Growth-associated protein 43 is associated with faster functional decline among amyloid-positive individuals with objectively defined subtle cognitive decline and mild cognitive impairment.

Objective: Objectively defined subtle cognitive decline (Obj-SCD) is an emerging classification that may identify individuals at risk for future decline and progression to Alzheimer's disease prior to a diagnosis of mild cognitive impairment (MCI). Growth-associated protein 43 (GAP-43), a cerebrospinal fluid (CSF) marker of synaptic dysfunction, has been shown to relate to an increased risk of converting to dementia, although it is unclear whether GAP-43 alterations may be detected in pre-MCI stages. Therefore, in the present study, we examined CSF GAP-43 levels among individuals with Obj-SCD cross-sectionally and also examined whether baseline GAP-43 predicts future functional decline.

Method: Six hundred forty-four participants from the Alzheimer's Disease Neuroimaging Initiative were divided into six groups based on (a) cognitive status (cognitively unimpaired [CU], Obj-SCD, or MCI) and (b) Aβ status (+ or -).

Results: The CU- group had lower baseline GAP-43 than all Aβ+ groups, but not the other Aβ- groups. Higher GAP-43 levels were associated with faster decline across the entire sample. When moderation by group was examined, higher GAP-43 at baseline predicted faster functional decline for the Obj-SCD+ and MCI+ groups, compared to the CU- group.

Conclusions: Results extend prior work investigating biomarker associations in Obj-SCD to GAP-43 and show that high baseline CSF GAP-43 is associated with a faster rate of functional decline in Aβ+ individuals who are classified as Obj-SCD or MCI. Importantly, our findings further demonstrate that CSF GAP-43 is associated with early and subtle cognitive changes detectable before the onset of MCI. (PsycInfo Database Record (c) 2025 APA, all rights reserved).