Altered functional connectivity pattern of hippocampal subfields in individuals with objectively‐defined subtle cognitive decline and its association with cognition and cerebrospinal fluid biomarkers

Recent studies have shown that in the preclinical phase of Alzheimer's disease (AD), subtle cognitive changes can be detected using sensitive neuropsychological measures, and have proposed the concept of objectively‐defined subtle cognitive decline (Obj‐SCD). We aimed to assess the functional alteration of hippocampal subfields in individuals with Obj‐SCD and its association with cognition and pathological biomarkers. Forty‐two participants with cognitively normal (CN), 29 with Obj‐SCD, and 55 with mild cognitive impairment (MCI) were retrospectively collected from the ADNI database. Neuropsychological performance, functional MRI, and cerebrospinal fluid (CSF) data were obtained. We calculated the seed‐based functional connectivity (FC) of hippocampal subfields (cornu ammonis1 [CA1], CA2/3/dentate gyrus [DG], and subiculum) with whole‐brain voxels. Additionally, we analyzed the correlation between FC values of significantly altered regions and neuropsychological performance and CSF biomarkers. The Obj‐SCD group showed lower FC between left CA1‐CA2/3/DG and right thalamus and higher FC between right subiculum and right superior parietal gyrus (SPG) compared with the CN and MCI groups. In the Obj‐SCD group, FC values between left CA2/3/DG and right thalamus were positively associated with Auditory Verbal Learning Test (AVLT) recognition (r = 0.395, p = 0.046) and CSF Aβ(1–42) levels (r = 0.466, p = 0.019), and FC values between left CA1 and right thalamus were positively correlated with CSF Aβ(1–42) levels (r = 0.530, p = 0.006). Taken together, dysfunction in CA1‐CA2/3/DG subregions suggests subtle cognitive impairment and AD‐specific pathological changes in individuals with Obj‐SCD. Additionally, increased subiculum connectivity may indicate early functional compensation for subtle cognitive changes.