Higher Risk Of Alzheimer's Disease Research Articles

Haplotype architecture of the Alzheimer's risk in the APOE region via co-skewness.

IntroductionAs a multifactorial polygenic disorder, Alzheimer's disease (AD) can be associated with complex haplotypes or compound genotypes.MethodsWe examined associations of 4960 single nucleotide polymorphism (SNP) triples, comprising 32 SNPs from five genes in the apolipoprotein E gene (APOE) region with AD in a sample of 2789 AD‐affected and 16,334 unaffected subjects.ResultsWe identified a large number of 1127 AD‐associated triples, comprising SNPs from all five genes, in support of definitive roles of complex haplotypes in predisposition to AD. These haplotypes may not include the APOE ε4 and ε2 alleles. For triples with rs429358 or rs7412, which encode these alleles, AD is characterized mainly by strengthening connections of the ε4 allele and weakening connections of the ε2 allele with the other alleles in this region.DiscussionDissecting heterogeneity attributed to AD‐associated complex haplotypes in the APOE region will target more homogeneous polygenic profiles of people at high risk of AD.

Semantic loss marks early Alzheimer's disease-related neurodegeneration in older adults without dementia.

ObjectiveTo assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)‐specific neurodegeneration using longitudinal multimodal neuroimaging measures.MethodsChange in verbal fluency was analyzed among 2261 non‐demented individuals with a follow‐up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non‐amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow‐up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18F‐fluorodeoxyglucose brain positron emission tomography (18F‐FDG‐PET) imaging (n = 756) using linear regression models across 2 years of follow‐up.ResultsSemantic fluency declined—fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)—while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18F‐FDG‐PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus–posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole‐brain neurodegeneration over time was associated with faster decline in both fluencies, while AD‐specific regions were associated with a faster rate of decline in semantic but not letter fluency.InterpretationThis study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD‐specific neurodegeneration.

Serum HDL Associated Antioxidant Activity in Alzheimer's Disease: Paraoxonase1 and Dysfunctional HDL.

Human serum paraoxonase1 (PON1) is a high-density lipoprotein (HDL) associated antioxidant enzymes. We aimed to research the PON1 activity in Alzheimer's disease (AD) not accompanied with any disorders and other conditions influencing the PON1 activity. We studied the PON1 activity and PON1 related lipid parameters in two groups, probable sporadic late onset AD (n:30) and those with healthy subjects (n:32). These groups were homogeneous, in which the subjects did not have any cardiovascular risk factors or other conditions affecting PON1 activity. We found increased high-density lipoprotein cholesterol (HDL-C) and significantly decreased PON1 activity in the AD patients. A patient with a PON1 activity value of ≤ 151 U/L had a 5.48-fold higher risk for AD, compared to those with a PON1 activity value of > 151 U/L. Decreased PON1 activity may play a role in the oxidative stress (OS) related pathogenesis of AD. An increased HDL-C with the decreased PON1 activity may bring the concept of dysfunctional HDL into question in the pathogenesis of AD. It may be emphasized in the pathogenesis of AD for further studies.

Body mass index is associated with smaller medial temporal lobe volume in those at risk for Alzheimer's disease.

Body mass index (BMI) has a complex relationship with Alzheimer's disease (AD); in midlife, high BMI is associated with increased risk for AD, whereas the relationship in late-life is still unclear. To clarify the relationship between late-life BMI and risk for AD, this study examined the extent to which genetic predisposition for AD moderates BMI and AD-related biomarker associations. Participants included 126 cognitively normal older adults at baseline from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Genetic risk for AD was assessed via polygenic hazard score. AD-related biomarkers assessed were medial temporal lobe volume and cerebrospinal fluid (CSF) biomarkers. Hierarchical linear regressions were implemented to examine the effects of BMI and polygenic hazard score on AD-related biomarkers. Results showed that BMI moderated the relationship between genetic risk for AD and medial temporal lobe volume, such that individuals with high BMI and high genetic risk for AD showed lower volume in the entorhinal cortex and hippocampus. In sex-stratified analyses, these results remained significant only in females. Finally, BMI and genetic risk for AD were independently associated with CSF biomarkers of AD. These results provide evidence that high BMI is associated with lower volume in AD-vulnerable brain regions in individuals at genetic risk for AD, particularly females. The genetic pathways of AD may be exacerbated by high BMI. Environmental and genetic risk factors rarely occur in isolation, which underscores the importance of looking at their synergistic effects, as they provide insight into early risk factors for AD that prevention methods could target.

