Cognitive resilience among APOE ε4 carriers in the oldest old

Hayden, Kathleen M.; Gaussoin, Sarah A.; Hunter, Jaimie C.; Manson, Jo Ann E.; Sachs, Bonnie C.; Shadyab, Aladdin H.; Tindle, Hilary A.; Mossavar‐Rahmani, Yasmin; Mozhui, Khyobeni; Snively, Beverly M.; Rapp, Stéphen R.; Resnick, Susan M.

doi:10.1002/gps.5199

Cited by 13 publications

(14 citation statements)

References 55 publications

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“…Reverse causality is a possible explanation as low cholesterol may be secondary to the pathophysiologic processes related to dementia itself (including altered cholesterol metabolism in the brain) [42] or may reflect worse overall health and nutrition seen in later stages of dementia. Most recently, in a study of resilience factors in APOE4-positive women, levels of total cholesterol and LDL were significantly higher in APOE4 dementia-free survivors compared with non-APOE4 carriers [43].…”

Section: Discussionmentioning

confidence: 99%

Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study

et al. 2022

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Introduction: The associations of kidney-metabolic biomarkers with cognitive impairment (CI) beyond the estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) and albuminuria levels are not well understood. In exploratory analysis, our objective was to determine the extent that three kidney-metabolic factors, previously proposed as mechanisms of CI and commonly abnormal in chronic kidney disease (CKD), were associated with prevalent CI in CKD participants, adjusted for kidney function measures. Methods: The study cohort included community-dwelling individuals aged ≥45 years with CKD (eGFR <60), not requiring dialysis, recruited from four health systems. We examined the serum biomarkers bicarbonate (CO2), TNFαR1, and cholesterol as primary exposures. A structured neuropsychological battery conducted by trained staff measured global and domain-specific cognitive performance. Logistic regression analyses estimated the cross-sectional associations between kidney-metabolic measures and global and cognitive domain-specific moderate/severe (Mod/Sev) CI, adjusted for the eGFR, urinary albumin-creatinine ratio (UACR, mg/g), demographics, comorbid conditions, and other kidney-metabolic biomarkers commonly abnormal in CKD. Results: Among 436 CKD participants with mean age 70 years, 16% were Black, the mean eGFR was 34, and the median [IQR] UACR was 49 [0.0, 378] mg/g. In adjusted models, increased TNFαR1 was associated with global Mod/Sev CI (odds ratio [95% confidence interval] = 1.40 [1.02, 1.93]; p = 0.04); low bicarbonate (CO2 <20 mEq/L) with Mod/Sev memory impairment (3.04 [1.09, 8.47]; p = 0.03), and each 10-mg/dL lower cholesterol was associated with Mod/Sev executive function/processing speed impairment (1.12 [1.02, 1.23]; p = 0.02). However, after adjustment for multiple comparisons, these associations were no longer significant nor were any other kidney-metabolic factors significant for any CI classification. Conclusion: In exploratory analyses in a CKD population, three kidney-metabolic factors were associated with CI, but after adjustment for multiple comparisons, were no longer significant. Future studies in larger CKD populations are needed to assess these potential risk factors for CI.

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Section: Discussionmentioning

confidence: 99%

Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study

et al. 2022

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“…However, it has been reported that up to 70% of cognitively normal (CN) individuals have some degree of AD pathology at death and about 30% of these CN individuals meet the criteria for intermediate or high ADNC [ 1 , 7 , 8 , 23 , 58 ]. These CN individuals with intermediate to high ADNC are often described as “cognitively resilient.” Investigations into the unique characteristics of these resilient people have ranged from studies of their clinical and lifestyle differences [ 1 , 10 , 21 , 42 ], neuropathologic differences [ 26 , 43 , 50 ], genetic differences [ 15 , 47 ], brain imaging and metabolic signatures [ 2 , 41 , 51 ], as well as their distinct synaptic characteristics and cytokine profiles [ 6 , 44 , 63 ]. Findings from these studies have revealed higher education levels in the resilient, more engagement in physical and social/mental activities [ 1 , 10 , 42 ], fewer neuropathologic comorbidities [ 1 , 26 , 43 , 50 ], single nucleotide polymorphisms (SNPs) related to immune response, as well as vascular, metabolic and mental health being associated with resilience against amyloidosis [ 15 , 47 ], imaging and metabolic signatures suggesting better maintenance of structure (cortical thickness) and function (FDG-PET) despite AD pathologic change, especially in the anterior cingulate and temporal pole [ 2 , 41 , 51 ], and synapses with fewer tau and Aβ-oligomers in the post-synaptic densities and less ApoE in the pre-synaptic synaptosomes in the resilient [ 44 , 54 , 63 ].…”

