# The LOAD2 mouse model of late-onset alzheimer’s disease exhibits an accelerated onset of locomotor and anxiety deficits

## TL;DR

A new mouse model of late-onset Alzheimer’s disease shows early signs of movement and anxiety issues, but not memory loss, similar to early symptoms in humans.

## Contribution

The LOAD2 mouse model integrates key genetic risk factors for late-onset Alzheimer’s disease and exhibits early locomotor and anxiety deficits.

## Key findings

- LOAD2 mice show reduced locomotor activity and heightened anxiety at 18 months compared to controls.
- Spatial memory and fear learning remain intact in LOAD2 mice at both 18 and 24 months.
- LOAD2 mice do not show cognitive impairments beyond normal aging in memory tasks.

## Abstract

Late-onset alzheimer’s disease is the most common form of dementia, and it arises from complex genetic and environmental interactions. Preclinical models that replicate the slow progression and long prodromal phase of late-onset alzheimer’s disease are critical for identifying early therapeutic targets. The LOAD2 mouse model, developed on the C57BL/6J genetic background, integrates key late-onset alzheimer’s disease genetic risk factors: APOE4, Trem2*R47H, and an App allele encoding humanised amyloid beta. This study aimed to characterise key disease-relevant phenotypes of LOAD2 mice during ageing. Behavioural assays were conducted on 18- and 24-month-old LOAD2 and age-matched C57BL/6J wild-type control mice. At 18 months, LOAD2 mice exhibited significantly reduced locomotor activity compared to wild-type controls. However, this difference was diminished at 24 months as wild-type mice displayed an age-related decline in total distance travelled. Similarly, anxiety-like behaviour was elevated in 18-month-old LOAD2 mice relative to wild-type controls, but this difference was no longer evident at 24 months due to increased anxiety levels in aged wild-type mice. In contrast, spatial working memory and associative fear learning were intact in both LOAD2 and wild-type mice at 18 and 24 months of age, indicating no age- or genotype-dependent deficits in these forms of memory. Both groups of mice performed equally poorly in novel object and novel location recognition tasks at both ages. Thus, compared to age-matched wild-type mice, LOAD2 mice exhibit early locomotor deficits and heightened anxiety, but not overt cognitive impairment beyond that of normal ageing. These phenotypes are reminiscent of prodromal symptoms of late-onset alzheimer’s disease in humans.