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The goal of this study was to examine the association of the APOE ε4 allele with the late-life cognitive trajectory and test the hypothesis that the association of ε4 with cognitive decline is explained by Alzheimer's disease (AD) neuropathology. Participants (N = 581) came from 2 longitudinal clinical-pathologic studies of aging and dementia, the Religious Orders Study (ROS) and the Memory and Aging Project (MAP). Longitudinal measures of cognition were derived from detailed annual neuropsychological testing. Uniform neuropathologic evaluations provided quantitative measures of AD pathology, chronic cerebral infarctions, and Lewy bodies. Participants with 1 or more copies of the ε4 allele (ε2/4 excluded) were considered ε4 carriers. Random change point models were applied to examine the association of the ε4 allele with onset of terminal decline as well as preterminal and terminal slopes. On average, the onset of terminal decline occurred around 3 years before death, and the rate of terminal decline was eightfold faster than the preterminal decline. The presence of the ε4 allele was associated with an earlier onset of terminal decline and faster rates of decline before and after its onset. After adjusting for AD pathology, the ε4 allele was no longer associated with onset of terminal decline or preterminal slope, and the association with terminal slope became marginal. The APOE ε4 allele is an important determinant of late-life change in cognition, including terminal decline, and works primarily through AD pathology. [ABSTRACT FROM AUTHOR]

Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood., Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species., Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively., Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Carrying the apoE ε4 allele (E4+) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4 − ), E4+ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance in n-3 DHA metabolism in E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+v. E4 − . A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4 − . In E4+, mean plasma [13C]DHA was 31 % lower than that in E4 − , and cumulative β-oxidation of [13C]DHA was higher than that in E4 − 1–28 d post-dose (P≤ 0·05). A genotype × time interaction was detected for cumulative β-oxidation of [13C]DHA (P≤ 0·01). The whole-body half-life of [13C]DHA was 77 % lower in E4+ compared with E4 − (P≤ 0·01). In E4+ and E4 − , the percentage dose of [13C]DHA recovered/h as 13CO2 correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117 % steeper in E4+ compared with E4 − (P≤ 0·05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of 13C-labelled fatty acids other than DHA cannot be deduced from the present study. [ABSTRACT FROM PUBLISHER]

Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia and is responsible for significant individual morbidity and mortality, and economic impact on the health care system. Neurodegeneration (including neuronal atrophy and/ or loss) are attributed to extraneuronal toxic amyloid oligomers and proteins, intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau, region-specific diminished cerebral glucose metabolism, synaptic dysfunction, and mitochondrial dysfunction. Several of these pathologic changes may occur decades before symptom onset, leaving ample time for implementing prevention strategies that target the earliest stages of the disease. In recent years, a myriad of modifiable and nonmodifiable risk factors have been elucidated.We describe the latest criteria for the diagnosis of AD, including earliest diagnostic stage of preclinical AD, which has the highest potential for research, including diagnosis and disease modification. We discuss both FDA-approved pharmacologic treatments, as well as nonpharmacologic strategies for AD therapeutics, including prevention via evidence-based, low-risk interventions. Genotype is an important consideration in managing patients on the AD continuum, as presence of the APOE ε4 allelemay influence response to treatment.We present the most current evidence relating to pharmacogenomics, nutrigenomics, and distinctive nutritional requirements targeted toward AD. [ABSTRACT FROM AUTHOR]

We assessed the interaction between the APOE ε4 allele and education level in the etiology of Alzheimer's disease (AD) among memory clinic patients from the multicenter DESCRIPA study. Subjects (n = 544) were followed for 1 to 5 years. We used Cox's stratified survival modeling, adjusted for age, gender, and center. APOE ε4 predicted the onset of AD-type dementia in middle (HR 3.45 95% CI 1.79-6.65, n = 222) and high (HR 3.67 95% CI 1.36-9.89, n = 139) but not in low educated subjects (HR 0.81, 95% CI 0.38-1.72, n = 183). This suggests that mechanisms in developing Alzheimer-type dementia may differ between educational groups that raises questions related to Alzheimer-type dementia prevention. [ABSTRACT FROM AUTHOR]

Abstract: Cognitive impairment implicates many factors beyond phenytoin monotherapy in patients with epilepsy. Apolipoprotein E ε4 allele has been reported to play a role in severe memory impairment that ultimately progresses to Alzheimer''s disease (AD); however, knowledge about its role in cognitive impairment in patients with epilepsy is lacking. Our study proposes the possible involvement of the APOE ε4 allele in cognitive impairment in patients with epilepsy which is further worsened by phenytoin monotherapy. Assessment of the APOE ε4 allele in a population with epilepsy will help to identify the patients vulnerable to cognitive impairment and, therefore, the corrective therapy that needs to be addressed. [Copyright &y& Elsevier]

