**1. Introduction**

Down syndrome (DS), a genetic condition caused predominantly by the triplication of chromosome 21, is highly associated with the development of Alzheimer's disease (AD) [1]. Chromosome 21 includes the amyloid precursor protein (APP) gene, and triplication results in overexpression of APP and related proteins, accelerating the accumulation of misfolded amyloid in the brain [2–4]. Additional AD risk factors are also associated with DS including a higher propensity for neuroinflammation, oxidative damage, sleep apnea, and reduced cognitive reserve due to premorbid intellectual disability [1,5–7]. Indeed, AD pathological changes have been documented in adults with DS as young as 20 years, and nearly all adults with DS show the amyloid plaques and neurofibrillary tangles associated with AD by 40 years of age [8–10].

**Citation:** Harp, J.P.; Koehl, L.M.; Pelt, K.L.V.; Hom, C.L.; Doran, E.; Head, E.; Lott, I.T.; Schmitt, F.A. Cognitive and Behavioral Domains That Reliably Differentiate Normal Aging and Dementia in Down Syndrome. *Brain Sci.* **2021**, *11*, 1128. https:// doi.org/10.3390/brainsci11091128

Academic Editor: Corrado Romano

Received: 15 July 2021 Accepted: 22 August 2021 Published: 25 August 2021

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DS is associated with different physical morphology, intellectual disabilities, and reduced lifespan compared to the typically developing population. Associated health problems include atlantoaxial instability, musculoskeletal and dental conditions, congenital heart disease, hematologic conditions, obesity, hypothyroidism, obstructive sleep apnea, impaired hearing and vision, and overall increased functional dependence due to behavioral, psychiatric, and intellectual impairments [7,11–14]. Advances in medical management of these co-morbidities have lowered mortality from early-life conditions, but one consequence of lengthened lifespan is that more individuals with DS now survive to the age of risk for AD [15].

Due to the need for preventative care and ongoing management of chronic health conditions associated with DS, health professionals and advocacy groups recommend the integration of DS-specific care in primary care settings [14,16,17]. Healthcare systems have made progress toward this end, but there is a need for improvement [11,18]. Cognitive screening and monitoring for dementia is particularly difficult, as cognitive measurement is complicated by pre-existing intellectual disability (ID), large inter- and intra-individual variability in cognition and behavior, tolerability of testing methods, and the lack of an identified "gold standard" neurocognitive battery, even for research purposes [19,20]. Moreover, neurocognitive tests are not feasible in primary care settings due to the lengthy procedures and specialized training needed for the interpretation of comprehensive evaluations.

In recent studies, our group has sought to establish an evidence base for abbreviated neurobehavioral examination procedures appropriate for in-office dementia monitoring by community practitioners caring for patients with DS [21]. Performance measures in our long-term cohort studies include the Brief Praxis Test (BPT) [22] and the Severe Impairment Battery (SIB) [23]. Informant measures included the Dementia Questionnaire for People with Learning Disabilities (DLD) [24] and Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) [25]. The BPT, SIB, and DLD have all been used in early DS clinical trials assessing the effects of anticholinesterase therapy [26] as well as antioxidants [27,28]. Moreover, the SIB has long been validated as a cognitive measure for severe impaired individuals with AD [29]. The Vineland-II has been widely used and validated in the DS population [30–32] and adaptive behavior decline is a diagnostic criterion for AD, necessitating the inclusion of this type of measure in this study. These measures were selected at the outset of the two parent cohorts from which the present data are drawn, and target the domains of cognition (SIB, DLD), praxis (BPT), and functional independence (DLD, Vineland-II) that underlie both NINCDS-ADRDA and DSM-IV criteria for dementia/major neurocognitive disorder.

The present study seeks to further identify the key components that are useful for dementia detection through three aims:

