Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, USA.
Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
J Alzheimers Dis. 2023;95(4):1449-1467. doi: 10.3233/JAD-230035.
Sex differences impact Alzheimer's disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology.
Examine how AD risk factors (age, APOEɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures.
Individuals from the OASIS-3 cohort (age 42-95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231).
In absence of AD risk factors (APOEɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β= -0.007). Regression modeling including APOEɛ4 allele carriers (Aβ-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β= 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β= 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the Trail Making Test (p < 0.05).
Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOEɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOEɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.
性别差异会影响阿尔茨海默病（AD）的神经病理学，但在疾病的前驱阶段，细胞到网络层面的功能障碍尚不清楚。海马兴奋-抑制平衡（EIB）的改变最近与早期 AD 病理学有关。
使用连接组水平的测量方法，检查 AD 风险因素（年龄、APOEɛ4、淀粉样蛋白-β）如何与认知正常的男性和女性的海马 EIB 相关。
研究了 OASIS-3 队列中的个体（年龄 42-95 岁）（N=437），其中一部分年龄在 65 岁以上的个体进行了神经心理学测试（N=231）。
在没有 AD 风险因素（APOEɛ4/Aβ+）的情况下，男性的全脑 EIB 随年龄的增长比女性更为显著（p=0.021，β=-0.007）。包括 APOEɛ4 等位基因携带者（Aβ-）的回归模型仅在女性中显示出右侧海马的 AGE-by-APOE 显著正交互作用（p=0.013，β=0.014），并在包括 Aβ+个体时仍然存在（p=0.012，β=0.014）。神经心理学测试的偏相关分析显示 EIB 与女性存在显著相关性：右侧海马 EIB 与类别流畅性呈正相关，全脑 EIB 与 Trail Making Test 呈正相关（p<0.05）。
EIB 在正常衰老过程中出现性别差异，并随 AD 风险的不同而不同。结果表明，APOEɛ4 在女性中比淀粉样蛋白更能破坏海马平衡。女性组中兴奋增加与神经心理学表现呈正相关，这表明在认知障碍之前存在双重潜在有益影响。这突显了女性 APOEɛ4 相关过度兴奋的转化相关性，可能为这一脆弱人群的 AD 进展提供治疗靶点或早期干预措施。
