Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid

Buckley, Rachel F.; Mormino, Elizabeth C.; Chhatwal, Jasmeer P.; Schultz, Aaron P.; Rabin, Jennifer S.; Rentz, Dorene M.; Acar, Diler; Properzi, Michael J.; Dumurgier, Julien; Jacobs, Heidi I.L.; Gómez-Isla, Teresa; Johnson, Keith A.; Sperling, Reisa A.; Hanseeuw, Bernard; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.neurobiolaging.2019.02.019

Cited by 62 publications

(78 citation statements)

References 41 publications

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“…As important context, there are known sex by APOE ε4 interactive effects, with evidence for more deleterious effects of APOE ε4 on cognition, hippocampal structure, brain function at rest, and tau pathology in women than men ([6, 39], for a recent review see [40]). The present analysis showed that men and women did not differ in number of APOE ε4 carriers and also controlled for effects of APOE ε4.…”

Section: Discussionmentioning

confidence: 99%

Cognitively normal women with Alzheimer’s disease proteinopathy show relative preservation of memory but not of hippocampal volume

et al. 2019

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BackgroundWe examined interactive effects of sex, diagnosis, and cerebrospinal fluid (CSF) amyloid beta/phosphorylated tau ratio (Aβ/P-tau) on verbal memory and hippocampal volumes.MethodsWe assessed 682 participants (350 women) from BioFINDER (250 cognitively normal [CN]; and 432 symptomatic: 186 subjective cognitive decline [SCD], 246 mild cognitive impairment [MCI]). General linear models evaluated effects of Alzheimer’s disease (AD) proteinopathy (CSF Aß/p-tau ratio), diagnosis, and sex on verbal memory (ADAS-cog 10-word recall), semantic fluency (animal naming fluency), visuospatial skills (cube copy), processing speed/attention functions (Symbol Digit Modalities Test and Trail Making Part A), and hippocampal volumes.ResultsAmyloid-positive (Aβ/P-tau+) CN women (women with preclinical AD) showed memory equivalent to amyloid-negative (Aβ/P-tau−) CN women. In contrast, Aβ/P-tau+ CN men (men with preclinical AD) showed poorer memory than Aβ/P-tau− CN men. Symptomatic groups showed no sex differences in effect of AD proteinopathy on memory. There was no interactive effect of sex, diagnosis, and Aβ/P-tau on other measures of cognition or on hippocampal volume.ConclusionsCN women show relatively preserved verbal memory, but not general cognitive reserve or preserved hippocampal volume in the presence of Aβ/P-tau+. Results have implications for diagnosing AD in women, and for clinical trials.

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Section: Discussionmentioning

confidence: 99%

Cognitively normal women with Alzheimer’s disease proteinopathy show relative preservation of memory but not of hippocampal volume

et al. 2019

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“…A later, more generalized autopsy study from Braak and colleagues also observed that women who were APOE4 carriers met the criteria for Braak stages II (entorhinal cortex) and III (hippocampus) 3 years earlier than non-carriers [104]. Several more recent studies have also reported a female-dominant effect of APOE genotype on tau levels prior to AD diagnosis [12,105,106]. In each of these studies, the authors reported that APOE4 possession increases CSF tau levels specifically in female APOE4 carriers, with two of the studies reporting that this APOE4-associated effect on CSF tau levels was only present when the women were positive for Aß pathology [105,106].…”

Section: Apoe4 Associated With Decreased Amyloid Plaque Depositionmentioning

confidence: 94%

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review

et al. 2020

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Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer’s disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4−) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4− AD patients. On the other hand, APOE4− AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4− AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.

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“…Sex difference is becoming focused in AD research field. 25,26 A new cohort with increased samples will help us to understand the effects of sex on outcomes. We could not measure blood glucose levels during the course of our study until 18 months of age, because any stressful or invasive procedure might have impacts on lifespan of our mice.…”

Section: App Nl-f/wt Knock-in; Ob/ob Mice Despite the Minimal And Comentioning

confidence: 99%

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

et al. 2019

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Abbreviations: Aβ, β-amyloid; AD, Alzheimer's disease; APP, amyloid precursor protein; CNS, central nervous system; DEA, diethylamine; GFAP, glial fibrillary acidic protein; INSR, insulin receptor; IRS1, insulin receptor substrate-1; IRS2, insulin receptor substrate-2; PDK1, pyruvate dehydrogenase kinase 1; PSD95, post-synaptic density protein 95; SYT1, synaptotagmin 1; NF-H, neurofilament heavy chain. AbstractClinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/ diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/ diabetes and AD significantly reduce life expectancy. We generated App NL-F/wt knock-in; ob/ob mice by crossing App NL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-β (Aβ) affects the lifespan of ob/ob mice. App NL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, App NL-F/wt knockin mice, and ob/ob mice. Notably, the Aβ42 levels were increased at minimum levels before deposition in App NL-F/wt knock-in mice and App NL-F/wt knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in App NL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and App NL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young App NL-F/wt knock-in; ob/ob mice. |SHINOHARA et Al.

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Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid

Cited by 62 publications

References 41 publications

Cognitively normal women with Alzheimer’s disease proteinopathy show relative preservation of memory but not of hippocampal volume

Cognitively normal women with Alzheimer’s disease proteinopathy show relative preservation of memory but not of hippocampal volume

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

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