To test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of APOE 4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.

Using general additive mixed models, we assessed the relations of PGS for AD, including variants in APOE with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4–95 years, mean visit age 39.7 years, SD 26.9 years), followed for up to 11 years.

AD-PGS and APOE 4 in isolation showed a significant negative effect on hippocampal volume. The effect of a 1 sample SD increase in AD-PGS on hippocampal volume was estimated to –36.4 mm³ (confidence interval [CI]: –71.8, –1.04) and the effect of carrying 4 allele(s) –107.0 mm³ (CI: –182.0, –31.5). Offset effects of AD-PGS and APOE 4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed.

Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in cognitively healthy persons, not being confined to clinical populations or older age. This emphasizes that a broader population and age range may be relevant targets for attempts to prevent AD.

为了验证阿尔茨海默病 (AD) 的遗传风险可能代表着生命早期对大脑的稳定影响这一假设，而不是主要依赖于年龄，我们对 1,181 人的寿命样本进行了调查，总共进行了 2,690 次脑部扫描， AD 的较高多基因风险评分 (PGS) 和APOE 4 的存在是否与开始时较低的海马体积相关，作为一种抵消效应，或者可能在老年时更快下降。

使用一般的加法混合模型，我们评估了 PGS 与 AD 的关系，包括APOE的变异与海马体积及其在认知健康纵向寿命样本中的变化（年龄范围：4-95 岁，平均就诊年龄 39.7 岁，SD 26.9 岁)，长达 11 年。

AD-PGS 和APOE 4 单独显示对海马体积有显着的负面影响。AD-PGS 增加 1 个样本 SD 对海马体积的影响估计为 –36.4 mm ³（置信区间 [CI]：–71.8，–1.04），携带 4 个等位基因的影响估计为 –107.0 mm ³（ CI：–182.0，–31.5）。AD-PGS 和APOE 4 的抵消效应存在于海马发育中，并且未始终观察到年龄和遗传风险对体积变化的相互作用。

AD 多基因风险的内表型表现可以在认知健康的人的整个生命周期中看到，而不仅限于临床人群或老年人。这强调了更广泛的人口和年龄范围可能是预防 AD 的相关目标。