TY - JOUR
T1 - Onset of Preclinical Alzheimer Disease in Monozygotic Twins
AU - Konijnenberg, Elles
AU - Tomassen, Jori
AU - den Braber, Anouk
AU - Ten Kate, Mara
AU - Yaqub, Maqsood M
AU - Mulder, Sandra D
AU - Nivard, Michel G
AU - Vanderstichele, Hugo
AU - Lammertsma, Adriaan A
AU - Teunissen, Charlotte E
AU - van Berckel, Bart N M
AU - Boomsma, Dorret I
AU - Scheltens, Philip
AU - Tijms, Betty M
AU - Visser, Pieter Jelle
N1 - Funding Information: This work has received support from the EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). This work received in-kind sponsoring of the CSF assay from ADx NeuroSciences and Euroimmun, and the PET tracer [18F]flutemetamol from GE Healthcare. We thank all participating twins for their dedication. Funding Information: This work has received support from the EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). This work received in‐kind sponsoring of the CSF assay from ADx NeuroSciences and Euroimmun, and the PET tracer [F]flutemetamol from GE Healthcare. 18 Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - Objective: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. Methods: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aβ) aggregation as measured by the Aβ1–42/1–40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta-secretase 1, Aβ1–40, and Aβ1–38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. Results: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73–0.86, all p < 0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50–0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aβ1–38 in one twin correlated with Aβ1–42/1–40 ratios, and t-tau and p-tau levels in their cotwins (r range = −0.28 to 0.58, all p <.007). Within-pair differences in Aβ production markers related to differences in tau levels (r range = 0.49–0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD. Interpretation: Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021.
AB - Objective: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. Methods: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aβ) aggregation as measured by the Aβ1–42/1–40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta-secretase 1, Aβ1–40, and Aβ1–38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. Results: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73–0.86, all p < 0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50–0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aβ1–38 in one twin correlated with Aβ1–42/1–40 ratios, and t-tau and p-tau levels in their cotwins (r range = −0.28 to 0.58, all p <.007). Within-pair differences in Aβ production markers related to differences in tau levels (r range = 0.49–0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD. Interpretation: Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021.
UR - http://www.scopus.com/inward/record.url?scp=85102001407&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ana.26048
DO - https://doi.org/10.1002/ana.26048
M3 - Article
C2 - 33583080
SN - 0364-5134
VL - 89
SP - 987
EP - 1000
JO - Annals of Neurology
JF - Annals of Neurology
IS - 5
ER -