Raffaele Cacciaglia

Effects of APOE-ε4 allele load on brain morphology in a cohort of middle-aged healthy individuals with enriched genetic risk for Alzheimer's disease

Apolipoprotein E (APOE)‐ε4 is the major genetic risk factor for Alzheimers disease. However, the dose‐dependent impact of this allele on brain morphology of healthy individuals remains unclear.

Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets

Alzheimers disease (AD) is characterized by an accumulation of β-amyloid (Aβ42) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that Aβ42 accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the so-called preclinical stage of the AD (pre-AD). It also has been proved that the GM atrophy profile is not linear, both in normal ageing but, especially, on AD. However, several other factors may influence this association and may have an impact on the generalization of results from different samples. In this work, we estimate differences in rates of GM volume change in cognitively healthy elders in association with baseline core cerebrospinal fluid (CSF) AD biomarkers, and assess to what these differences are sample dependent. We report the dependence of atrophy rates, measured in a two-year interval, on Aβ42, computed both over continuous and categorical values of Aβ42, at voxel-level (p < 0.001; k < 100) and corrected for sex, age and education. Analyses were performed jointly and separately, on two samples. The first sample was formed of 31 individuals (22 Ctrl and 9 pre-AD), aged 60–80 and recruited at the Hospital Clinic of Barcelona. The second sample was a replica of the first one with subjects selected from the ADNI dataset. We also investigated the dependence of the GM atrophy rate on the basal levels of continuous p-tau and on the p-tau/Aβ42 ratio. Correlation analyses on the whole sample showed a dependence of GM atrophy rates on Aβ42 in medial and orbital frontal, precuneus, cingulate, medial temporal regions and cerebellum. Correlations with p-tau were located in the left hippocampus, parahippocampus and striatal nuclei whereas correlation with p-tau/Aβ42 was mainly found in ventral and medial temporal areas. Regarding analyses performed separately, we found a substantial discrepancy of results between samples, illustrating the complexities of comparing two independent datasets even when using the same inclusion criteria. Such discrepancies may lead to significant differences in the sample size needed to detect a particular reduction on cerebral atrophy rates in prevention trials. Higher cognitive reserve and more advanced pathological progression in the ADNI sample could partially account for the observed discrepancies. Taken together, our findings in these two samples highlight the importance of comparing and merging independent datasets to draw more robust and generalizable conclusions on the structural changes in the preclinical stages of AD.

CHARACTERISTIC BRAIN VOLUMETRIC CHANGES IN THE AD PRECLINICAL SIGNATURE

biomarker severity from CON to AD, with SCD showing a small, but significant difference from CON in the EC and HPC. Results: Qualitatively, morphometry results showed a gradient of changes from CON to AD in the EC and HPC (Figure 1), especially for the left EC and right HPC, but with SCD not significantly different from CON. Furthermore, compared to CON, SCD had significant lower right lingual surface (p1⁄4.021), left posterior cingulate thickness (p1⁄4.026), right rostral anterior cingulate thickness (p1⁄4.012), left supramarginal surface (p1⁄4.019) and volume (p1⁄4.039), however none of those differences resisted FDR correction. Grading results (Figure 2) were similar to morphometry, with a gradient of changes from CON to AD, especially for the left EC and right HPC, but no significant difference between SCD and CON. Conclusions:Based on these results, baseline morphometric measures and TPMDgrading scores for EC and HPC do not capture the difference related to the cognitive complaint between SCD and CON. Longitudinal follow-up is required to determine their positive predictive values for AD pathology.

White matter microstructure is altered in cognitively normal middle-aged APOE -ε4 homozygotes

BackgroundThe ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimers disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail.MethodsWe examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 207 heterozygotes, and 257 noncarriers). We examined the impact of age and APOE genotype on these parameters using tract-based spatial statistics.ResultsHealthy APOE-ε4 homozygotes display increased WM diffusivity in regions known to be affected by AD. The effects in AxD were much smaller than in RD, suggesting a disruption of the myelin sheath rather than pure axonal damage.ConclusionsThese findings could be interpreted as the result of the reduced capacity of the ε4 isoform of the APOE protein to keep cholesterol homeostasis in the brain. Because cerebral lipid metabolism is strongly related to the pathogenesis of AD, our results shed light on the possible mechanisms through which the APOE-ε4 genotype is associated with an increased risk of AD.

INTERACTION BETWEEN AGE AND APOE GENOTYPE ON THE COGNITIVE PERFORMANCE OF HEALTHY INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE

P3-550 INTERACTION BETWEEN AGE AND APOE GENOTYPE ON THE COGNITIVE PERFORMANCE OF HEALTHY INDIVIDUALSATRISKFORALZHEIMER’S DISEASE Marta Crous-Bou, Gonzalo S anchez-Benavides, Raffaele Cacciaglia, Nina Gramunt, Carolina Minguillon, Karine Fauria, Juan Domingo Gispert, Jos e Luis Molinuevo, Barcelonabeta Brain Research Center, Barcelona, Spain; Barcelonabeta Brain Research Center, Barcelona, Spain. Contact e-mail: mcrous@fpmaragall.org

SUBJECTIVE COGNITIVE DECLINE (SCD) AND SCD PLUS COGNITIVE PERFORMANCE AND STRUCTURAL IMAGING CORRELATES IN THE ALFA COHORT

F1-03-01 SUBJECTIVE COGNITIVE DECLINE (SCD) AND SCD PLUS COGNITIVE PERFORMANCE AND STRUCTURAL IMAGING CORRELATES IN THE ALFA COHORT Gonzalo S anchez-Benavides, Marta Crous-Bou, Raffaele Cacciaglia, Nina Gramunt, Juan Domingo Gispert, Jos e Luis Molinuevo, Barcelonabeta Brain Research Center, Barcelona, Spain; Barcelonabeta Brain Research Center, Barcelona, Spain. Contact e-mail: gsanchezb@ fpmaragall.org

IMPACT OF APOE GENETIC VARIANT ON BRAIN MORPHOLOGY IN A COHORT OF COGNITIVELY HEALTHY MIDDLE-AGED INDIVIDUALS WITH ENRICHED GENETIC RISK FOR ALZHEIMER’S DISEASE

526 middle-aged healthy adults. A) Mean-centered bar plots showing GM volumetric differences among the five APOE genotype groups. Spatial coordinates are given in the Montral Neurological Institute (MNI) standard space. B) Statistical parametric maps displaying main effects of APOE genotype on GM volumes. The bilateral hippocampus and thalamus are represented in cold and warm colors, respectively. Podium Presentations: Thursday, July 20, 2017 P1465