Association of Age-Related Macular Degeneration on Alzheimer or Parkinson Disease: A Retrospective Cohort Study

To determine the association of age-related macular degeneration (AMD) with Alzheimer disease (AD) and Parkinson disease (PD). Retrospective cohort study. The study population consisted of 308,340 participants aged 50 years or older from the Korean National Health Insurance Service-Health Screening Cohort. After exclusion of participants with AMD during 2002, participants were detected for AMD during 2003-2005. Starting from January 1, 2006, all participants were followed up for AD and PD until December 31, 2013. Multivariate Cox proportional hazards regression was used to calculate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for AD and PD risk. Compared to non-AMD participants, AMD patients had higher risk for AD (aHR 1.48, 95% CI 1.25-1.74) and PD (aHR 1.46, 95% CI 1.14-1.88). The risk-increasing association of AMD with AD (aHR 2.25, 95% CI 1.39-3.66) and PD (aHR 2.02, 95% CI 1.00-4.08) were preserved among participants who were never-smokers, did not consume alcohol, and exercised regularly. Finally, AMD was associated with higher risk of AD (aHR 1.96, 95% CI 1.46-2.65 for age <70 years and aHR 1.53, 95% CI 1.26-1.86 for age ≥70 years) and PD (aHR 1.90, 95% CI 1.29-2.80 for age <70 years and aHR 1.47, 95% CI 1.06-2.04 for age ≥70 years) according to subgroups divided by age. Compared to non-AMD participants, AMD patients had higher risk for AD and PD even among those with healthy lifestyle behaviors. Patients with AMD must be closely monitored for possible subsequent development of AD or PD.

The relationship between cognitive impairment and homocysteine in a B12 and folate deficient population in China: A cross-sectional study.

Alzheimer disease (AD) is the most common neurodegenerative disease in the world. The relationship between AD and homocysteine (Hcy) is contradictory.A community-based investigation was conducted to find patients with AD in a vitamin B deficient population (≥55 years old) in Lüliang area in China. Venous blood samples were collected. Serum Hcy, folate, and vitamin B12 were measured. For each case, 4 controls were selected matched with age to evaluate the relationship between Hcy and AD.The crude prevalence of AD among people ages 55 years or older in this area was 8.60%. There were significant differences in serum Hcy and B12 between the case and control groups. We found that the higher level of serum Hcy was associated with a high risk of AD, and higher education level, higher folate and B12 concentration were protective factors to AD.Adjustment of diet structure and supplementation of folate and B12 may offer potential therapeutic measures in this area.

Associations between neighborhood built environment and cognition vary by apolipoprotein E genotype: Multi-Ethnic Study of Atherosclerosis.

We examined whether neighborhood built environment (BE) and cognition associations in older adults vary by apolipoprotein E (APOE) genotype, a genetic risk factor for Alzheimer's disease (AD). We conducted a cross-sectional analysis of 4091 participants. Neighborhood characteristics included social and walking destination density (SDD, WDD), intersection density, and proportion of land dedicated to retail. Individuals were categorized as APOE ε2 (lower AD risk), APOE ε4 (higher AD risk), or APOE ε3 carriers. Among APOE ε2 carriers, greater proportion of land dedicated to retail was associated with better global cognition, and greater SDD, WDD, intersection density, and proportion of land dedicated to retail was associated with better processing speed. These associations were not observed in APOE ε3 or ε4 carriers. APOE ε2 carriers may be more susceptible to the potentially beneficial effects of denser neighborhood BEs on cognition; however, longitudinal studies are needed.

Neurometabolic Evidence Supporting the Hypothesis of Increased Incidence of Type 3 Diabetes Mellitus in the 21st Century.

