TY - JOUR
T1 - Longitudinal modeling of cognitive aging and the TOMM40 effect
AU - Caselli, Richard J.
AU - Dueck, Amylou C.
AU - Huentelman, Matthew J.
AU - Lutz, Michael W.
AU - Saunders, Ann M.
AU - Reiman, Eric M.
AU - Roses, Allen D.
N1 - Funding Information:
This study was funded by P30AG19610 , R01AG6031581 , Deane Drug Discovery Institute (Duke University), and the Arizona Alzheimer Research Consortium . The authors thank Ms. Sandra Yee-Benedetto, Mr. Bruce Henslin, Ms. Marci Zomok, and Ms. Jessie Jacobsen for expert technical assistance.
PY - 2012/11
Y1 - 2012/11
N2 - Background: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline. Methods: An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two. Results: There were significant effects overall for both TOMM40 (linear effect, P =.04; quadratic effect, P =.03) and APOE (linear effect, P =.06; quadratic effect, P =.008), with no significant interaction (P =.63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P =.009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P =.006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect. Conclusion: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.
AB - Background: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline. Methods: An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two. Results: There were significant effects overall for both TOMM40 (linear effect, P =.04; quadratic effect, P =.03) and APOE (linear effect, P =.06; quadratic effect, P =.008), with no significant interaction (P =.63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P =.009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P =.006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect. Conclusion: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.
KW - APOE
KW - Cognitive aging
KW - Preclinical Alzheimer's disease
KW - TOMM40
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UR - http://www.scopus.com/inward/citedby.url?scp=84867852032&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2011.11.006
DO - 10.1016/j.jalz.2011.11.006
M3 - Article
C2 - 23102119
AN - SCOPUS:84867852032
SN - 1552-5260
VL - 8
SP - 490
EP - 495
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 6
ER -