Bristol-Myers Squibb Global Clinical Research, Wallingford, CT, USA.
Alzheimers Dement. 2013 Mar;9(2):e1-73. doi: 10.1016/j.jalz.2010.12.005. Epub 2012 Mar 7.
Retrospective data are presented to support a spectrum of early Alzheimer's disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed.
现有的数据支持了一种早期阿尔茨海默病（AD）的连续谱，该连续谱由性别和基因型定义。在该连续谱的两端，不同表型的潜在神经退行性机制是不同的，一端是与突触胆碱能神经传递早期失败相关的神经胶质活性低下，另一端是与由于髓鞘的加速性年龄相关破坏导致神经网络连接丧失相关的神经胶质过度激活。在早期 AD 中，男性 butyrylcholinesterase K 变体携带者携带一个或两个载脂蛋白 E4 等位基因，具有明显的内侧颞叶萎缩、突触功能障碍、认知能力下降和聚集的β-淀粉样肽积累。增加受损但仍具有功能的胆碱能突触中的突触乙酰胆碱可改善认知症状，而增加神经胶质支持突触和清除β-淀粉样肽的能力可能具有疾病修饰作用。相反，慢性神经胶质过度激活也可能驱动退行性过程，在 butyrylcholinesterase K 变体阴性的女性中，普遍的神经胶质过度激活可能是从轻度认知障碍到 AD 的主要驱动因素。女性比男性更容易出现加速性年龄相关的髓鞘破坏、更广泛的白质丢失、神经网络连接丧失、全脑萎缩和功能下降。增加细胞外乙酰胆碱水平可阻断神经胶质激活，减少髓鞘丢失和对神经网络连接的损害，并具有疾病修饰作用。在以性别、基因型和年龄为特征的极端之间，病理生理学可能是混合的，这种连续谱可能解释了遗忘型轻度认知障碍的大部分异质性。保持神经网络的功能完整性可能是增强认知储备和显著延迟痴呆发病和进展的重要组成部分，特别是在女性中。需要前瞻性地证实这些假设。讨论了对未来研究和治疗机会的影响。
