Five-Year Longitudinal Brain Volume Change in Healthy Elders at Genetic Risk for Alzheimer’s Disease

Abstract

Neuropathological changes associated with Alzheimer’s disease (AD) precede symptom onset by more than a decade. Possession of an Apolipoprotein-E (APOE) ε4 allele is the strongest genetic risk factor for late onset AD. Cross-sectional studies of cognitively intact elders have noted smaller hippocampal/medial temporal volumes in ε4 carriers (ε4+) compared to ε4 non-carriers (ε4-). Few studies, however, have examined long-term, longitudinal, anatomical brain changes comparing healthy ε4+ and ε4- individuals. The current five-year study examined global and regional volumes of cortical and subcortical grey and white matter and ventricular size in 42 ε4+ and 30 ε4- individuals. Cognitively intact participants, ages 65-85 at study entry, underwent repeat anatomical MRI scans on three occasions: baseline, 1.5, and 4.75 years. Results indicated no between group volumetric differences at baseline. Over the follow-up interval, the ε4+ group experienced a greater rate of volume loss in total grey matter, bilateral hippocampi, right hippocampal subfields, bilateral lingual gyri, parahippocampal gyrus, and right lateral orbitofrontal cortex compared to the ε4- group. Greater loss in grey matter volumes in ε4+ participants were accompanied by greater increases in lateral, third and fourth ventricular volumes. Rate of change in white matter volumes did not differentiate the groups. The current results indicate that longitudinal measurements of brain atrophy can serve as a sensitive biomarker for identifying neuropathological changes in persons at genetic risk for AD and potentially, for assessing the efficacy of treatments designed to slow or prevent disease progression during the preclinical stage of AD.

Longitudinal change in regional brain volumes with exposure to repetitive head impacts

“…Higher baseline NfL levels were associated with greater volumetric decline in left hippocampus (33.2 mm 3 /y, p < 0.001) and mid anterior corpus callosum (7.68 mm 3 , p = 0.015), with a trend seen in the left amygdala, right thalamus, and mid corpus callosum. Higher baseline tau levels were not correlated with regional volumetric changes.…”

“…Previous work has suggested that monitoring regional brain volumes through MRI may serve as a potential tool to recognize and follow structural brain changes. 3 Measurement of hippocampal volumes has been well-studied in Alzheimer disease (AD) and is commonly used as a secondary outcome measure in AD clinical trials. 4 Similarly, we and others have reported associations between volumes of certain brain regions and exposure to RHI as well as clinical outcomes in cross-sectional studies.…”

Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

“…Longitudinal studies are crucial to identify genetic and environmental factors that influence the rate of these brain changes throughout development (Giedd et al, 1999;Gogtay et al, 2004;Shaw, Gogtay, & Rapoport, 2010) and aging (Raz et al, 2005). Interindividual differences in brain development are associated with general cognitive function (Ramsden et al, 2011;Schnack et al, 2015;Oschwald et al, 2019), and risk for psychiatric disorders (Shaw et al, 2009;Liberg et al, 2016) and neurological diseases (Reiter et al, 2017;Eshaghi et al, 2018;Jiskoot et al, 2019). Genetic factors involved in brain development and aging overlap with those for cognition (Brans et al, 2010;Brouwer et al, 2014) and risk for neuropsychiatric disorders (Brans et al, 2008).…”

The associations of the BDNF and APOE polymorphisms, hippocampal subfield volumes, and episodic memory performance across the lifespan

“…However, the number of studies investigating effects of APOE polymorphisms on hippocampal subfields in healthy cohorts is very limited and the results have been inconsistent so far (de Flores et al, 2015). While some studies found that APOE ϵ2 carriers had smaller volumes in CA3/DG subfield (Mueller, Schuff, Raptentsetsang, Elman, & Weiner, 2008;Mueller & Weiner, 2009), others suggested these effects were limited to the Sub (Burggren et al, 2008;Donix et al, 2010) or affected all three subfields (Reiter et al, 2017). In addition, the associations between BDNF polymorphisms and hippocampal subfields and hippocampal subregions have not yet been investigated in healthy populations.…”