Association of serum‐based mitophagy biomarkers and spatial navigation performance in Alzheimer´s disease

Abstract Background Mitophagy is a process of intracellular protein homeostasis through which cells eliminate senescent and dysfunctional mitochondria. Altered mitophagy contributes to Alzheimer´s disease (AD) pathology and is associated with worse cognitive functions. We evaluated association of levels of mitophagy proteins (ULK1, BNIP3L, PINK1, and TFEB in serum and ULK1 and PINK 1 in cerebrospinal fluid [CSF]) with spatial egocentric (body‐centered) and allocentric (world‐centered) navigation performance, which is typically impaired in early stages of AD. Method Participants with AD aMCI (n=39), mild AD dementia (n=19), and cognitively normal (CN) older adults (n=20) underwent cognitive assessment and brain MRI. Diagnosis of AD was supported by positivity of AD biomarkers in CSF or amyloid PET imaging. Spatial navigation assessment was performed using real‐space and computerized versions of a human analog of the Morris Water Mate Test (hMWM). The hMWM had four tasks: first, with start position and landmarks (combined allocentric‐egocentric), second, only with start position (egocentric), third, only with landmarks (allocentric), and fourth, with landmarks after 30 minutes (allocentric delayed). Result Levels of mitophagy proteins in the CN group were not associated with performance in any of the spatial navigation tasks (ps > .091). In the AD aMCI group, higher levels of CSF PINK1 were associated with more accurate spatial navigation performance in the computerized egocentric‐allocentric task (r = ‐0.39; p = .030) and the association of higher levels of CSF ULK1 with worse spatial navigation performance in computerized allocentric delayed task approached statistical significance (r = 0.36; p = .054). Levels of mitophagy proteins in the AD dementia group were not associated with performance in any of the spatial navigation tasks (ps > .068). Conclusion Higher level of CSF PINK1 was associated with more accurate egocentric‐allocentric spatial navigation performance in computerized task and higher levels of CSF ULK were associated with worse allocentric navigation performance. These findings support the hypothesis that normal cognition requires efficient mitophagy and more research is needed to evaluate the role of various mitophagy markers in AD.