Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure.
This study investigated whether APOE4 status moderates the association ...between elevated depressive symptoms, cognitive function, and brain structure.
Stroke- and dementia-free participants (n = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status.
Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4 + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample.
Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4 + .
Amylin, a gut-brain axis hormone, and amyloid-beta peptides (Aβ), a major component of the Alzheimer's disease (AD) brain, share several features, including similar β-sheet secondary structures, ...binding to the same receptor and being degraded by the same protease, insulin degrading enzyme (IDE). However, while amylin readily crosses the blood brain barrier (BBB) and mediates several activities including improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reaction and perhaps enhancing neural regeneration, Aβ has no known physiological functions. Thus, abundant Aβ in the AD brain could block or interfere with the binding of amylin to its receptor and hinder its functions. Recent studies using animal models for AD demonstrate that amylin and its analog reduce the AD pathology in the brain and improve cognitive impairment in AD. Given that, in addition to amyloid plaques and neurofibrillary tangles, perturbed cerebral glucose metabolism and cerebrovascular damage are the hallmarks of the AD brain, we propose that giving exogenous amylin type peptides have the potential to become a new avenue for the diagnosis and therapeutic of AD. Although amylin's property of self-aggregation may be a limitation to developing it as a therapeutic for AD, its clinical analog, pramlintide containing 3 amino acid differences from amylin, does not aggregate like human amylin, but more potently mediates amylin's activities in the brain. Pramlintide is an effective drug for diabetes with a favorable profile of safety. Thus a randomized, double-blind, placebo-controlled clinical trial should be conducted to examine the efficacy of pramlintide for AD. This review summarizes the knowledge and findings on amylin type peptides and discuss pros and cons for their potential for AD.
INTRODUCTION
The precise apolipoprotein E (APOE) ε4‐specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear.
METHODS
Plasma protein modules/cascades were analyzed using weighted ...gene co‐expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p‐tau), and brain glucose metabolism, stratified by APOE genotype.
RESULTS
The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C‐reactive protein (CRP), complement C3, and complement factor H (CFH), had dose‐dependent associations with CSF p‐tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD.
DISCUSSION
The study identifies the APOE ε4–specific CRP–C3–CFH inflammation pathway for AD, suggesting potential drug targets for the disease.
Highlights
Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.
CRP, C3, and CFH had dose‐dependent associations with CSF p‐Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.
Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.
The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) ...genotype and ACE inhibitors on AD.
This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined.
A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education.
The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.
We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 ...participants (238, normal cognition NC; 185, mild cognitive impairment MCI; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37–0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49–0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35–2.79), and correlated with all neuropsychological tests (r's = 0.13–0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10–0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.
•Baseline plasma neurofilament light was higher in Alzheimer's disease dementia than mild cognitive impairment and normal cognition.•Baseline plasma neurofilament light was associated with baseline cognitive test score and predicted subsequent decline but did not predict diagnostic conversion.•Baseline plasma total tau was higher in Alzheimer's disease dementia than mild cognitive impairment and normal cognition.•There were no statistically significant effects for baseline plasma total tau on cognitive decline or diagnostic conversion.
Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic ...variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
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