Health system-community partnerships in a Medicaid nutrition and housing program, 2020-2023: a mixed-methods evaluation.

Mild cognitive impairment (MCI) is the symptomatic predementia phase of Alzheimer’s disease (AD) mainly marked by memory decline and cognitive impairment, commonly accompanied by neuropsychiatric symptoms (NPS) (; ). Subsyndromal depression (SSD) is one of the most common NPS in MCI, with an incidence rate ranging from 37% to 46% (). MCI patients with SSD (MCID) exhibit poorer quality of life and greater impairments in daily activities (; ). Moreover, SSD in MCI has been associated with greater cognitive deficits, AD-related brain atrophy, faster cognitive decline, and increased risk of progression to dementia (). Of note, compared with non-depressed MCI patients, MCID individuals exhibit more pronounced deficits in language memory, executive function, processing speed, and visual memory (). These findings support that MCID is not simply a combination of MCI and depression but rather represents a distinct clinical phenotype with unique neural substrates. Therefore, elucidating the distinct clinical and neurobiological characteristics of MCID is essential for the development of targeted interventions aimed at addressing both cognitive and depressive symptoms. Genetic factors, particularly the apolipoprotein E (APOE) ε4 allele, play a crucial role in MCI and AD pathogenesis. Notably, recent studies suggest that APOE ε4 homozygosity represents a genetic subtype with higher risk and potentially distinct neural mechanisms compared with heterozygotes or non-carriers (; ). Previous studies have shown that individuals carrying two copies of APOE ε4 have a lifetime risk of developing AD is significantly higher than that of heterozygotes or non-carriers (), reinforcing the key role of the APOE ε4 number in MCI. Accumulating evidence indicates that APOE ε4 is associated with accelerated cognitive decline and greater atrophy in hippocampal and neocortical structures, with some effects showing an allele dose-dependent pattern (). APOE ε4 has also been associated with increased depressive symptom burden in older adults, suggesting that ε4-related vulnerability may extend from cognitive impairment to affective dysfunction (). However, most previous studies have classified individuals simply as APOE ε4 carriers or non-carriers, rather than explicitly modeling ε4 allele dosage. The neurobiological mechanisms linking APOE ε4 allele burden to the coexistence of cognitive impairment and depressive symptoms in MCID remain largely unclear. With the rapid advancement of neuroimaging techniques, APOE ε4-related neural alterations in specific brain regions have been increasingly investigated (). A previous meta-analysis found that hippocampal atrophy is significantly greater in APOE ε4 carriers compared with non-carriers (), and studies of geriatric depression report pronounced hippocampal volume reductions in APOE ε4 carriers, especially in the right hippocampus (). Previous studies have found that APOE ε4 carriers showed increased connectivity between the left hippocampus and the left insula and lateral prefrontal region (), indicating that the APOE ε4 allele is associated with a more pronounced degree of hippocampal network breakdown. Although previous studies have examined APOE ε4-related alterations in hippocampal connectivity, the extent to which these alterations vary according to ε4 allele dosage in patients with MCID remains unclear. Therefore, the present study aimed to characterize connectivity alterations associated with APOE ε4 heterozygosity and homozygosity in MCID.