Objective We aimed to investigate three reports of a possible role of early parental death in late onset dementia. We tested a multivariate model of risk factors for late onset dementia that included established (female sex, a family history of dementia, APOE ε4) and putative influences (vascular risk factors, years of full-time education, parental ages at death, and childhood IQ) on dementia risk. Methods We examined contributions of early life and late life risk factors for dementia by using childhood social and family data and blood samples obtained at interview at age about 78 years. In 1997-1999, we recruited 281 subjects without dementia from a 1932 Scottish IQ survey of children born in 1921 and followed them up to 2010 (at age 88). Binary logistic regression and Bayesian structural equation modelling were used to model dementia risk. Results Risk of dementia was associated with increasing age from 77 to 88 years, female sex, death of either parent before age 11 and APOE ε4 genotype. Family history of dementia, childhood IQ, years of education and vascular risk factors did not contribute to the model. Conclusions Our multivariate models of the possible causes of late onset dementia confirm previous associations of dementia with female sex and APOE ε4 genotype and supports earlier reports of a role for early parental death. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Object: In this article we tested the hypothesis that the level of two biochemical markers of brain injury may be associated with the apolipoprotein E (APOE) ε4 allele. Methods: In this prospective consecutive study patients with sTBI were included (n = 48). Inclusion criteria were Glasgow Coma Scale (GCS) score ≤ 8 at the time of intubation and sedation, patient age between 15 and 70 years, an initial cerebral perfusion pressure > 10 mmHg, and arrival to our level-one trauma university hospital within 24 h after trauma. Blood samples for neuron-specific enolase (NSE) and S-100B were collected as soon as possibly after arrival, and then twice daily (12-h intervals) for 5 consecutive days. Venous blood was used for APOE genotype determination. Clinical outcome at 3 months after injury was assessed with the Extended Glasgow Outcome Scale (GOSE). Results: Significantly higher levels of the maximal S-100B (S-100B) and area under the curve (S-100B) were found in subjects with the APOE ε4 allele compared to those with non-ε4. A similar tendency was observed for NSE and NSE, though not statistically significant. Conclusion: Our data indicate that there might be a gene-induced susceptibility to severe traumatic brain injury and that patients with the APOE ε4 allele may be more predisposed to brain cellular damage measured as S-100B and NSE. Thus, it seems to be of importance to consider the APOE genotype in interpreting the levels of the biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is a progressive, neurodegenerative disorder that impairs memory and semantic processing. AD patients and MCI patients at risk for AD show altered N400 ERP responses to incongruent visual and verbal stimuli. AD patients exhibit neuropathology in olfactory brain areas before cognitive symptoms, suggesting the potential for olfactory processing to reflect early pathology. Despite this, odor congruency has not been examined. We investigated odor–image congruency in older adults at genetic risk for AD. ApoE ε4 carriers and non-carriers were screened for anosmia, severe hyposmia, and dementia. Olfactory ERPs were measured 600–1300ms following odor–image pairs. Odors were each presented once congruently and once incongruently via an olfactometer. Pz amplitude significantly decreased on incongruent trials in e4 carriers. Pz amplitude differences on congruous and incongruous trials were larger in non carriers. Regression indicated that congruency showed very high sensitivity and specificity for correctly classifying ε4 carriers from non-carriers. [Copyright &y& Elsevier]

Primary objective: The influence of apolipoprotein (APOE) on neuropsychological outcome was investigated in 19 patients (25.79 ±± 7.22 years) with mild-to-moderate traumatic brain injury and 14 matched healthy control subjects (27.43 ±± 6.65 years). Research design: Within- and between-group comparisons were employed. Methods and procedure: APOE genotype was determined using the Polymerase Chain Reaction--Restriction Fragment Length Polymorphism method. Verbal learning and memory, speed of processing and executive function were assessed at 6 weeks and 6 months post-injury. A three-way [Group**Type**Time] ANOVA with repeated measures on the third factor was employed to determine the differences between groups and APOE genotype. Main outcomes and results: No Group**APOE Genotype**Time interaction was found for all neuropsychological measures, Auditory Verbal Learning Test ( p == 0.484, ηη2 == 0.017), Trail Making Test-B ( p == 0.454, ηη2 == 0.019), Controlled Oral Word Association ( p == 0.107, ηη2 == 0.087) and Wisconsin Card Sorting Test-64 ( p == 0.291, ηη2 == 0.038). The results of this pilot study support earlier findings that showed no relationship between APOE εε4 and poor recovery in the same population. Conclusion: The preliminary findings suggest no clear APOE genotype influence on neuropsychological outcome in mild and moderate TBI patients. Large-scale studies with longer follow-up duration are warranted. [ABSTRACT FROM AUTHOR]

