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

ABSTRACT: Objective: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. Methods: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. Results: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. Conclusions: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.

SUBMITTER: Walhovd KB

PROVIDER: S-EPMC7577559 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Walhovd Kristine B KB Fjell Anders M AM Sørensen Øystein Ø Mowinckel Athanasia Monika AM Reinbold Céline Sonja CS Idland Ane-Victoria AV Watne Leiv Otto LO Franke Andre A Dobricic Valerija V Kilpert Fabian F Bertram Lars L Wang Yunpeng Y

Neurology. Genetics 20200908 5

<h4>Objective</h4>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 <i>APOE</i> ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.<h4>Methods</h ...[more]

PMID: 33134508

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Project description:BackgroundThe hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)].MethodsThirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes.ResultsBaseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome.ConclusionsThis is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

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

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

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