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P4‐260: NEUROIMAGING CORRELATES OF PSEN1 MUTATION‐RELATED SPASTIC PARAPARESIS
Author(s) -
Shi Yonggang,
Qiao Yuchuan,
Wang Junyan,
Sweeney Melanie D.,
Montoya Lucy,
Chui Helena C.,
Ringman John M.
Publication year - 2019
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 - 10.1016/j.jalz.2019.06.3929
Subject(s) - corticospinal tract , spasticity , medicine , neuroimaging , diffusion mri , psychology , modified ashworth scale , magnetic resonance imaging , neuroscience , pathology , physical medicine and rehabilitation , radiology
Background: Apolipoprotein E (APOE) is the major Alzheimer’s disease (AD) susceptibility gene. Compared to the most common APOE3/3 genotype, each additional APOE4 allele is associated with a higher AD risk, such that APOE4 homozygotes have the highest risk. While the APOE2 allele is associated with a lower AD risk, it remains to be clarified whether APOE2 homozygotes have a particularly low risk. Methods: Data from nearly 5,000 clinically and neuropathologically characterized Alzheimer’s dementia cases and cognitively and neuropathologically unaffected controls were used to compute Alzheimer’s dementia odds ratios (ORs) for the six common APOE genotypes free from the confounding effects of neuropathologically misclassified cases and controls. Findings were then compared to those from nearly 24,000 clinically characterized but neuropathologically unconfirmed cases and controls and from nearly 29,000 in the combined cohort. Results: In the neuropathologically confirmed cohort, APOE2 homozygotes had a 0.34 Alzheimer’s dementia OR (95% confidence interval [CI] 0.120.95) compared to the relatively low-risk APOE2/3 genotype (P1⁄40.04). APOE2/2, 2/3, 3/3, 2/4, 3/4, and 4/4 ORs were 0.13 (95% CI 0.05-0.36), 0.39 (95% CI 0.30-0.50), 1.00, 2.68 (95% CI 1.65-4.36), 6.13 (95% CI 5.08-7.41), and 31.22 (95% CI 16.5958.75) compared to APOE3/3; 1.00, 2.92, 7.58, 20.33, 46.51, and 236.74 compared to the lowest risk APOE2/2 genotype; and 0.004, 0.012, 0.032, 0.086, 0.196, and 1.000 compared to the highest risk APOE4/4 genotype, respectively. Indeed, Alzheimer’s dementia ORs were 99.6% (95% CI 98.6-99.9%) lower in APOE2 homozygotes compared to APOE4 homozygotes. APOE2 gene dose and APOE4 gene dose had a significantly greater impact on the magnitude of ORs in the neuropathologically confirmed cohort than in the neuropathologically unconfirmed or combined cohorts. Conclusions: This study demonstrates an exceptionally low risk of clinically and neuropathologically confirmed Alzheimer’s dementia in APOE2 homozygotes, a greater than previously estimated impact of APOE and its variants on Alzheimer’s dementia risk, and the potential value of evaluating putative AD risk factors in numerous clinically and biologically characterized cases and controls. Finding and targeting the factors by which APOE and its variants influence AD risk could have a major impact on the understanding, treatment and prevention of this terrible disease.