*Article* **Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models**

**Christy L. Hom 1,\* , Katharine A. Kirby <sup>2</sup> , Joni Ricks-Oddie 2,3, David B. Keator <sup>1</sup> , Sharon J. Krinsky-McHale <sup>4</sup> , Margaret B. Pulsifer <sup>5</sup> , Herminia Diana Rosas <sup>6</sup> , Florence Lai <sup>6</sup> , Nicole Schupf 7,8, Ira T. Lott <sup>9</sup> and Wayne Silverman <sup>9</sup>**

	- Boston, MA 02114, USA; rosas@helix.mgh.harvard.edu (H.D.R.); flai@partners.org (F.L.)

**Abstract:** Accurate identification of the prodromal stage of Alzheimer's disease (AD), known as mild cognitive impairment (MCI), in adults with Down syndrome (MCI-DS) has been challenging because there are no established diagnostic criteria that can be applied for people with lifelong intellectual disabilities (ID). As such, the sequence of cognitive decline in adults with DS has been difficult to ascertain, and it is possible that domain constructs characterizing cognitive function in neurotypical adults do not generalize to this high-risk population. The present study examined associations among multiple measures of cognitive function in adults with DS, either prior to or during the prodromal stage of AD to determine, through multiple statistical techniques, the measures that reflected the same underlying domains of processing. Participants included 144 adults with DS 40–82 years of age, all enrolled in a larger, multidisciplinary study examining biomarkers of AD in adults with DS. All participants had mild or moderate lifelong intellectual disabilities. Overall AD-related clinical status was rated for each individual during a personalized consensus conference that considered performance as well as health status, with 103 participants considered cognitively stable (CS) and 41 to have MCI-DS. Analyses of 17 variables derived from 10 tests of cognition indicated that performance reflected three underlying factors: language/executive function, memory, and visuomotor. All three domain composite scores significantly predicted MCI-DS status. Based upon path modeling, the language/executive function composite score was the most affected by prodromal AD. However, based upon structural equation modeling, tests assessing the latent construct of memory were the most impacted, followed by those assessing visuomotor, and then those assessing language/executive function. Our study provides clear evidence that cognitive functioning in older adults with DS can be characterized at the cognitive domain level, but the statistical methods selected and the inclusion or exclusion of certain covariates may lead to different conclusions. Best practice requires investigators to understand the internal structure of their variables and to provide evidence that their variables assess their intended constructs.

**Citation:** Hom, C.L.; Kirby, K.A.; Ricks-Oddie, J.; Keator, D.B.; Krinsky-McHale, S.J.; Pulsifer, M.B.; Rosas, H.D.; Lai, F.; Schupf, N.; Lott, I.T.; et al. Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models. *Brain Sci.* **2021**, *11*, 1220. https://doi.org/ 10.3390/brainsci11091220

Academic Editor: Sien Hu

Received: 13 July 2021 Accepted: 14 September 2021 Published: 16 September 2021

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**Keywords:** mild cognitive impairment; Alzheimer's disease; Down syndrome; cognitive decline; neuropsychological tests; cognitive function