The most recent evidence supports the existence of a link between type 2 diabetes (T2DM) and Alzheimer's Disease (AD), described by the new term: type 3 diabetes (T3D). The increasing incidence of T2DM in the 21st century and accompanying reports on the higher risk of AD in diabetic patients prompts the search for pathways linking glycemia disturbances and neurodegeneration. It is suggested that hyperglycemia may lead to glutamate-induced excitotoxicity, a pathological process resulting from excessive depolarization of membrane and uncontrolled calcium ion influx into neuronal cells. On the other hand, it has been confirmed that peripheral insulin resistance triggers insulin resistance in the brain, which may consequently contribute to AD by amyloid beta accumulation, tau phosphorylation, oxidative stress, advanced glycation end products, and apoptosis. Some literature sources suggest significant amylin involvement in additional amyloid formation in the central nervous system, especially under hyperamylinemic conditions. It is particularly important to provide early diagnostics in people with metabolic disturbances, especially including fasting insulin and HOMA-IR, which are necessary to reveal insulin resistance. The present review reveals the most recent and important evidence associated with the phenomenon of T3D and discusses the potential lacks of prevention and diagnostics for diabetes which might result in neurometabolic disorders, from a pharmacotherapy perspective.

A Novel Ensemble-Based Machine Learning Algorithm to Predict the Conversion From Mild Cognitive Impairment to Alzheimer's Disease Using Socio-Demographic Characteristics, Clinical Information, and Neuropsychological Measures.

Background: Despite the increasing availability in brain health related data, clinically translatable methods to predict the conversion from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) are still lacking. Although MCI typically precedes AD, only a fraction of 20–40% of MCI individuals will progress to dementia within 3 years following the initial diagnosis. As currently available and emerging therapies likely have the greatest impact when provided at the earliest disease stage, the prompt identification of subjects at high risk for conversion to AD is of great importance in the fight against this disease. In this work, we propose a highly predictive machine learning algorithm, based only on non-invasively and easily in-the-clinic collectable predictors, to identify MCI subjects at risk for conversion to AD.Methods: The algorithm was developed using the open dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), employing a sample of 550 MCI subjects whose diagnostic follow-up is available for at least 3 years after the baseline assessment. A restricted set of information regarding sociodemographic and clinical characteristics, neuropsychological test scores was used as predictors and several different supervised machine learning algorithms were developed and ensembled in final algorithm. A site-independent stratified train/test split protocol was used to provide an estimate of the generalized performance of the algorithm.Results: The final algorithm demonstrated an AUROC of 0.88, sensitivity of 77.7%, and a specificity of 79.9% on excluded test data. The specificity of the algorithm was 40.2% for 100% sensitivity.Conclusions: The algorithm we developed achieved sound and high prognostic performance to predict AD conversion using easily clinically derived information that makes the algorithm easy to be translated into practice. This indicates beneficial application to improve recruitment in clinical trials and to more selectively prescribe new and newly emerging early interventions to high AD risk patients.

Association of PPP2R1A with Alzheimer's disease and specific cognitive domains

In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease (AD), a genome-wide association study was performed on a population isolate from Eastern Canada, referred to as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 is associated with higher AD risk and younger age at AD onset in APOE4− individuals. After surveying the region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when compared with age-matched controls. Using an independent cohort of cognitively normal individuals with a parental history of AD, we found that the rs10406151 C variant is significantly associated with lower visuospatial and constructional performances. The association of the rs10406151 C variant with AD risk appears to involve brain PPP2R1A gene expression alterations. However, the exact pathological pathway by which this variant modulates AD remains elusive.

Semantic network function captured by word frequency in nondemented APOE ε4 carriers.

Accurate identification of the earliest cognitive changes associated with Alzheimer's disease (AD) is critically needed. Item-level information within tests of category fluency, such as lexical frequency, harbors valuable information about the integrity of semantic networks affected early in AD. To determine the potential of lexical frequency as a cognitive marker of AD risk, we investigated whether lexical frequency of animal fluency output differentiated APOE ε4 carriers from noncarriers in a cross-sectional design among older African-American adults without dementia. We analyzed animal fluency performance using mean number of items and mean lexical frequency among 230 cognitively normal African Americans with and without the APOE ε4 allele. Lexical frequency was higher in APOE ε4 carriers than noncarriers when analyzed as a mean score and within time bins. In contrast, we found no group difference in the number of items produced. Lexical frequency was particularly sensitive to ε4 status after the first 10 s of the 60-s animal fluency task. Our results suggest that psycholinguistic features may hold value as a cognitive biomarker for identifying people at high risk of AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Amyloid-β immunotherapy for alzheimer disease: Is it now a long shot?

