Abstract
Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD. To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD. This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of dementia, and available DNA data who were enrolled in prospective studies of memory and aging from September 1, 2005, to August 31, 2016. Clinical, biomarker, and genetic data were extracted on January 17, 2017, and data analyses were conducted from July 1, 2017, to August 20, 2019. The associations of acquired (ie, years of education; body mass index; history of cardiovascular disease, hypertension, hypercholesterolemia, diabetes, active depression within 2 years, traumatic brain injury, tobacco use, and unhealthy alcohol use; and retrospective determination of AAO) and heritable factors (ie, ethnicity/race, paternal or maternal inheritance, parental history of early-onset dementia, APOE ε4 allele status, and AD polygenic risk scores) to intergenerational difference in AAO of AD were quantified using stepwise forward multivariable regression. Missense or frameshift variants within genes associated with AD pathogenesis were screened using whole-exome sequencing. There were 164 participants with symptomatic AD, known parental history of dementia, and available DNA data (mean [SD] age, 70.9 [8.3] years; 90 [54.9%] women) included in this study. Offspring were diagnosed with symptomatic AD a mean (SD) 6.1 (10.7) years earlier than their parents (P < .001). The adjusted R2 for measured acquired and heritable factors for intergenerational difference in AAO of AD was 0.29 (F8,155 = 9.13; P < .001). Paternal (β = -9.52 [95% CI, -13.79 to -5.25]) and maternal (β = -6.68 [95% CI, -11.61 to -1.75]) history of dementia, more years of education (β = -0.58 [95% CI -1.08 to -0.09]), and retrospective determination of AAO (β = -3.46 [95% CI, -6.40 to -0.52]) were associated with earlier-than-expected intergenerational difference in AAO of AD. Parental history of early-onset dementia (β = 21.30 [95% CI, 15.01 to 27.59]), presence of 1 APOE ε4 allele (β = 5.00 [95% CI, 2.11 to 7.88]), and history of hypertension (β = 3.81 [95% CI, 0.88 to 6.74]) were associated with later-than-expected intergenerational difference in AAO of AD. Missense or frameshift variants within genes associated with AD pathogenesis were more common in participants with the greatest unexplained variability in intergenerational AAO of AD (19 of 48 participants [39.6%] vs 26 of 116 participants [22.4%]; P = .03). Acquired and heritable factors were associated with a substantial proportion of variability in intergenerational AAO of AD. Variants in genes associated with AD pathogenesis may contribute to unexplained variability, justifying further study.
Highlights
After age, genetic factors are the second-greatest factors associated with risk of symptomatic Alzheimer disease (AD)
Paternal (β = −9.52 [95% CI, −13.79 to −5.25]) and maternal (β = −6.68 [95% CI, −11.61 to −1.75]) history of dementia, more years of education (β = −0.58 [95% CI −1.08 to −0.09]), and retrospective determination of at symptomatic onset (AAO) (β = −3.46 [95% CI, −6.40 to −0.52]) were associated with earlier-than-expected intergenerational difference in AAO of AD
Parental history of early-onset dementia (β = 21.30 [95% CI, 15.01 to 27.59]), presence of 1 APOE ε4 allele (β = 5.00 [95% CI, 2.11 to 7.88]), and history of hypertension (β = 3.81 [95% CI, 0.88 to 6.74]) were associated with later-than-expected intergenerational difference in AAO of AD
Summary
Genetic factors are the second-greatest factors associated with risk of symptomatic Alzheimer disease (AD). It is not surprising that offspring of parents with dementia have an increased lifetime risk of symptomatic AD,[1,2] with the greatest risk experienced by those with a maternal history or with 2 affected parents[3,4,5] and those who inherited 1 or 2 copies of the APOE (OMIM 107741) ε4 allele.[6] Prior studies have suggested that disease expression may change across generations, with the offspring of affected parents experiencing an earlier age at symptomatic onset (AAO) of AD.[1,2,7,8] A 2017 study by Livingston et al[9] suggested that the cumulative effects of acquired and heritable traits are associated with intergenerational dementia risk. These same factors may be exploited to delay onset of AD and improve patient outcomes
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