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Updated: Jul 17, 2026
Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease
Published on: November 14, 2017
APOE ε4-associated hippocampal atrophy trajectories across the Alzheimer's disease continuum: a systematic review,
Minnuo Cai1,2, Hang Lei1, Yuetong Zhang1
1Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
Background:
Predicting patient-specific neurodegenerative trajectories is essential for targeted interventions in Alzheimer's disease. Although the APOE-ε4 allele is the predominant genetic risk factor for hippocampal atrophy, whether its structural impact reflects a static developmental phenotype or an accelerated neurodegenerative process conditional on amyloid pathology remains unresolved.
Objectives:
To quantify the effect of APOE-ε4 on hippocampal volume via cross-sectional meta-analysis, and to validate the gene-dose effect through independent longitudinal modeling in two cohorts.
Eligibility Criteria:
Original observational neuroimaging studies reporting hippocampal volume stratified by APOE genotype in human participants across the Alzheimer's disease continuum.
Information Sources:
PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to August 2025.
Risk Of Bias:
Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) adapted for cross-sectional studies.
Included Studies And Synthesis Of Results:
The meta-analysis included 18 studies (N = 4, 311) and indicated reduced hippocampal volume in carriers (ICV-corrected stratum: SMD = -0.41, 95% CI [-0.67, -0.16], p = 0.004; I 2 = 74.0%), with the effect absent in uncorrected analyses. Longitudinal gene-dose models, run independently in the post-QC NACC LMM sample (N = 3, 239; imaging extraction N = 3, 248) and ADNI (N = 1, 150) cohorts and combined via fixed-effect meta-analysis, demonstrated a dose-dependent acceleration of hippocampal atrophy: homozygotes exhibited a pooled additional volume loss of -58.25 mm3/year (95% CI [-89.26, -27.23], p = 2.33 × 10-4; I 2 = 0%) and heterozygotes -34.32 mm3/year (95% CI [-52.31, -16.32], p = 1.85 × 10-4) relative to non-carriers.
Limitations:
Biomarker-stratified analyses used baseline-only CSF measurements subject to time-varying confounding and should be interpreted as exploratory. Moderate between-cohort heterogeneity was observed for the heterozygote effect (I 2 = 63.0%).
Conclusions And Implications:
These findings provide two-cohort evidence for a dose-dependent APOE-ε4 effect on hippocampal atrophy rates. Exploratory biomarker-stratified analyses in ADNI suggest this acceleration may be conditional on amyloid-β positivity, a hypothesis requiring validation with time-varying causal models.
Systematic Review Registration:
https://www.crd.york.ac.uk/PROSPERO/view/CRD420251243460, PROSPERO: CRD420251243460.
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