The amyloid-β (Aβ) cascade hypothesis of Alzheimer disease (AD) holds that brain accumulation of Aβ initiates the disease process. Accordingly, drug research has targeted Aβ production, clearance, and deposition as therapeutic strategies. Unfortunately, candidate drugs have failed to show clinical benefit in established, early, or prodromal disease, or in those with high AD risk. Currently, monoclonal antibodies specifically directed against the most neurotoxic Aβ forms are undergoing large-scale trials to confirm initially encouraging results. However, recent findings on the normal physiology of Aβ suggest that accumulation may be compensatory rather than the pathological initiator. If this is true, alternative strategies will be needed to defeat this devastating disease. ANN NEUROL 2019;85:303-315.

Identifying multiple domain memory impairment in high-risk group for Alzheimer's disorder

Introduction: Occasional lapses in memory in elderly people are often considered as normal aging process and not a warning sign of serious mental deterioration or Alzheimer's disease (AD). When memory loss becomes so pervasive and severe that it disrupts daily activities, it becomes a signal for early AD. As the disease is irreversible and progressive in nature, identification of persons with high risk of developing AD is becoming a priority. The objective of this study was to identify and characterize the deficits in the memory performance of patients who presented with memory difficulties, without any other significant cognitive decline, and identified with high risk. Subject and Methods: Consecutive patients of both sexes in the age range of 55–70 years, who presented with problem in memory, were screened on the Mini–Mental State Examination and further assessed on the Dementia Rating Scale. Patients identified with high risk for AD were assessed for their memory profile using the PGI Memory Scale and further compared with healthy controls. Results: The high-risk group performed significantly lower than controls in domains of recent memory, delayed recall, verbal retention for dissimilar pairs, visual retention, and recognition. Conclusion: Multiple memory domains are affected in high-risk group for AD. Although they did not qualify to be diagnosed with AD, their memory profile is distinct with healthy controls and may be indicative of proneness for the disease.

Understanding the Correlation between Alzheimer’s Disease Polygenic Risk, Wealth, and the Composition of Wealth Holdings

We investigate how genetic risk of developing Alzheimer's Disease (AD) relates to saving behavior. Using nationally representative data from the 1992-2014 Health and Retirement Study (HRS), we find that genetic predisposition for AD correlates with, but is not causally related to older individuals’ wealth holdings. People with higher Alzheimer’s Disease polygenic risk score (PGS) hold roughly 9 percent more wealth in CDs (hands-off assets) and around 11 percent, 15 percent, and 7 percent less wealth in stocks, IRAs, and other financial assets (hands-on assets) respectively. We explore three hypotheses that could explain these correlations. We hypothesize that people with high risk of AD choose different portfolios: (i) because they know their polygenic risk of developing Alzheimer’s Disease and related dementia, (ii) because they have lower cognitive capacity, and (iii) because the genome-wide association studies (GWAS) process that generated the Alzheimer’s Disease PGS failed to fully account for the aging process. Our extended model results show that the first two hypotheses do not account for the observed correlation. Consistent with the third hypothesis, the interaction between age and the Alzheimer’s Disease PGS does explain the correlation between genetic traits and asset holdings.

An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer's disease—A cohort study of 95,442 individuals

IntroductionWe tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimer's disease (AD). MethodsWe studied 95,442 individuals enrolled in the Copenhagen General Population Study. In genetic analyses, we further included 8367 individuals from the Copenhagen City Heart Study. In the two studies, 1189 and 35 developed AD during median 8 years follow-up. ResultsThe multifactorially adjusted hazard ratio for risk of AD for a one standard deviation lower levels of complement C3 was 1.11 (95% confidence interval: 1.04–1.19) in all individuals and 1.66 (1.33–2.07) in APOE ε44 carriers. In Mendelian randomization, the corresponding genetic estimates were 1.66 (1.05–2.63) overall and 1.99 (0.52–7.65) in APOE ε44 carriers. DiscussionLow baseline levels of complement C3 were associated with high risk of AD. The risk was amplified in APOE ε44 highly susceptible individuals, and these findings were substantiated by a Mendelian randomization approach, potentially implying causality. Based on these findings, we present and thoroughly discuss an updated Alzheimer hypothesis incorporating low complement C3 levels.