Abstract: Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis ( HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 ( AGTR1) c.1166A →→ C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens'' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ℇε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A →→ C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ℇε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML. [ABSTRACT FROM AUTHOR]

Background: Late-onset Alzheimer disease (LOAD) is a clinically heterogeneous complex disease defined by progressively disabling cognitive impairment. Psychotic symptoms which affect approximately one-half of LOAD subjects have been associated with more rapid cognitive decline. However, the variety of cognitive trajectories in LOAD, and their correlates, have not been well defined. We therefore used latent class modeling to characterize trajectories of cognitive and behavioral decline in a cohort of AD subjects. Methods: 201 Caucasian subjects with possible or probable Alzheimer's disease (AD) were evaluated for cognitive and psychotic symptoms at regular intervals for up to 13.5 years. Cognitive symptoms were evaluated serially with the Mini-mental State Examination (MMSE), and psychotic symptoms were rated using the CERAD behavioral rating scale (CBRS). Analyses undertaken were latent class mixture models of quadratic trajectories including a random intercept with initial MMSE score, age, gender, education, and APOE ε4 count modeled as concomitant variables. In a secondary analysis, psychosis status was also included. Results: AD subjects showed six trajectories with significantly different courses and rates of cognitive decline. The concomitant variables included in the best latent class trajectory model were initial MMSE and age. Greater burden of psychotic symptoms increased the probability of following a trajectory of more rapid cognitive decline in all age and initial MMSE groups. APOE e4 was not associated with any trajectory. Conclusion: Trajectory modeling of longitudinal cognitive and behavioral data may provide enhanced resolution of phenotypic variation in AD. [ABSTRACT FROM AUTHOR]

Objective: Se is an essential trace element in human nutrition associated with antioxidant activity. Previous studies on predictors of toenail Se or serum Se have mostly concentrated on demographic factors such as age and gender. The present paper examines the association between apoE genotype and Se levels in nail samples in a rural elderly Chinese cohort. Design: Two thousand Chinese aged 65 years and over from four counties in China were enrolled in a cohort to study the association of Se with cognitive decline. Nail samples were collected from each participant and analysed for Se levels. Dietary Se intake was estimated from an FFQ using Se contents measured in food items collected from each village. Blood samples on filter cards were collected and analysed for apoE genotype. Mixed-effect models were constructed with nail Se level as the dependent variable and each village as the random effect, which controlled for the potential confounding effect from correlation in Se measures obtained from participants residing in the same village. Results: In this elderly Chinese cohort, carriers of the apoE ϵ4 allele had significantly lower Se levels measured in nail samples than non-carriers after adjusting for other significant covariates and controlling for estimated dietary Se intake. There was no significant difference between the two genotypes on estimated Se dietary intake (P=0·6451). Conclusions: Future studies are needed to examine the mechanism underlying the association between the apoE ϵ4 allele and Se levels, including the role of oxidative stress and that of reduced lipid metabolism in the apoE ϵ4 carriers. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects more than 5 million Americans. Currently, a definitive and unequivocal diagnosis of AD can only be confirmed histopathogically via postmortem autopsy, demonstrating the need for objective measures of cognitive functioning for those at risk for AD. The single most important genetic risk factor of AD is the apolipoprotein E (ApoE) ℇ4 allele. The present study investigated olfactory and cognitive processing deficits in ApoE ℇ4+ individuals using a cross-modal recognition memory task and an objective electrophysiological measure, the event-related potential (ERP). Ten ℇ4+ individuals (5 M, 5 F, mean [M]= 75.1 years) and 10 age- and gender-matched ℇ4− individuals (5 M, 5 F, M = 71 years) sequentially encoded a set of 16 olfactory stimuli and were subsequently shown names of odors previously presented (targets) or not (foils). EEG activity was recorded from 19 electrodes as participants distinguished targets from foils using a two-button mouse. P3 latencies were significantly longer in ℇ4+ individuals, and intraclass correlations demonstrated differential activity between the two groups. These findings are consistent with a compensatory hypothesis, which posits that nondemented ℇ4+ individuals will expend greater effort in cognitive processing or engage in alternative strategies and therefore require greater activation of neural tissue or recruitment of different neural populations. The findings also suggest that cross-modal ERP studies of recognition memory discriminate early neurocognitive changes in ApoE ℇ4+ and ApoE ℇ4− individuals and may contribute to identifying the phenotype of persons who will develop Alzheimer's disease. [ABSTRACT FROM AUTHOR]

