Abstract
Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD‐BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD‐BXDs and the relationship to cognitive decline in these mice. We found that age‐ and AD‐related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD‐BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging‐ and AD‐related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD‐related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.
Highlights
Alzheimer's dementia (AD) is defined by the slow progression of cognitive deficits, including memory loss and dementia, accompanied by the accumulation of β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles.[1]
Similar to the narrow beam task, we found no correlation between performance on the inclined screen test and long-term CFM in male Ntg- and AD-BXD strains or female AD-BXD strains (Figure 6B,C), suggesting impairments in vestibular function and proprioception may be independent of cognitive decline
Consistent with our finding that there was no influence of genotype on grip strength, we found no significant interaction of genotype with strain (F(26,839) < 1, n.s.). These results suggest that age and genetic background profoundly impact muscle strength and decline and that this is not impacted by the presence of the AD transgene
Summary
Alzheimer's dementia (AD) is defined by the slow progression of cognitive deficits, including memory loss and dementia, accompanied by the accumulation of β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles.[1]. Significant progress in understanding the pathophysiology of AD has been made using mouse models incorporating familial mutations in amyloid precursor protein (APP) and/or presenilin-1 (PSEN1), originally designed to recapitulate the cognitive symptoms of AD Several of these models have been reported to exhibit sensorimotor deficits, suggesting that motor impairments are an inherent part of the disease process.[7,8,9,10,11,12,13] infrequent assessment of motor phenotypes in AD animal models, variability in the tests used to assess motor function, and use of a single sex has led to conflicting reports on the impact of AD transgenes on motor function.[7,10,11,14,15]. We hypothesized that the AD-BXD panel would exhibit age-related decline in sensorimotor function that is exacerbated by the presence of the AD transgene and that diverse genetic backgrounds would influence the expressivity of the 5XFAD transgene to modify the onset and severity of motorrelated phenotypes
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