*2.1. Clinical Assessments*

Patients underwent annual clinical evaluations and cognitive assessments, including tests standardized for use in individuals with DS (Test of Severe Impairment [27], Verbal Fluency Test [28] and the Dementia Questionnaire for People with Learning Disabilities [26]). Dementia status was determined by a neurologist with experience in diagnosing AD in the DS population. Blood collected at the time of clinical diagnosis of AD included thyroid function tests (TSH and Free T4), Vitamin B12 levels, and APOE genotyping; in a subset of the cohort, blood was sent for the evaluation of thyroid autoantibodies including TPO antibodies and/or thyroglobulin (Tg).

Age of onset of AD was determined based on at least a one-year progressive decline in two or more cognitive domains. Early onset was defined as having an AD onset greater than one standard deviation (SD) below the mean age of AD onset for the cohort, and late onset was defined as greater than one SD above the mean age of AD onset for this group. In our cohort, the mean (SD) age of AD onset was 53 (6). Therefore, early AD onset refers to onset before the age 47, typical AD onset as occurring between ages 47 and 59, and late AD onset as occurring after the age of 59.

*Article* 

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

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

*Article* 

*Article* 

**Citation:** Lai, F.; Mercaldo, N.D.; Wang, C.M.; Hersch, M.S.; Hersch, G.G.; Rosas, H.D.; Association between Hypothyroidism Onset and Alzheimer Disease Onset in Adults with Down Syndrome. *Brain Sci.* 

**Citation:** Lai, F.; Mercaldo, N.D.; Wang, C.M.; Hersch, M.S.; Hersch, G.G.; Rosas, H.D.; Association between Hypothyroidism Onset and Alzheimer Disease Onset in Adults with Down Syndrome. *Brain Sci.* 

**Citation:** Lai, F.; Mercaldo, N.D.; Wang, C.M.; M.S.; Hersch, G.G.; Rosas, H.D.; Association between Hypothyroidism Onset and Alzheimer Disease Onset in Adults with Down Syndrome. *Brain Sci.* 

https://doi.org/10.3390/xxxxx

Academic Editor: Rebecca Sims

Received: 31 July 2021 Accepted: 8 September 2021 Published: 16 September 2021

https://doi.org/10.3390/xxxxx

**2021**, *11*, x.

Academic Editor: Rebecca Sims

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institu-

tional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Received: 31 July 2021 Accepted: 8 September 2021 Published: 16 September 2021

https://doi.org/10.3390/xxxxx

**2021**, *11*, x.

Academic Editor: Rebecca Sims

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institu-

tional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Received: 31 July 2021 Accepted: 8 September 2021 Published: 16 September 2021

tional affiliations.

**2021**, *11*, x.

Age of hypothyroidism onset, which was obtained from caregivers and available for 111 of the 152 patients (73%) with a reported history of hypothyroidism, was the age at which thyroid supplementation was first started based on abnormal thyroid function tests. rosas@helix.mgh.harvard.edu (H.D.R.) 2 Massachusetts General Hospital, Boston, MA 02114, USA 3 McLean Hospital, Belmont, MA 02478, USA 4 Harvard College, Harvard University, Cambridge, MA 02138, USA;

**Disease Onset in Adults with Down Syndrome** 

cassandrawang@college.harvard.edu

**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** 

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
