From the Genetic Epidemiology Program, Department of Internal Medicine (L.A.C.-A., J.M.F., C.C.T., H.K.), Center for Alzheimer's Care, Imaging and Research, Department of Neurology (N.L.F.), and Department of Family and Preventive Medicine (K.S.), University of Utah School of Medicine; Huntsman Cancer Institute (L.A.C.-A., H.K.); George E. Wahlen Department of Veterans Affairs Medical Center (L.A.C.-A.), Salt Lake City; Department of Psychology (J.T., C.C.), Utah State University, Logan; and Departments of Biology and Neuroscience (J.S.K.K.), Brigham Young University, Provo, UT.
Neurology. 2019 Apr 9;92(15):e1745-e1753. doi: 10.1212/WNL.0000000000007231. Epub 2019 Mar 13.
The inherited component for Alzheimer disease (AD) risk has focused on close relatives; consideration of the full family history may improve accuracy and utility of risk estimates.
A population resource including a genealogy of Utah pioneers from the 1800s linked to Utah death certificates was used to estimate relative risk for AD based on specific family history constellations, including from first- to third-degree relatives.
Any affected first-degree relatives (FDR) significantly increased risk of AD (≥1 FDRs: relative risk [RR] 1.73, 95% confidence interval [CI] [1.59-1.87]; ≥2 FDRs: RR 3.98 [3.26-4.82]; ≥3 FDRs: RR 2.48 [1.07-4.89]; ≥4 FDRs: RR 14.77 [5.42-32.15]). Affected second-degree relatives (SDR) increased risk even in the presence of affected FDRs (FDR = 1 with SDR = 2: RR 21.29 [5.80-54.52]). AD only in third-degree relatives (TDR) also increased risk (FDR = 0, SDR = 0, TDR ≥3: RR 1.43 [1.21-1.68]). Mixed evidence was observed for differences in risk based on maternal compared to paternal inheritance; higher risks for men than women with equivalent family history, and higher risk for individuals with at least one affected FDR regardless of the relative's age at death, were observed.
This population-based estimation of RRs for AD based on family history ascertained from extended genealogy data indicates that inherited genetic factors have a broad influence, extending beyond immediate relatives. Providers should consider the full constellation of family history when counseling patients and families about their risk of AD.
阿尔茨海默病（AD）的遗传因素主要集中在近亲身上；考虑完整的家族史可能会提高风险评估的准确性和实用性。
利用一个包括 19 世纪犹他州拓荒者系谱的人群资源，并与犹他州死亡证明相关联，根据特定的家族史模式（包括一级至三级亲属）来估计 AD 的相对风险。
任何受影响的一级亲属（FDR）均显著增加 AD 的发病风险（≥1 FDR：相对风险[RR]1.73，95%置信区间[CI] [1.59-1.87]；≥2 FDR：RR 3.98 [3.26-4.82]；≥3 FDR：RR 2.48 [1.07-4.89]；≥4 FDR：RR 14.77 [5.42-32.15]）。即使存在受影响的 FDR，受影响的二级亲属（SDR）也会增加风险（FDR=1 且 SDR=2：RR 21.29 [5.80-54.52]）。仅有三级亲属（TDR）受累的 AD 也会增加风险（FDR=0，SDR=0，TDR≥3：RR 1.43 [1.21-1.68]）。基于母系而非父系遗传的风险差异存在混合证据；与具有相同家族史的女性相比，男性的风险更高，无论相对死亡年龄如何，只要有一个以上受影响的 FDR，个体的风险就会增加。
基于从扩展系谱数据中确定的家族史对 AD 的 RR 进行的这种基于人群的估计表明，遗传因素具有广泛的影响，超出了直系亲属的范围。在为患者及其家属提供 AD 风险咨询时，临床医生应考虑家族史的全貌。
