Nonlinear cerebral atrophy patterns across the Alzheimer's disease continuum: impact of APOE4 genotype

Gispert, Juan Domingo; Rami, Lorena; Sánchez‐Benavides, Gonzalo; Falcon, Carles; Tucholka, Alan; Rojas, Santiago; Molinuevo, José Luís

doi:10.1016/j.neurobiolaging.2015.06.027

Cited by 47 publications

(61 citation statements)

References 83 publications

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“…It is an intriguing possibility that an over-engagement with the parahippocampus and anterior cingulate by e4+ individuals throughout youth may provoke a neurogenic response that leads to the relative enlargement in these areas, as observed in our mid-age e4+ cohort. This pattern of non-linear cerebral atrophy has been reported in a recent study across several key brain areas, including the medial temporal structures (79). In that study, a thicker parahippocampal cortex among e4+ individuals was observed in the prodromal AD cohort, but the increased cortical thickness was not maintained and, mirroring previous findings in the hippocampus (71,72), it reverted at later stages of the disease profile.…”

Section: Discussionsupporting

confidence: 77%

Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

et al. 2016

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Abstract-The presence of the e4 allele of apolipoprotein E (APOE) gene is the best known genetic risk factor for Alzheimer's disease. In this study we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences between those that carry the e4 allele (e4+) and those that only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age 21 years); and a mid-age group (average age 50 years). High-resolution T1-weighted MRI scans were analyzed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. This data was correlated against behavioural findings on the same cohort. Resting-state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there is a positive correlation between the thickness of the parahippocampal cortex in young e4+ and performance on an episodic memory task. Young e4+ also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid age, e4+ had structural differences compared to e3/e3 in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than e3/e3. We discuss the possibility that an over-engagement with these regions by e4+ in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE-driven differences in the brain, with greater functional connectivity among young e3/e3 and greater white matter volume in the young e4+.

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Section: Discussionsupporting

confidence: 77%

Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

et al. 2016

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“…The same group showed that the cortex was thicker in healthy controls with low CSF Aβ levels in the absence of abnormal p‐ tau levels; whereas the cortex was thinner in subjects with abnormal CSF levels of both Aβ and p‐ tau (Fortea et al, ). In a wider study of the AD continuum (including cognitively intact subjects, subjects with MCI and dementia), a transient increase in hippocampal volume was reported for subjects with low composite AD‐CSF indices (defined as the sum of the normalized CSF concentrations of Aβ and tau reflecting the level of pathology and position along the AD continuum) followed by decline at higher indices (Gispert et al, ). These recent studies and our own results suggest that pathological burden is not necessarily associated with universal volumetric decline as described in several models of AD (Jack et al, ).…”

Section: Discussionmentioning

confidence: 99%

Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Tardif

Devenyi

Amaral

et al. 2017

Human Brain Mapping

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Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-β 1-42 (Aβ) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple-sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra-hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment.

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“…Results were considered significant if surviving a whole‐brain voxel‐wise statistical threshold of p < .001 applying a cluster extent threshold correction of 100 contiguous voxels. This procedure is reliably conservative and further protects against Type I error (Gispert et al, 2015; Wishart et al, 2006). Finally, to reduce dimensionality and to search for common patterns of brain morphology variability associated to EM and EFs, we additionally performed a principal component analysis separately performed for the two cognitive domains and repeated all the above analyses using the extracted principal components as dependent variables (Gaskin & Happell, 2014).…”

Section: Methodsmentioning

confidence: 99%

Episodic memory and executive functions in cognitively healthy individuals display distinct neuroanatomical correlates which are differentially modulated by aging

Cacciaglia

Molinuevo

Sánchez‐Benavides

et al. 2018

Human Brain Mapping

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The neuroanatomical bases of episodic memory (EM) and executive functions (EFs) have been widely addressed in patients with brain damage and in individuals with neurologic disorders. These studies reported that larger brain structures support better outcomes in both cognitive domains, thereby supporting the “bigger is better” account. However, relatively few studies have explored the cerebral morphological properties underlying EM and EFs in cognitively healthy individuals and current findings indicate no unitary theoretical explanation for the structure–function relationship. Moreover, existing studies have typically restricted the analyses to a priori defined regions of interest. Here we conducted unbiased voxel‐wise analysis of the associations between regional gray as well as white matter volumes (GMv; WMv) and performance in both cognitive domains in a sample of 463 cognitively intact individuals. We found that efficiency in EM was predicted by lower GMv in brain areas belonging to the default‐mode network (DMN). By contrast, EFs performance was predicted by larger GMv in a distributed set of regions, which overlapped with the executive control network (ECN). Volume of white matter bundles supporting both cross‐cortical and interhemispheric connections was positively related to processing speed. Furthermore, aging modulated the relationship between regional volumes and cognitive performance in several areas including the hippocampus and frontal cortex. Our data extend the critical role of the DMN and ECN by showing that variability in their morphological properties, and not only their activation patterns, affects EM and EFs, respectively. Moreover, our finding that aging reverts these associations supports previously advanced theories of cognitive neurodevelopment.

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Nonlinear cerebral atrophy patterns across the Alzheimer's disease continuum: impact of APOE4 genotype

Cited by 47 publications

References 83 publications

Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Episodic memory and executive functions in cognitively healthy individuals display distinct neuroanatomical correlates which are differentially modulated by aging

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