Contribution of genetic and environmental factors to the onset of preclinical Alzheimer’s disease - a monozygotic twin study

Objective To study the genetic contribution to the start of Alzheimer’s disease as signified by abnormalities in amyloid and tau biomarkers in cognitively intact older identical twins. Methods We studied in 96 monozygotic twin-pairs relationships between Aβ aggregation as measured by the ratio Aβ1-42/1-40 in cerebrospinal fluid (CSF) and positron emission tomography (PET), and CSF markers for Aβ production (BACE1, Aβ1-40 and 1-38) and tau. Associations amongst markers were tested with Generalized Estimating Equations including a random effect for twin status, adjusted for age, gender, and APOE 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 status. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range 0.76, 0.88; all p<0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strong (r range 0.49, 0.52; all p<0.0001). Cross-twin cross-trait analysis showed that Aβ1-38 in one twin correlated with Aβ1-42/1-40 ratios, t-tau and p-tau levels in their co-twins (r range 0.18, 0.58; all p<.07). 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. ### Competing Interest Statement HV is working on behalf of Biomarkable bvba for ADx NeuroSciences, who provided the ELISA's used in this study. The other authors do not have a competing interest. ### Funding Statement This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant n 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre, Amsterdam, an Institutional Review Board certified by the U.S. Office of Human Research Protections (IRB number IRB00002991 under Federal-wide Assurance- FWA00017598). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available from the corresponding author after signing a material transfer agreement.