6 7 8 Abstract 24Spatial navigation is impaired in early stages of Alzheimer's disease (AD), and 25 may be a defining behavioral marker of preclinical AD. Nevertheless, limitations of 26 diagnostic criteria for AD and within animal models of AD make characterization of 27 preclinical AD difficult. A new rat model (TgF344-AD) of AD overcomes many of these 28 limitations, though spatial navigation has not been comprehensively assessed. Using the 29 hidden and cued platform variants of the Morris water task, a longitudinal assessment of 30 spatial navigation was conducted on TgF344-AD (n=16) and Fischer 344 (n=12) male 31 and female rats at three age ranges: 4 to 5 months, 7 to 8, and 10 to 11 months of age.
32TgF344-AD rats exhibited largely intact navigation at 4-5 and 7-8 months of age, with 33 deficits in the hidden platform task emerging at 10-11 months of age. In general, TgF344-34 AD rats displayed less accurate swim trajectories to the platform and a wider search area 35 around the platform region compared to wildtype rats. Impaired navigation occurred in 36 the absence of deficits in acquiring the procedural task demands or navigation to the cued 37 platform location. Together, the results indicate that TgF344-AD rats exhibit comparable 38 deficits to those found in individuals in the early stages of AD. 39 40 41 42 43 44 45 46 47Alzheimer's disease (AD) is the most common form of dementia in the United 48 States and is characterized by progressive cognitive decline and neurodegeneration 49 (Association and others, 2017). AD pathology, marked by amyloid plaques and 50 neurofibrillary tangles that accumulate throughout the limbic system and hippocampus, is 51 predicted to initiate up to 20 years prior to the onset of behavioral symptoms (Gao et al., 52 1998; Mielke et al., 2014). Although the long preclinical period poses a significant 53 challenge to early diagnosis of AD (Dubois et al., 2016; Graham et al., 2017) subtle 54 changes in memory, as observed in amnestic mild cognitive impairment (aMCI), can 55 indicate an increased risk of progressing to dementia (Petersen, 2004; Winblad et al., 56 2004). However, because not all cases of aMCI progress to AD, there is a growing need 57 for sensitive behavioral assessments for AD diagnosis.
58Mounting evidence suggests that spatial disorientation, sometimes referred to as 59 wandering, are among the earliest memory complaints in AD (Bianchini et al., 2014; Bird 60 et al., 2010; Chan et al., 2016; Guariglia and Nitrini, 2009; Pai and Jacobs, 2004; Yew et 61 al., 2013). In general, disorientation is characterized as deficient localization of hidden 62 goals (Hort et al., 2007), a loss of direction sense (Cushman et al., 2008; deIpolyi et al., 63 2007; Monacelli et al., 2003; Tu et al., 2015), or an impairment in correctly identifying 64 familiar spatial scenes after a small change in view-point (Bird et al., 2010; Chan et al., 65 2016). Deficits in establishing or utilizing map-like (allocentric) frameworks for 66 navigation ...