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Associations between rare microglia-linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals.

ABSTRACT: Introduction:Recent exome sequencing studies have identified three novel risk variants associated with Alzheimer's disease (AD). However, the mechanisms by which these variants confer risk are largely unknown. Methods:In the present study, the impact of these rare coding variants (in ABI3, PLCG2, and TREM2) on all subcortical volumes is determined in a large sample of young healthy individuals (N = 756-765; aged 22-35 years). Results:After multiple testing correction (P CORRECTED < .05), rare variants were associated with basal ganglia volumes (TREM2 and PLCG2 effects within the putamen and pallidum, respectively). Nominal associations between TREM2 and reduced hippocampal and thalamic volumes were also observed. Discussion:Our observations suggest that rare variants in microglia-mediated immunity pathway may contribute to the subcortical alterations observed in AD cases. These observations provide further evidence that genetic risk for AD may influence the volume of subcortical volumes and increase AD risk in early life processes.

SUBMITTER: Lancaster TM

PROVIDER: S-EPMC6501059 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Associations between rare microglia-linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals.

Lancaster Thomas M TM

Alzheimer's & dementia (Amsterdam, Netherlands) 20190502

<h4>Introduction</h4>Recent exome sequencing studies have identified three novel risk variants associated with Alzheimer's disease (AD). However, the mechanisms by which these variants confer risk are largely unknown.<h4>Methods</h4>In the present study, the impact of these rare coding variants (in <i>ABI3, PLCG2</i>, and <i>TREM2</i>) on all subcortical volumes is determined in a large sample of young healthy individuals (N = 756-765; aged 22-35 years).<h4>Results</h4>After multiple testing cor ...[more]

PMID: 31080872

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Project description:PurposeIn an increasingly aging society, it is of great importance to consider trajectories of subcortical volumes at different ages for understanding biological markers of aging. Thus, we investigated sex, age, and their interactions on subcortical volumes, including the basal ganglia (caudate, putamen, accumbens, and pallidum), thalamus, hippocampus, and amygdala.MethodsWe analyzed the adult lifespan trajectory of subcortical volumes and asymmetries in 563 healthy subjects aged from 19 to 86 using magnetic resonance imaging (MRI) data from the publicly available 7IXI data set.ResultsThe sex made strong contributions to the trajectories of subcortical volumes with aging, including the right putamen, right pallidum, bilateral thalamus, hippocampus, and amygdala. The volume of the right putamen, right pallidum, and right thalamus decreased more rapidly in males than in females, and the volume of the left thalamus, bilateral hippocampus, and amygdala in males followed a quadratic model, while those in females followed a linear decline model. The asymmetries in the caudate and hippocampus showed a linear decline, and a sex and age interaction was found in the hippocampus; that is, the asymmetry in the hippocampus decreased only in the males and not in the females. Changes in the accumbens and pallidum fit quadratic trajectories, in which females increased until 39.26 years old in the accumbens asymmetry and then began to rapidly decline, and males showed a linear decline. The asymmetry in the pallidum in males and females showed a slow decreasing period until almost 45 years of age and then increased.ConclusionThe results suggest that compared with females, males have a faster decline in the volume of the right putamen, right pallidum, and right thalamus, while aging occurred later but also faster in the left thalamus, bilateral hippocampus, and amygdala. Interestingly, we found the inflection point in the thalamus, bilateral hippocampus, and amygdala volume in the quadratic model, and after this point, the volume change accelerated with aging, which may have resulted from the stronger work pressure in the middle-aged men and the low levels of testosterone in the older adults. The interaction of age and sex on individual subcortical structures provides evidence to support the impact of sex on psychopathologies associated with degenerative brain disorders in the elderly. The findings may be significant to investigate the occurrence and prevalence of degenerative brain disorders in males and females. Future studies can focus on the functional and behavioral relations with subcortical structures for preventive measures of related disorders.

Dataset Information

Associations between rare microglia-linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals.

Publications

Associations between rare microglia-linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals.

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