Dysbiosis of gut microbiota and Alzheimer’s Disease

Alzheimer's Disease (AD) is a degenerative,&amp;nbsp;chronic, progressive disease of CNS. Pathological&amp;nbsp;changes that develop in the course of the disease lead to&amp;nbsp;memory loss, alteration of thought, and deterioration of&amp;nbsp;other brain functions. The disease progresses slowly,&amp;nbsp;resulting in cell death and brain damage (Jiang 2017;&amp;nbsp;Knopman 2016).&amp;nbsp;Increased permeability of the intestinal and blood&amp;nbsp;brain barrier due to microbial dysbosis plays a role in&amp;nbsp;the pathogenesis of AD and other neurodegenerative&amp;nbsp;disorders associated with aging. In addition, intestinal&amp;nbsp;microbiota bacterial populations secrete amyloids and&amp;nbsp;lipopolysaccharides in large quantities, which may&amp;nbsp;contribute to the modulation of signaling pathways and&amp;nbsp;the production of proinflammatory cytokines associated&amp;nbsp;with the pathogenesis of AD (Jiang 2017). Amyloid&amp;nbsp;precursor protein (APP) , which constitutes Aβ plaques&amp;nbsp;and is normally secreted by intestinal bacteria, is&amp;nbsp;expressed by the enteric nervous system. However, the&amp;nbsp;accumulation corrupts the CNS functions. Escherichia&amp;nbsp;Coli and Salmonella Enterica are some of the many&amp;nbsp;bacterial strains that express and secrete APP and play a&amp;nbsp;role in the pathogenesis of AD (Tse 2017).&amp;nbsp;Production and clearance of Aβ in CNS is a&amp;nbsp;dynamic change and some bacteria and fungi are&amp;nbsp;amyloid secretions, which disrupt the dynamic balance&amp;nbsp;of Aβ protein in CNS and increase the amyloid levels.&amp;nbsp;This causes Aβ protein accumulation in the brain and a&amp;nbsp;high risk of AD (Hill 2015).It is very important for&amp;nbsp;cognitive function in serotonin, 95% of serotonin is&amp;nbsp;synthesized in intestines and intestinal microorganisms&amp;nbsp;play an important role in the synthesis of serotonin.&amp;nbsp;There is evidence that serotonin may reduce the&amp;nbsp;formation of Aβ plaques and thus reduce AD risk (Hill&amp;nbsp;2015; Jiang 2017).

APOE and Alzheimer's Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer's Pathogenesis.

Alzheimer's disease (AD) is an immutable neurodegenerative disease featured by the two hallmark brain pathologies that are the extracellular amyloid ß (Aß) and intraneuronal tau protein. People carrying the APOE4 allele are at high risk of AD concerning the ones carrying the ε3 allele, while the ε2 allele abates risk. ApoE isoforms exert a central role in controlling the transport of brain lipid, neuronal signaling, mitochondrial function, glucose metabolism, and neuroinflammation. Regardless of widespread indispensable studies, the appropriate function of APOE in AD etiology stays ambiguous. Existing proof recommends that the disparate outcomes of ApoE isoforms on Aβ accretion and clearance have a distinct function in AD pathogenesis. ApoE-lipoproteins combine diverse cell-surface receptors to transport lipids and moreover to lipophilic Aβ peptide, that is believed to begin deadly events that generate neurodegeneration in the AD. ApoE has great influence in tau pathogenesis, tau-mediated neurodegeneration, and neuroinflammation, as well as α-synucleinopathy, lipid metabolism, and synaptic plasticity despite the presence of Aβ pathology. ApoE4 shows the deleterious effect for AD while the lack of ApoE4 is defensive. Therapeutic strategies primarily depend on APOE suggest to lessen the noxious effects of ApoE4 and reestablish the protective aptitudes of ApoE. This appraisal represents the critical interactions of APOE and AD pathology, existing facts on ApoE levels in the central nervous system (CNS), and the credible active stratagems for AD therapy by aiming ApoE. This review also highlighted utmost ApoE targeting therapeutic tactics that are crucial for controlling Alzheimer's pathogenesis.

Differential effects of completed and incomplete pregnancies on the risk of Alzheimer disease.