NF-κB, a major transcription factor controlling inflammation, is activated in Alzheimer’s disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-κB activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-κB and an amplification of the inflammatory process. Apolipoprotein E (ApoE) ε4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-κB and enhanced brain inflammation. In a case-control study in 300 AD patients and 300 healthy controls, we examined whether the CARD8 (p.C10X) polymorphism, independently or in concert with the ApoE ε4 allele, might predispose to AD. Women, but not men, carrying the CARD8 AA genotype (truncated protein) had a 2.39-fold higher risk of developing AD than subjects with the CARD8 TT genotype (full-length protein). This association with susceptibility to AD was independent of the ApoE ε4 allele. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives – Severe head injury (HI) and the apolipoprotein E (ApoE) ℇ4 allele are risk factors for dementia. The corresponding effect of falls causing HI without explicit traumatic brain injury (TBI) in association with the ApoE ℇ4 is not known. Materials and methods – Altogether 134 persons aged 70 years or older constituted a retrospective population sample, who scored ≥26 in the MiniMental State Examination (MMSE) test at baseline and were clinically examined for dementia 9 years afterward. Fall-related HI causing superficial laceration or bruises or wounds that require suturing were prospectively recorded during the 9-year follow-up. We used Cox regression with age at the diagnosis of dementia as a dependent variable. Results – Twenty-eight (21%) subjects had falls causing HI without explicit TBI, the ApoE ℇ4 allele was seen in 44 (33%), and clinical dementia was diagnosed in 25 (19%). Adjusted for the baseline MMSE score, sex and educational status, the hazard ratio for subsequent dementia in subjects having falls with HI without explicit TBI and the ApoE ℇ4 allele as compared with those who do not possess these characteristics was 2.70 (95% confidence interval, 1.02–7.16). Conclusions – According to the results of this small retrospective study, falls with HI without explicit TBI in connection with the ApoE ℇ4 allele is associated with subsequent dementia among older adults. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the frequency of apolipoprotein (APOE) alleles and determine whether APOE type 4 allele (ℇ4) was associated with edentulousness even when certain factors were controlled. Background: The APOE are important in lipid homeostasis, and APOE ℇ4 has been found in many diseases and to have a negative impact on longevity. Tooth loss is more common in ill aged subjects with low income and education. Materials and methods: In a population-based study involving 1860 subjects between 35 and 85 years 1321 dentate (mean age = 54; 54% women, 46% men) and 539 edentulous (mean age = 72; 62% women, 38% men) subjects were studied. Logistic regression was performed with dentate/edentulous as dependent variables and years of education, socio-economic status, social network, stress level, handicap from birth, 23 various diseases and APOE ℇ4 as covariates. Thereafter, APOE ℇ4 frequencies were studied in 342 dentate and 336 edentulous subjects 50–85 years of age. The subjects were matched with regard to age, gender, years of education, living condition, stress level, handicap from birth and 23 various diseases. Results: APOE allele frequency in the total group was ℇ2 = 7.8%, ℇ3 = 76.4% and ℇ4 = 15.8%. Age, living condition, years of education and APOE ℇ4 were significant covariates in edentulous subjects ( p ≤ 0.001). APOE ℇ4 in the matched groups revealed significant differences between the dentate group and the edentulous group (χ2 = 5.68; p = 0.017). There was no group effect ( F(29,648) = 0.849; p < 0.696; Wilks’ lambda = 0.963). In the dentate group, the frequencies of APOE were: ℇ2 = 8.8%, ℇ3 = 77.9% and ℇ4 = 13.3%. Corresponding frequencies of APOE in the edentulous group were: ℇ2 = 6.6%, ℇ3 = 75.4% and ℇ4 = 18.0%. Conclusion: Despite matching both groups with regard to different background factors, the edentulous group had a higher frequency of APOE ℇ4 than the dentate group. Thus, genetic factors might contribute to greater risk in developing complex oral diseases leading to tooth loss or just be an indication that the subjects in our study carrying APOE ℇ4 are more fragile. [ABSTRACT FROM AUTHOR]

