**6. Conclusions**

In conclusion, our study suggests that the early onset of hypothyroidism in DS is significantly associated with an early onset age of AD, and that it is independent of APOE adjustments. We observed a positive association between the ages of AD and hypothyroidism onset after accounting for APOE-Ɛ4 (correlation: 0.44, 0.24, 0.60; odds ratio: 1.09, 1.05–1.14). However, an early age of hypothyroidism onset and the presence of the APOE-Ɛ4 allele were independently associated with the early age of AD onset. Similar findings were observed when accounting for other factors. Our study provides evidence for the importance of hypothyroidism and associated pathological mechanisms for risk of AD in DS. G.G.; Rosas, H.D.; Association between Hypothyroidism Onset and Alzheimer Disease Onset in Adults with Down Syndrome. *Brain Sci.*  **2021**, *11*, x. https://doi.org/10.3390/xxxxx Academic Editor: Rebecca Sims 4 allele status, BMI, vitamin B12 status, or presence of OSA. This emphasizes the importance of early testing for TSH, thyroid hormone and thyroid autoantibodies, and treatment with thyroid replacement as needed. Future studies are needed to determine the mechanisms by which a history of hypothyroidism affects AD risk and onset, including its relationship with other genetic, inflammatory or metabolomic alterations present in adults with DS.

**Citation:** Lai, F.; Mercaldo, N.D.; Wang, C.M.; Hersch, M.S.; Hersch,

*Article* 

**and Herminia Diana Rosas 1,2,3**

thyroidism; thyroid autoantibodies; TSH; Free T4; APOE Ɛ4 **1. Introduction**  Adults with Down syndrome (DS) have an especially high risk for developing Alz-Received: 31 July 2021 Accepted: 8 September 2021 Published: 16 September 2021 **Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institu-**Author Contributions:** Conceptualization: F.L., H.D.R.; methodology: N.D.M., F.L., H.D.R., C.M.W., M.S.H., G.G.H.; formal analysis: N.D.M.; data curation: C.M.W., M.S.H., G.G.H.; writing—review and editing, all authors. All authors have read and approved the submitted version and agree to be personally accountable for the author's own contributions and for ensuring that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and documented in the literature. All authors have read and agreed to the published version of the manuscript.

heimer disease (AD), with onset at least two decades earlier than in the general population [1,2]. Although there is great variation in the age of AD onset, from as early as 40 to as tional affiliations. **Funding:** This research was funded by the Libbi Thomas Foundation.

late as 70 or older [3,4], this variability in onset is poorly understood. The leading hypothesis for the pathogenesis of AD in DS has been attributed to overexpression of the gene for amyloid precursor protein (APP) located on the triplicated chromosome 21 [5], alt-**Copyright:** © 2021 by the authors. Li-**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Massachusetts General Hospital (Protocol # 2016P00198).

hough factors other than amyloid likely influence the wide range of AD onset age in those censee MDPI, Basel, Switzerland. **Informed Consent Statement:** Patient consent was waived due to the retrospective nature of the study.

with DS, just as they do in sporadic AD. Some of these factors include not only the Apolipoprotein Ɛ4 (APOE Ɛ4) genotype, but other genetic factors, as well as environmen-This article is an open access article distributed under the terms and con-**Data Availability Statement:** Data are available for review by request to corresponding author.

tal or biological factors and co-existing medical conditions. Thyroid dysfunction, including congenital, subclinical, and autoimmune thyroid conditions [6], is a very common medical co-morbidity in individuals with DS. In a large ditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). **Acknowledgments:** The authors are grateful to the many adults with Down syndrome who entrusted themselves to our clinical care and to their families and caregivers who supported them. We thank Courtney Jordan and Kelsey Shelofsky for their assistance.

**Conflicts of Interest:** The authors declare no conflict of interest. The funding foundation had no role in the design of the study, in the collection of the data, in the statistical analysis, in the interpretation of the data or in the writing of the manuscript.

*Brain Sci.* **2021**, *11*, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/brainsci

**Association between Hypothyroidism Onset and Alzheimer** 

**Florence Lai 1,2,3,\*, Nathaniel D. Mercaldo 1,2, Cassandra M. Wang 4, Micaela S. Hersch 5, Giovi G. Hersch 6** 

2 Massachusetts General Hospital, Boston, MA 02114, USA

4 Harvard College, Harvard University, Cambridge, MA 02138, USA;

1 Harvard Medical School, Boston, MA 02115, USA; nmercaldo@mgh.harvard.edu (N.D.M.);

5 School of Nursing, Simmons University, Boston, MA 02115, USA; micaela.hersch@simmons.edu 6 College of Arts & Sciences, Boston University, Boston, MA 02215, USA; herschgi@bu.edu

**Abstract:** Adults with Down syndrome (DS) have an exceptionally high frequency of Alzheimer disease (AD) with a wide variability in onset, from 40 to 70 years of age. Equally prevalent in DS is hypothyroidism. In this study, we sought to quantify the relationship between the two. A total of 232 adults with DS and AD were stratified into three AD onset age groups: early (<47 years), typical (48–59), and late (>59). Among patients with available data, differences in the distributions of demographics, hypothyroidism variables (presence, age of onset), thyroid function tests, thyroid autoantibodies, and APOE genotypes were assessed (e.g., chi-squared, Mann–Whitney tests). Spearman and partial Spearman correlations and ordinal logistic regression models were constructed to quantify the association between ages of AD and hypothyroidism onset with and without covariate

**Keywords:** Down syndrome; early-onset Alzheimer disease; late-onset Alzheimer disease; hypo-

**Disease Onset in Adults with Down Syndrome** 

rosas@helix.mgh.harvard.edu (H.D.R.)

cassandrawang@college.harvard.edu

\* Correspondence**:** flai@partners.org

3 McLean Hospital, Belmont, MA 02478, USA