To investigate the effects of completed pregnancy with childbirth and incomplete pregnancy without childbirth on the late-life cognition and the risk of Alzheimer disease (AD) in women. Using the pooled data of 3,549 women provided by 2 population-based cohort studies, we conducted logistic regression analyses to examine retrospectively the associations of completed and incomplete pregnancy with the risks of mild cognitive impairment and AD. For women without dementia, we also conducted analyses of covariance to examine the associations of completed and incomplete pregnancy with Mini-Mental State Examination (MMSE) score. Grand multiparous women who experienced ≥5 completed pregnancies showed an ≈1.7-fold higher risk of AD than those who experienced 1 to 4 completed pregnancies (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.04-2.72), while those who had incomplete pregnancies showed half the level of AD risk compared with those who never experienced an incomplete pregnancy (OR 0.43, 95% CI 0.24-0.76 for 1 incomplete pregnancy; OR 0.56, 95% CI 0.34-0.92 for ≥2 incomplete pregnancies). In women without dementia, the grand multiparous had worse MMSE scores than those with 1 to 4 completed pregnancies (p < 0.001), while those who experienced ≥1 incomplete pregnancies had better MMSE scores than those who never experienced an incomplete pregnancy (p = 0.008). Grand multiparity was associated with high risk of AD, while incomplete pregnancy was associated with low risk of AD in late life.

Dietary Fat Intake and Risk of Alzheimer's Disease and Dementia: A Meta-Analysis of Cohort Studies.

Epidemiological studies showed that dietary fat intake is associated with Alzheimer's disease (AD) and dementia risk, however, the association remain inconsistent. This metaanalysis aimed to systematically examine the association of dietary fat intake with AD and dementia risk. We have systematically searched PubMed, Embase and the Cochrane Library up to May 1st 2017. Prospective cohort studies were included if they reported on the association of dietary fat intake with AD and dementia risk. Multivariate-adjusted relative risks (RRs) for the highest versus lowest category were pooled by using a random-effects model. A total of 8630 participants and 633 cases from four independent prospective cohort studies were included in the present meta-analysis. A higher dietary saturated fat intake was significantly associated with an increased risk of 39% and 105% for AD (RR: 1.39; 95% CI: 1.00, 1.94) and dementia (RR: 2.05; 95% CI: 1.06, 3.98), respectively. Dose-response analysis indicated a 4 g/day increment of saturated fat intake was related to 15% higher risk of AD (RR: 1.15; 95% CI: 1.01, 1.31). However, there was no significant association found between dietary intake of total, monounsaturated, polyunsaturated fat and AD or dementia risk. This meta-analysis provides significant evidence of positive association between higher saturated fat intake and AD and dementia risk.

Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention.

Humans possess three genetic isoforms of apolipoprotein E (ApoE)-ApoE2, ApoE3, and ApoE4-that confer differential risk for Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. This study sought to investigate the impact of human ApoE isoforms on brain energy metabolism, an area significantly perturbed in preclinical AD. A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism, focusing on pathways leading to the generation of acetyl-CoA, in human ApoE gene-targeted replacement female mice. Consistent with our previous findings, brains expressing ApoE2 exhibited the most robust profile, whereas brains expressing ApoE4 displayed the most deficient profile on the uptake and metabolism of glucose, the primary fuel for the brain. Specifically, the three ApoE brains differed significantly in facilitated glucose transporters, which mediate the entry of glucose into neurons, and hexokinases, which act as the "gateway enzyme" in glucose metabolism. Interestingly, on the uptake and metabolism of ketone bodies, the secondary energy source for the brain, ApoE2 and ApoE4 brains showed a similar level of robustness, whereas ApoE3 brains presented a relatively deficient profile. Further, ingenuity pathway analysis indicated that the PPAR-γ/PGC-1α signaling pathway could be activated in the ApoE2 brain and inhibited in the ApoE4 brain. Notably, PGC-1α overexpression ameliorated ApoE4-induced deficits in glycolysis and mitochondrial respiration. Overall, our data provide additional evidence that human ApoE isoforms differentially modulate brain bioenergetic metabolism, which could serve as a potential mechanism contributing to their discrete risk impact in AD.SIGNIFICANCE STATEMENT We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.