Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan

Abstract

ObjectiveTo 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 ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.MethodsUsing 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.ResultsAD-PGS and APOE ε4 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 ε4 allele(s) –107.0 mm3 (CI: –182.0, –31.5). Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed.ConclusionsEndophenotypic 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.

Individual variations in “Brain age” relate to early life factors more than to longitudinal brain change

“…An exception is Elliott and colleagues 3 , who found that middle-aged individuals with higher brain age already exhibited poorer cognitive function and brain health at age three years. This fits a robust corpus of literature showing effects of lifelong, stable influences as indexed by childhood IQ 14 , genetics 10 , and neonatal characteristics 8 on brain and cognitive variation in old age.…”

“…If brain age reflects accelerated brain aging, cross-sectional brain age delta - indexed by the centercept - should be positively associated with yearly increases of brain age delta over time (brain age delta long ) . If the early-life account plays a substantial role, one should observe a relationship between brain age and early factors - indexed here as birth weight and polygenic scores for brain age (PGS-BA) given evidence of lifelong effects of genetic risk on age-related phenotypes 9,10 ( Fig. 1b ).…”

“…In addition, we also assessed brain change with a composite score of brain change and change in the different raw brain features. If early-life influences play a substantial role, one should observe a relationship between brain age and early factors -indexed here by birth weight and polygenic scores for brain age (PGS-BA) given evidence of lifelong effects of genetic effect on age-related phenotypes 9,10 (Fig. 1b).…”

The bidirectional causal effects of brain morphology across the life course and risk of Alzheimers disease: A cross-cohort comparison and Mendelian randomization meta-analysis

“…We observe an age-dependent decrease in the volume of structures such as the thalamus, caudate and accumbens in UK Biobank participants agreeing with the variable neurodegeneration hypothesis. Walhovd et al 41 examined the association between AD PRS and hippocampal volume in 1,181 cognitively healthy people with a wide age range (4–95 years). They identified an effect of a higher AD PRS on reduced hippocampal volumes in a sample of young adults, which was consistent across age groups.…”

Neurology: Genetics Year in Review

“…How and when these risk loci mediate pathogenesis of AD is a broad question and active area of research. Walhovd et al 7 studied the relationship between increased polygenic risk in AD and structural brain measures decades before the predicted development of neurodegenerative disease. The group analyzed hippocampal volume by brain MRI from 1,181 cognitively normal individuals aged 4–96 years.…”