在没有认知障碍的老年人中,通常观察到MRI扫描中大脑容量减少和更明显的白质高强度。然而,目前尚不清楚,在认知正常的成年人中,这些指标的变化率是否随着迟发性阿尔茨海默病的遗传风险而有所不同,包括APOE-13C4、APOE-13C2和阿尔茨海默病多基因风险评分(AD-PRS),以及这些关系是否受到其他变量的影响。这项纵向研究在基线时具有正常认知的中年和老年人的协调数据集中,检查了与APOE基因型(N=1541)和AD-PRS(N=1093)相关的区域脑容量和白质高信号的轨迹(平均基线年龄=66岁,SD=9.6),平均MRI随访5.3年(最大=24年)。通过三种方式对容积MRI扫描中的萎缩进行量化:(i)易罹患阿尔茨海默病的区域的综合评分(SPARE-AD);(ii)海马体积;和(iii)反映晚期非阿尔茨海默病相关脑老化的区域的综合评分(SPARE-BA)。总体白质高强度体积来自液体衰减反转恢复(FLAIR)MRI。使用线性混合效应模型,在SPARE-AD复合物和海马中对萎缩有APOE-4基因剂量效应,4/4携带者中萎缩最严重,其次是4个杂合子,最低的是3个纯合者和2/2和2/3个携带者,他们彼此没有区别。在受教育程度较高(P<0.04)和基线年龄较低(P<0.03)的人群中,APOE-º4与萎缩的负相关性降低。在SPARE-AD(P=0.035)和海马(P=0.014)中,较高的AD-PRS也与更大的萎缩有关。独立于APOE-º4状态。在SPARE-AD中,APOE-2状态(2/2和2/3合并)与基线水平或萎缩无关,备用BA或海马体,但与白质高强度增加有关(P=0.014)。此外,存在与白质高信号相关的APOE-º4×AD-PRS相互作用(P=0.038),在具有较高AD-PRS的APOE-º4携带者中,白质高信号增加更大。APOE和AD-PRS与MRI测量的关联在性别上没有差异。这些结果表明,APOE-º4和AD-PRS独立且相加地影响对阿尔茨海默病敏感的脑容量的纵向下降,并协同增加认知正常个体的白质高强度积累。相反,APOE-º2主要影响白质高强度积累,不是脑萎缩.结果与阿尔茨海默病的遗传因素以区域特异性方式影响萎缩的观点一致。可能反映了临床前神经变性,和阿尔茨海默病的风险基因有助于白质高强度形成。
Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer\'s disease, including APOE-ɛ4,
APOE-ɛ2 and Alzheimer\'s disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer\'s disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer\'s disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of
APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status.
APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an
APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS.
APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer\'s disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer\'s disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer\'s disease risk genes contribute to white matter hyperintensity formation.