Altered brain morphometry and its association with cognitive decline and APOE gene in normal people at risk for Alzheimer's disease

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory impairment. Identifying early markers of AD is critical for timely diagnosis and intervention. Objective This study aimed to characterize the neuropsychological and pathological features of cognitively unimpaired (CU) individuals who later progressed to mild cognitive impairment (MCI) or AD, referred to as At-Risk CU. The goal was to support accurate staging and inform early therapeutic strategies. Methods Participants were categorized into CU, At-Risk CU, MCI, and AD groups. Data analyses focused on neuroimaging scans, neuropsychological assessments, cerebrospinal fluid (CSF) biomarkers (including Aβ 1–40 /Aβ 1–42 and p-Tau/t-Tau), and APOE genotypes. Voxel-based morphometry (VBM) was employed to assess gray matter (GM) volume and white matter (WM) integrity. Statistical analyses were conducted to evaluate group differences and associations. Results VBM revealed progressive GM atrophy and WM disruptions across the continuum from CU to At-Risk CU, MCI, and AD, particularly in the hippocampus and adjacent regions. Neuropsychological assessments showed significant cognitive decline across stages, while dynamic changes in CSF biomarkers in At-Risk CU suggested compensatory mechanisms. The APOE ε4 allele was strongly associated with AD progression, whereas the ε2 allele demonstrated protective effects. GM volume was significantly correlated with ADAS11 and ADAS13 scores. Conclusions This study identifies At-Risk CU as a distinct and clinically meaningful stage in AD progression, marked by structural, cognitive, and biomarker alterations. Integrating neuropsychological assessments, neuroimaging, and CSF biomarkers may facilitate early detection and enable targeted interventions to improve outcomes for individuals at elevated risk of AD.