Abstract: Neuroinflammation and abnormal phosphorylation of TAU proteins have been implicated in the etiology of Alzheimer''s disease (AD). Several studies have suggested the G-308A promoter polymorphism in one of the proinflammatory cytokine genes tumor necrosis factor-α (TNF-α) encoding TNF-α may be associated with AD pathogenesis. Association between the Q7R polymorphism in saitohin (STH), a gene nested within the intron of the Tau gene, has also been reported. To determine whether these two polymorphisms contribute to the risk for late-onset AD (LOAD) in Chinese, we have investigated 207 sporadic LOAD patients and 222 healthy controls. The associations of the AA genotype and A-allele with LOAD (χ 2 = 8.74, df = 1, P = 0.0031, and χ 2 = 4.47, df = 1, P = 0.035) were found. After stratifying by apolipoprotein E allele 4 (APOE ε4) status, increased LOAD risks associated with the AA genotype and A-allele only in the APOE ε4 non-carriers (χ 2 = 9.21, df = 1, P = 0.002; χ 2 = 10.02, df = 1, P = 0.0015) were seen. These results suggested that the TNF-α gene G-308A polymorphism might be a risk factor for LOAD and dependent on APOE ε4 status in Chinese. Homozygous Q/Q of STH Q7R polymorphism was the only one genotype found in either LOAD group or controls. No R allele was detected in LOAD and control groups. The extremely rare frequency of the ancestral R allele differs sharply from that observed in studies in the Caucasian population, suggesting obvious ethnic differences. [Copyright &y& Elsevier]

Objective: Cognitive impairments are common sequelae of traumatic brain injury (TBI) and are often associated with the natural process of aging. Few studies have examined the effect of both age and TBI on cognitive functioning. The purpose of this study was to compare cognitive functioning between older adults who sustained a TBI to an age-matched group of individuals without a brain injury and to determine whether the presence or absence of a genetic marker apolipoprotein ϵ (APOEϵ4 allele) accounts for additional cognitive decline in both groups examined. Methods and procedures: Cognitive performance was measured by 11 neuropsychological tests, in 54 adults with TBI aged 55 and older and 40 age-matched control participants. All participants were reexamined 2 to 5 years later. Setting: Community volunteer-based sample examined at a large, urban medical center. Main outcome measure(s): California Verbal Learning Test; Wechsler Memory Scale-III (Logical Memory I & II; Visual Reproduction I & II); Grooved Pegboard; Woodcock-Johnson Test of Cognitive Ability (Visual Matching and Cross-out); Wisconsin Card Sorting Test; Trail Making Test A & B; Conners' Continuous Performance Task; Wechsler Adult Intelligence Scale-III (Vocabulary); Controlled Oral Word Association Test; and Boston Naming Test. Results: Participants with TBI had lower scores on tests of attention and verbal memory than did participants with no disability. Neither group exhibited a significant decline in cognitive function over time. The presence of the APOE ϵ4 allele did not account for additional decline in cognitive function in either group. Conclusion(s): The findings suggest that older adults with TBI may not be at increased risk for cognitive decline over short time periods (2 to 5 years) even if they are carriers of the APOE ϵ4 allele. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that a preclinical phase of Alzheimer's disease (AD) exists several years or more prior to the overt manifestation of clinical symptoms and is characterized by subtle neuropsychological and brain changes. Identification of individuals prior to the development of significant clinical symptoms is imperative in order to have the greatest treatment impact by maintaining cognitive abilities and preserving quality of life. Functional magnetic resonance imaging (fMRI) offers considerable promise as a non-invasive tool for detecting early functional brain changes in asymptomatic adults. In fact, evidence to date indicates that functional brain decline precedes structural decline in preclinical samples. Therefore, fMRI may offer the unique ability to capture the dynamic state of change in the degenerating brain. This review examines the clinical utility of blood oxygen level dependent (BOLD) fMRI in those at risk for AD as well as in early AD. We provide an overview of fMRI findings in at-risk groups by virtue of genetic susceptibility or mild cognitive decline followed by an appraisal of the methodological issues concerning the diagnostic usefulness of fMRI in early AD. We conclude with a discussion of future directions and propose that BOLD-fMRI in combination with cerebral blood flow or diffusion techniques will provide a more complete accounting of the neurovascular changes that occur in preclinical AD and thus improve our ability to reliably detect early brain changes prior to disease onset. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate whether higher circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and α1-antichymotrypsin (ACT) are associated with worse cognitive function and decline in old age. DESIGN: Two independent population-based cohort studies. SETTING: The Rotterdam Study (mean follow-up 4.6 years) and the Leiden 85-plus Study (maximal follow-up 5 years). PARTICIPANTS: Three thousand eight hundred seventy-four individuals, mean age 72, from the Rotterdam Study, and 491 individuals, all aged 85, from the Leiden 85-plus Study. MEASUREMENTS: Both studies assessed global cognition, executive function, and memory. Linear regression analyses were used in the current study to investigate the associations between inflammatory markers and cognitive function and decline. RESULTS: In the Rotterdam Study, higher levels of CRP and IL-6 were cross-sectionally associated with worse global cognition and executive function ( P<.05). ACT was not associated with cognitive function. In the Leiden 85-plus Study, estimates were similar for CRP, although not statistically significant. Higher IL-6 levels were related to a steeper annual decline in memory function in the longitudinal analysis in the Leiden 85-plus Study ( P<.05). The effect of higher IL-6 levels on global and memory function decline was stronger in apolipoprotein E (APOE) ℇ4 carriers ( P-interaction=.01) than in those who were not ( P-interaction=.05). In the Rotterdam Study, higher IL-6 levels were related to a steeper annual decline in global cognition in APOE ℇ4 carriers only. CONCLUSION: Systemic markers of inflammation are only moderately associated with cognitive function and decline and tend to be stronger in carriers of the APOE ℇ4 allele. Systemic markers of inflammation are not suitable for risk stratification. [ABSTRACT FROM AUTHOR]

