Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

Abstract

Background: Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions. Methods: We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score (CCS) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL. Results: There was a negative association between the CCS and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele. Conclusion: The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.

Low Subicular Volume as an Indicator of Dementia-Risk Susceptibility in Old Age

“…The formation of Aβ plaques is believed to be one of the earliest changes in the hypothesized pathophysiological continuum of AD and to start decades before manifestation of the clinical syndrome ( Braak and Braak, 1997 ; Jack et al, 2010 ; Sperling et al, 2011 ; Villemagne et al, 2013 ; Jansen et al, 2015 ; Parker et al, 2019 ). Several studies on healthy old-aged persons have consistently demonstrated an association between increased brain Aβ burden, reduced hippocampal volume, and increased risk for cognitive dysfunction ( Rentz et al, 2010 ; Rodrigue et al, 2012 ; Vos et al, 2013 ; Hsu et al, 2015 ; Donohue et al, 2017 ; Bilgel et al, 2018 ; Fletcher et al, 2018 ; Haller et al, 2019 ; Parker et al, 2019 ; Svenningsson et al, 2019 ; Yassi et al, 2019 ). While the precise mechanism of how years of Aβ accumulation in the human brain may be linked to dementia is still not very well-understood, increased cerebral Aβ plaque load is nevertheless considered to represent a major risk factor for developing AD at old age ( Tomlinson et al, 1968 ; Knopman et al, 2003 ; Bennett et al, 2006 ; Mintun et al, 2006 ; Rowe et al, 2007 ; Marchant et al, 2012 ; Jack et al, 2014 ).…”

APOE moderates the effect of hippocampal blood flow on memory pattern separation in clinically normal older adults

“…Although the APOE e4 allele has been associated with substantial variation in the structure (Cohen et al, 2001; Den Heijer et al, 2002; Haller et al, 2020; Jak et al, 2007; Lind et al, 2006; Montagne et al, 2020; Plassman et al, 1997; Weintraub et al, 2020) and function of the medial temporal lobes (Bookheimer et al, 2000; De Marco et al, 2017; Filippini et al, 2009; Fleisher et al, 2009; Han et al, 2007; Nichols et al, 2012; Suri et al, 2015; Suthana et al, 2010; Zheng et al, 2018), our APOE e4 groups did not differ in resting hippocampal blood flow. Prior investigations of MTL blood flow in APOE e4 carriers have been mixed, with some identifying no difference in hippocampal blood flow between groups (Bangen et al, 2017; Hays et al, 2019), and others demonstrating altered resting CBF across widespread medial temporal, frontal and parietal regions (Tai et al, 2016; Wierenga et al, 2014).…”

Functional Brain Network Connectivity Patterns Associated With Normal Cognition at Old-Age, Local β-amyloid, Tau, and APOE4

“…Additional studies are needed to clarify connectivity in the context of the sequential progression of AD pathology (Hanseeuw et al, 2019), early functional change (McLaren et al, 2012), and potential opportunities for therapeutic intervention (Pini et al, 2018). The fact that these effects are observable before the manifestation of dementia, but still are related to APOE4 carrier status, may indicate relevance for the progression of early AD-pathology (Haller et al, 2019). Thus, further longitudinal studies are needed to investigate the temporal sequence of the observed changes, and whether they are associated with accelerated disease progression.…”