Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD.

Abstract

OBJECTIVE:

To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers.

METHODS:

Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF.

RESULTS:

A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF.

CONCLUSIONS:

In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.

• Authors: Stephanie A Schultz, Elizabeth A Boots, Burcu F Darst, Henrik Zetterberg, Kaj Blennow, Dorothy F Edwards, Rebecca L Koscik, Cynthia M Carlsson, Catherine L Gallagher, Barbara B Bendlin, Sanjay Asthana, Mark A Sager, Kirk J Hogan, Bruce P Hermann, Dane B Cook, Sterling C Johnson, Corinne D Engelman, Ozioma C Okonkwo
• Journal: Neurology (Neurology) Vol. 88 Issue 17 Pg. 1650-1658 (Apr 25 2017) ISSN: 1526-632X [Electronic] United States
• PMID: 28341646 (Publication Type: Journal Article)
• Copyright: © 2017 American Academy of Neurology.

Chemical References

• ABCA7 protein, human
• ATP-Binding Cassette Transporters
• Amyloid beta-Peptides
• Apolipoprotein E4
• Biomarkers
• CLU protein, human
• Clusterin
• MAPT protein, human
• Peptide Fragments
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• tau Proteins

Topics

• ATP-Binding Cassette Transporters (genetics)
• Aged
• Alzheimer Disease (epidemiology, genetics, physiopathology)
• Amyloid beta-Peptides (cerebrospinal fluid)
• Apolipoprotein E4 (genetics)
• Biomarkers (cerebrospinal fluid)
• Cardiorespiratory Fitness (physiology)
• Clusterin (genetics)
• Cohort Studies
• Cross-Sectional Studies
• Female
• Humans
• Male
• Middle Aged
• Multifactorial Inheritance
• Peptide Fragments (cerebrospinal fluid)
• Phosphorylation
• Registries
• Risk
• White People (genetics)
• Wisconsin
• tau Proteins (cerebrospinal fluid)