The relationship between apolipoprotein E (APOE) ε4 and change in cognition was examined in older men (n = 247; age = 75.0 ± 3.5 years) and women (n = 79; age = 70.8 ± 4.9 years) free of history of stroke. Participants were examined again 4.0 ± 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4 genotype. Men with ε4 showed greater decline in some measures of executive function and verbal memory compared to those without ε4; women with e4 showed greater decline in Trail Making test performance relative to women without the allele. A significant gender x APOE ε4 interaction was seen for change in performance on short delay cued recall. These results suggest that APOE ε4 is associated with cognitive decline differently in older adult men and women. [ABSTRACT FROM AUTHOR]

Background It is unclear whether the APOE ε4 allele is associated with distinct clinical features in dementia. Method 100 cases meeting ICD criteria for dementia were interviewed using standardized instruments and genotyped for APOE. The presence of the ε4 allele was used by a genetic algorithm neural network (GANN) to discriminate symptoms and signs. Results The GANN selected six features: gender, systolic blood pressure, absence of ankle tendon reflexes, history of weight loss, history of falls, and interviewer observed lability of mood. Using these features, a neural network discriminated cases according to ε4 highly accurately (area under receiver operating characteristic=0.83, sensitivity=0.78, specificity=0.78). Conclusions A GANN is able to discriminate a clinically distinct group of features among dementia patients who express the ε4 allele. Copyright © 2001 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The landscape of therapeutics for mild cognitive impairment and dementia is quite limited. While many single-agent trials of pharmaceuticals have been conducted, these trials have repeatedly been unable to show improvement in cognition. It is hypothesized that because Alzheimer's, like many other chronic illnesses, is not a monogenic illness, but is instead caused by the downstream effects of an individual's genetic variants interacting with each other, the environment, and lifestyle, that improving outcomes will require a personalized, precision medicine approach. This approach requires identifying and then addressing contributing genomic and other factors specific to each individual in a simultaneous fashion. Until recently, the utility of genomics as part of clinical decision-making for Alzheimer's and cognitive decline has been limited by the lack of availability of a genomic platform designed specifically to evaluate factors contributing to cognitive decline and how to respond to these factors The clinical decision support (CDS) platform used in the cases presented focuses on common variants that relate to topics including, but not limited to brain inflammation, amyloid processing, nutrient carriers, brain ischemia, oxidative stress, and detoxification pathways. Potential interventions based on the scientific literature were included in the CDS, but the final decision on what interventions to apply were chosen by each patient's physician. Interventions included supplements with "generally regarded as safe (GRAS)" rating, along with targeted diet and lifestyle modifications. We hypothesize that a personalized genomically targeted approach can improve outcomes for individuals with mild cognitive impairment who are at high risk of Alzheimer's. The cases presented in this report represent a subset of cases from three physicians' offices and are meant to provide initial proof of concept data demonstrating the efficacy of this method and provide support for this hypothesis. These patients were at elevated risk for Alzheimer's due to their apolipoprotein E ε4 status. While further prospective and controlled trials need to be done, initial case reports are encouraging and lend support to this hypothesis of the benefit of a genomically targeted personalized medicine approach to improve outcomes in individuals with cognitive decline who are at high risk for Alzheimer's., Competing Interests: AW is an employee at IntellxxDNATM. IntellxxDNATM was the genomics clinical decision support tool used in this study but has no financial interests. SH-C is the medical director of IntellxxDNA and does have ownership interest. CB is the CEO of IntellxxDNATM and does have ownership interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hausman-Cohen, Bilich, Kapoor, Maristany, Stefani and Wilcox.)