Section: Introductionmentioning

confidence: 99%

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

Walker

Dehkordi²,

Fracassi³

et al. 2022

acta neuropathol commun

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Clinical symptoms correlate with underlying neurodegenerative changes in the vast majority of people. However, an intriguing group of individuals demonstrate neuropathologic changes consistent with Alzheimer disease (AD) yet remain cognitively normal (termed “resilient”). Previous studies have reported less overall neuronal loss, less gliosis, and fewer comorbidities in these individuals. Herein, NanoString GeoMx™ Digital Spatial Profiler (DSP) technology was utilized to investigate protein expression differences comparing individuals with dementia and AD neuropathologic change to resilient individuals. DSP allows for spatial analysis of protein expression in multiple regions of interest (ROIs) on formalin-fixed paraffin-embedded sections. ROIs in this analysis were hippocampal neurofibrillary tangle (NFT)-bearing neurons, non-NFT-bearing neurons, and their immediate neuronal microenvironments. Analyses of 86 proteins associated with CNS cell-typing or known neurodegenerative changes in 168 ROIs from 14 individuals identified 11 proteins displaying differential expression in NFT-bearing neurons of the resilient when compared to the demented (including APP, IDH1, CD68, GFAP, SYP and Histone H3). In addition, IDH1, CD68, and SYP were differentially expressed in the environment of NFT-bearing neurons when comparing resilient to demented. IDH1 (which is upregulated under energetic and oxidative stress) and PINK1 (which is upregulated in response to mitochondrial dysfunction and oxidative stress) both displayed lower expression in the environment of NFT-bearing neurons in the resilient. Therefore, the resilient display less evidence of energetic and oxidative stress. Synaptophysin (SYP) was increased in the resilient, which likely indicates better maintenance of synapses and synaptic connections. Furthermore, neurofilament light chain (NEFL) and ubiquitin c-terminal hydrolase (Park5) were higher in the resilient in the environment of NFTs. These differences all suggest healthier intact axons, dendrites and synapses in the resilient. In conclusion, resilient individuals display protein expression patterns suggestive of an environment containing less energetic and oxidative stress, which in turn results in maintenance of neurons and their synaptic connections.

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“…Regarding the relationship among cognition, dyslipidemia, and APOϵ4, Reitz et al, Hayden et al, 59 and Wei et al 60 described an association among lipid metabolism, AD, and ϵ4 allele, but the mechanisms still require further research and larger sample sizes. 58 ‒ 60 …”

Section: Discussionmentioning

confidence: 99%

Association between Apoϵ4 allele and cardiometabolic and social risk factors with cognitive impairment in elderly population from Bogota

Pedraza

Camacho

Sierra

et al. 2021

Dement. neuropsychol.

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Being an ϵ4 carrier in the Apoϵ gene has been suggested as a modifying factor for the interaction between cardio-metabolic, social risk factors, and the development of cognitive impairment. Objective: The main objective of this study was to assess the existence of such interaction in a sample of Bogota’s elderly population. Methods: A cross-sectional study was conducted with 1,263 subjects older than 50 years. Each participant was diagnosed by consensus, after neuropsychological and neuropsychiatric evaluations, under a diagnosis of normal cognition, mild cognitive impairment (MCI) according to Petersen’s criteria, or dementia according to DSM-IV criteria. Apoϵ was typified and an analysis of MoCA test was performed in each group carrying or not ϵ4 allele. Results: Our study showed that 75% were women with a median age of 68 years (interquartile range 62–74 years) and a median schooling for 6 years (interquartile range 4–12 years). Dementia was related to low education level of ≤5 years OR=11.20 (95%CI 4.99–25.12), high blood pressure (HBP) OR=1.45 (95%CI 1.03–2.05), and age over 70 years OR=7.68 (95%CI 3.49–16.90), independently of being or not an ϵ4 allele carrier. Diabetic subjects with dementia carrying ϵ4 allele showed a tendency to exhibit lower scores on the MoCA test, when compared with noncarriers’ diabetic subjects with dementia. Conclusions: The presence of ϵ4 allele does not modify the relationship between cognitive impairment and the different cardio-metabolic and social risk factors, except in diabetic subjects ϵ4 carriers with dementia who showed a tendency to exhibit lower scores of the MoCA test, when compared with noncarriers’ diabetic subjects with dementia.

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Cognitive resilience among APOE ε4 carriers in the oldest old

Cited by 13 publications

References 55 publications

Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study

Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

Association between Apoϵ4 allele and cardiometabolic and social risk factors with cognitive impairment in elderly population from Bogota

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