: rs3755166: G/A | 775 | +0.0007 ± 0.0008 | 0.42 |
| Men | 351 | +0.0017 ± 0.0012 | 0.18 |
| Women | 424 | +0.0004 ± 0.0012 | 0.71 |
| MEGALIN: rs2075252: C/T | 775 | −0.0010 ± 0.0014 | 0.47 |
| Men | 351 | −0.0015 ± 0.0021 | 0.47 |
| Women | 424 | −0.0009 ± 0.0020 | 0.64 |
| MEGALIN: rs2228171: C/T | 775 | +0.003 ± 0.001 | 0.0204 |
| Men | 351 | +0.004 ± 0.002 | 0.0204 |
| Women | 424 | +0.0023 ± 0.0015 | 0.13 |
| Cognitive domain 1 | |||
| MEGALIN: rs3755166: G/A | 648 | +0.0071 ± 0.0176 | 0.45 |
| Men | 277 | −0.0212 ± 0.0474 | 0.45 |
| Women | 371 | +0.0260 ± 0.0234 | 0.27 |
| MEGALIN: rs2075252: C/T | 648 | +0.0368 ± 0.0293 | 0.21 |
| Men | 277 | +0.0666 ± 0.0474 | 0.16 |
| Women | 371 | +0.0179 ± 0.0383 | 0.64 |
| MEGALIN: rs2228171: C/T | 648 | +0.0092 ± 0.0232 | 0.69 |
| Men | 277 | −0.0103 ± 0.0378 | 0.79 |
| Women | 371 | +0.0216 ± 0.0299 | 0.47 |
| Cognitive domain 2 | |||
| MEGALIN: rs3755166: G/A | 648 | +0.0424 ± 0.0389 | 0.28 |
| Men | 277 | +0.0851 ± 0.0583 | 0.96 |
| Women | 371 | +0.0147 ± 0.053 | 0.78 |
| MEGALIN: rs2075252: C/T | 648 | −0.0710 ± 0.0649 | 0.27 |
| Men | 277 | +0.0050 ± 0.0990 | 0.96 |
| Women | 371 | −0.1323 ± 0.0873 | 0.13 |
| MEGALIN: rs2228171: C/T | 648 | +0.0866 ± 0.0513 | 0.09 |
| Men | 277 | +0.1136 ± 0.0791 | 0.15 |
| Women | 371 | +0.0836 ± 0.0681 | 0.22 |
n = 648–788. Note that each SNP is denoted by an rs number followed by the polymorphism in which one nucleotide is replaced by another (e.g., C/T or G/A). BVRT, Benton Visual Retention Test; CVLT-List A, California Verbal Learning Test, List A; CVLT-DFR, California Verbal Learning Test, Delayed Free Recall; DS-B, Digit Span Backward; DS-F, Digit Span Forward; HANDLS, Healthy Aging in Neighborhoods of Diversity Across the Life Span; MMSE, Mini-Mental State Examination; OLS, ordinary least square; SNP, single nucleotide polymorphism; Trails A, Trailmaking Test, Part A; Trails B, Trailmaking Test, Part B; VFT-C, Verbal Fluency Test, Categorical.
Cognitive scores were predicted at the mean age at follow-up before onset of dementia or for all time points by using a linear mixed model controlling for sex, race/ethnicity, education (years), and smoking status, with age added among the fixed-effects variables to allow for quadratic nonlinear change. The slope or annual rate of change was predicted from these models at the mean age at follow-up (i.e., between age 50 y and individual mean age at follow-up for each cognitive test). With the use of factor analysis, 2 factor scores were estimated and were labeled as the longitudinal annual rate of cognitive change in the following domains: Domain 1 (“Verbal memory and fluency”) and Domain 2 (“Visual/working memory”) (Supplemental Methods 1).
Based on multiple OLS regression models with the outcome being cognitive annual rate of change and main exposures being the 3 MEGALIN SNPs. The model controlled for first-visit age, mean age at follow-up, education, first-visit smoking status, first-visit self-reported type 2 diabetes, hypertension, cardiovascular disease, and BMI. The 10 principal components obtained from the genotype data with multidimensional scaling analysis (Supplemental Methods 3) were also added in a separate sensitivity analysis.
Significant main effects after family-wise Bonferroni correction: P < 0.05 for MMSE, BVRT, VFT-C, and cognitive domains and P < 0.025 for other cognitive tests.
P < 0.05 for the null hypothesis that sex × SNP interaction term = 0 in a model where the main effect of sex was added.