Alzheimer's disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive decline follows pathological changes including neurodegeneration on the Alzheimer's disease continuum. However, it is unclear which cognitive domains first become affected by neurodegeneration in amyloid-positive individuals and if sex or apolipoprotein ( APOE ) ε4 status differences affect this relationship., Methods: Data from 1233 cognitively unimpaired, amyloid-positive individuals 65 to 85 years of age were studied to assess the effect of hippocampal volume (HV) on cognition and to evaluate differences due to sex and APOE ε4 status., Results: Lower HV was linked with worse performance on measures of memory (free recall, total recall, logical memory delayed recall, Mini-Mental State Examination [MMSE]), executive functioning (digit symbol substitution, DSS), and the Preclinical Alzheimer's Cognitive Composite (PACC). Among both women and APOE ε4+ individuals, all cognitive measures, except MMSE, were associated with HV. DSS and PACC had the largest effect sizes in differentiating early and intermediate stage neurodegeneration., Discussion: Despite all cognitive measures being associated with HV, cognitive tests show differences in detecting early or late signs of neurodegeneration. Differences exist in association between cognition and neurodegeneration based on sex and APOE ε4 status., Competing Interests: The authors have no conflicts of interest to report except Ellen Grober, PhD, who receives a small royalty for commercial use of the Free and Cued Selective Reminding Test with Immediate Recall. The test is available at no cost for research or clinical activities from the Albert Einstein College of Medicine., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background and Purpose: The present study aimed to explore whether and how omega-3 (ω-3) supplementation could interact with genetic factors to modulate cognitive functions, amyloid pathologies, and Alzheimer's disease (AD) risk., Methods: A total of 1,670 non-demented participants (mean age 73 years, 47% females, 41% APOE ε4 carriers) were followed up for 10 years. Hierarchical regressions, linear mixed-effects models, and Cox proportional hazards models were used to examine the interaction effects of ω-3 supplementation with APOE ε4 and polygenic hazard scores, after adjusting for age, gender, education, cognitive diagnosis, insomnia, depression, anxiety, and cardiovascular risk score., Results: Individuals who progress to AD during the follow-up tend to take a shorter duration of ω-3 at baseline than those stable, for whom the difference remained significant only amongst APOE ε4 carriers (p < 0.01). The interaction term (APOE ε4 × ω-3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long-term ω-3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE ε4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of ω-3 use with memory and global cognition for APOE ε4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high-risk subjects defined by polygenic hazard scores., Conclusions: Long-term ω-3 intake may have a role in AD prevention in genetically at-risk populations., (© 2021 European Academy of Neurology.)

Introduction: There is limited and inconsistent reporting on the association between Life's Simple 7 (LS7) and dementia in the elderly population., Methods: Based on the Washington Heights-Inwood Columbia Aging Project (WHICAP), LS7 scores were estimated to assess cardiovascular health status. Associations between LS7 scores and incident dementia were investigated by Cox proportional hazards models., Results: Among 1987 subjects, 291 incident cases of dementia were identified over a median follow-up of 5.84 years. Compared with subjects in the poor cardiovascular health group (scores 0 to 5), those in intermediate (6 to 9) and optimal (10 to 14) groups had lower dementia risk, with the hazard ratio (HR; 95% confidence interval) being 0.74 (0.54 to 1.00) and 0.59 (0.38 to 0.91), respectively. These results were significant in apolipoprotein E genotype ε4 (APOE ε4) allele non-carriers but not in carriers., Discussion: Higher LS7 scores are protective for dementia, especially among the APOE ε4 noncarriers., (© 2021 the Alzheimer's Association.)

• The OSA + group demonstrated a significant cognitive decline versus the OSA- group among non-demented individuals. • In APOE ε4- group, our findings showed a significant OSA * age interaction for immediate recall of ADAS-cog11 and RVALT, but not MMSE. • No significant interaction that was observed in the APOE ε4+ individuals. We aimed to investigate whether obstructive sleep apnea (OSA) status affects the relationship between cognitive decline and age among non-demented elderly people. A total of 1422 participants (493 normal cognition and 929 amnestic mild cognitive impairment) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Based on the self-reported medical history of OSA, participants were categorized into two groups (OSA- and OSA +). Multiple linear regression models were performed to assess the effect of the OSA * Age interaction on MMSE, ADAS-cog11 and RAVLT immediate recall in non-demented group and in APOE ε4 carriers/non-carriers adjusting for gender and educational attainment. In the present study, the OSA + group demonstrated significant cognitive decline versus the OSA- group. In addition, in APOE ε4- group, our findings showed a significant OSA * age interaction for ADAS-cog11 and RVALT immediate recall, but not MMSE. No significant interaction was observed in the APOE ε4+ individuals. In conclusion, our findings implicate that OSA status may affect the association of age with cognitive impairment among non-demented older people. [ABSTRACT FROM AUTHOR]

