Protas, Hillary

AbstractBackgroundAPOE4 gene dose, the number of apolipoprotein E ‐ɛ4 (APOE4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and CSF measurements of amyloid‐β (Aβ) pathophysiology in APOE4 gene dose. Here, we characterize the core AD CSF biomarkers (Aβ42/40, pTau181, tTau), the neurodegeneration marker neurofilament light chain (NfL) and the glial biomarkers soluble TREM2 (sTREM2), and glial fibrillary acidic protein (GFAP) measurements in age‐matched 48‐70 year‐old cognitively unimpaired (CU) APOE4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs) from the Arizona cohort.MethodCSF biomarker measurements were performed at the University of Gothenburg using Lumipulse and ELISA immunoassays. CSF biomarker measurements were characterized and compared using linear‐tend ANOVAs in 12 HMs, 17 HTs, and 20 NCs who were CU, 48‐70 years old and did not differ significantly in their age, sex, or educational level.ResultAs expected, CSF Aβ42/40 ratios were inversely associated with APOE4 gene dose (linear trend, HM<HT<NC, p<0.05), and tTau/Aβ42 and pTau181/Aβ42 ratios were directly associated with APOE4 gene dose (HM>HT>NC p<0.05). Non‐significant trends suggested that CSF sTREM2 and sTREM2/pTau181 measurements were inversely associated with APOE4 gene dose (HM<HT≤NC, (0.05<p≤0.06). We failed to detect significant differences or linear trends in CSF pTau181, tTau, GFAP, or NfL measurements among these small subject groups.ConclusionAPOE4 gene dose is associated with measures of CSF Aβ42/40 and Aβ‐related tau pathophysiology, reflecting higher Aβ plaque burden in CU subjects close to their estimated ages at clinical onset. Additional studies are needed to clarify relationships between different Aβ, tau, neurodegenerative, inflammatory, and other CSF, or blood‐based biomarkers, and APOE4 gene dose in larger subject groups and at other ages.

Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.

AbstractIntroductionWe previously characterized associations between brain imaging measurements of amyloid‐β (Aβ) plaque burden and apolipoprotein E (APOE) ε4 gene dose in a small number of cognitively unimpaired late‐middle‐aged APOE ε4 homozygotes (HMs), heterozygotes (HTs), and noncarriers (NCs). We now characterize cross‐sectional Aβ plaque, tau tangle, and cortical atrophy (neurodegeneration) measurements, classifications, and associations with age in a larger number of unimpaired HMs, HTs, and NCs over a wider age range.MethodsWe analyzed 11C Pittsburgh compound B (Aβ) positron emission tomography (PET), flortaucipir (tau) PET, and volumetric magnetic resonance imaging data from 164 study participants of age 47–86 years, including 26 APOE ε4 HMs, 48 HTs, and 90 NCs matched for age and sex.ResultsAβ PET measurements rose, plateaued at the respective ages of 68 and 76, and then declined with age in unimpaired HM and HT groups. Compared with NCs, these two groups began to have significantly higher Aβ PET measurements at ages 62 and 70, respectively, and no longer had significantly higher measurements by ages 71 and 78, respectively. They began to have significantly higher entorhinal cortex tau PET measurements at ages 66 and 70, respectively, and no longer had significantly higher measurements by ages 74 and 78, respectively. Brain atrophy measurements tended to decline slowly with age in all three genetic groups. Their elevated tau PET measurements were attributable to those with positive Aβ PET scans. 41.0%, 18.0%, and 5.0% of the 47‐ to 70‐year‐old HMs, HTs, and NCs and 25.0%, 79.0%, and 38.0% of the 71‐ to 86‐year‐old HMs, HTs, and NCs had positive Aβ PET scans, and the long‐term recall memory scores are significantly higher in the older HMs than in HT and NC groups, suggesting resistance to Aβ deposition in those HMs who remained unimpaired at older ages.ConclusionsThis study provides information about Aβ plaque burden, tau tangle burden, and neurodegeneration in cognitively unimpaired persons at three levels of genetic risk for AD. Unimpaired APOE ε4 HMs can be studied before their 70s to evaluate the understanding of factors, processes, and interventions involved in the predisposition to and prevention of AD, and after their 70s, to discover factors, processes, and interventions involved in the resilience or resistance to and prevention of AD.