Background: The combinatorial effect of multiple genetic factors calculated as a polygenic risk score (PRS) has been studied to predict disease progression to Alzheimer's disease (AD) from mild cognitive impairment (MCI). Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE gene. These studies may have missed the APOE genotype-specific predictability of PRS for disease progression to AD., Methods: We analyzed 732 MCI from the Alzheimer's Disease Neuroimaging Initiative cohort, including those who progressed to AD within 5 years post-baseline (n = 270) and remained stable as MCI (n = 462). The predictability of PRS including and excluding the APOE region (PRS +APOE and PRS -APOE ) on the conversion to AD and its interaction with the APOE ε4 carrier status were assessed using Cox regression analyses., Results: PRS +APOE (hazard ratio [HR] 1.468, 95% CI 1.335-1.615) and PRS -APOE (HR 1.293, 95% CI 1.157-1.445) were both associated with a significantly increased risk of MCI progression to dementia. The interaction between PRS +APOE and APOE ε4 carrier status was significant with a P-value of 0.0378. The association of PRSs with the progression risk was stronger in APOE ε4 non-carriers (PRS +APOE : HR 1.710, 95% CI 1.244-2.351; PRS -APOE : HR 1.429, 95% CI 1.182-1.728) than in APOE ε4 carriers (PRS +APOE : HR 1.167, 95% CI 1.005-1.355; PRS -APOE : HR 1.172, 95% CI 1.020-1.346)., Conclusions: PRS could predict the conversion of MCI to dementia with a stronger association in APOE ε4 non-carriers than APOE ε4 carriers. This indicates PRS as a potential genetic predictor particularly for MCI with no APOE ε4 alleles., (© 2021. The Author(s).)

Physical activity (PA) and Alzheimer's disease are associated. However, how PA influences the cerebral β-amyloid (Aβ) burden remains unclear. The aim of this study was to determine if PA levels and/or functional capacity (FC) are associated with Aβ plaque deposition, and whether these associations differed according to APOE-ε4 genotype. A total of 117 women (69.7 ± 2.6 years; 33.3% APOE-ε4-carriers) from the Women's Healthy Ageing Project cohort (WHAP) were analyzed. PA was measured using the International Physical Activity Questionnaire and, FC was evaluated using the Timed Up and Go test (TUGt). Positron emission tomography with F-18 Florbetaben was carried out to assess cerebral Aβ burden, and quantified using standardized uptake value rations. The sample was split into PA and TUGt tertiles (T1, T2 and T3), and compared according to APOE-ε4 genotype (positive/negative). There were no significant differences in Aβ accumulation according to PA tertiles and APOE-ε4 genotype. Regarding FC, APOE-ε4+ participants in the first TUGt tertile (high performance) obtained significant lower Aβ accumulations compared with the other two tertiles ( p < 0.05). Comparing between genotypes, greater Aβ depositions were found between T2 and T3 in APOE-ε4+ compared with those who were APOE-ε4- ( p < 0.05). Values of TUGt ≥ 6.5 s (APOE-ε4+) and 8.5 s (APOE-ε4-) were associated with an increased risk of having higher Aβ retention. In conclusion, low performance in TUGt is associated with a negative effect on brain pathology with increasing cerebral Aβ depositions in older women who are APOE-ε4+. In physically active older women (> 600 METs·min/week), higher PA levels are not associated with reduction in Aβ depositions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pedrero-Chamizo, Szoeke, Dennerstein and Campbell.)

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (β = -0.633), executive functioning (β = -0.566), and global fractional anisotropy (β = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: Apolipoprotein E (ApoE) ε4 is known as a genetic risk factor for Alzheimer''s disease (AD). This study investigated the prevalence of imaging abnormalities suggestive of AD in cognitively normal ApoE ε4 carriers using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and voxel-based morphometry (VBM). Forty-five cognitive normal ApoE ε4 allele carriers and 45 noncarriers underwent both FDG positron emission tomography and magnetic resonance imaging (MRI). A total of 90 normal database sets were generated for the individual 45 ε4 carriers and 45 noncarriers. Mean z-scores in the predefined AD-specific regions of interest (ROI) were calculated for each ε4 carrier and noncarrier using the individually defined normal database. The prevalence of AD-like hypometabolism and atrophy in the ε4 carriers was 8.9% and 17.7%, respectively, and did not differ significantly from those in the noncarriers (8.9%, 8.8%). The majority of ε4 carriers showed preserved FDG uptake or gray matter concentration. [Copyright &y& Elsevier]