APOE4 Allele, Sex, and Dementia Risk in Parkinson’s Disease: Lessons From a Longitudinal Cohort

Introduction The effect of APOE4 allele on dementia risk is well established in Alzheimer’s disease and Parkinson’s disease (PD). However, it is unknown if sex modifies this relationship. We sought to determine the effect of sex on the relationship between APOE4 status and incident cognitive decline in PD. Methods Data from the prospectively collected longitudinal National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set (NDS) were analyzed. The NACC develops and maintains data from approximately 29 National Institutes of Aging-funded Alzheimer's Disease Research Centers. Further details may be found at the NACC web site ( www.alz.washington.edu ). The visit at which diagnosis of PD was made was termed the baseline visit. All patients with a PD diagnosis but without dementia at the baseline visit were included in the analyses. Results Presence of APOE4 allele was associated with higher odds (OR = 7.4; P < .001) of subsequent diagnosis of dementia and with a faster time to developing dementia ( P = .04). Those with APOE4 allele were more likely to have neuropathology associated with Alzheimer’s disease than those without APOE4 allele. We did not find any difference by sex. There were no differences between Lewy body pathology or neuron loss in the substantia nigra between the 2 groups. Sex was not associated with dementia risk in PD (OR = 0.53, P = .15) or with the time to dementia onset ( P = .22). Sex did not modify the relationship between the APOE4 allele and dementia onset in PD patients ( P = .12) Conclusions APOE4 allele status in PD may be a predictor of cognitive decline in PD but does not appear to be modified by sex.

Oxidative Stress Biomarkers and Mitochondrial DNA Copy Number Associated with APOE4 Allele and Cholinesterase Inhibitor Therapy in Patients with Alzheimer’s Disease

Studies of the oxidative/anti-oxidative status in patients with Alzheimer’s disease (AD) carrying different alleles of the apolipoprotein E (APOE) gene are currently inconclusive; meanwhile, data regarding mitochondrial DNA copy number (mtCN) remain limited. We herein determined the thiobarbituric acid reactive substances (TBARS), thiols, and mtCN in blood samples of 600 AD patients and 601 controls. A significantly higher oxidative TBARS (1.64 μmol/L), lower antioxidative thiols (1.60 μmol/L), and lower mtCN (2.34 log Delta Ct) were found in the AD cohort as compared to the non-AD cohort (1.54 μmol/L, 1.71 μmol/L, 2.46 log Delta Ct). We further identified the ε4 alleles (APOE4) and separated subjects into three groups according to the number of APOE4. A significant trend was noted in the TBARS levels of both AD and non-AD cohorts, highest in the homozygous two alleles (1.86 and 1.80 μmol/L), followed by heterozygous one allele (1.70 and 1.74 μmol/L), and lowest in the no APOE4 allele (1.56 and 1.48 μmol/L). Similar trends of lower thiols and mtCN were also found in the AD cohort. In our study of the influence of cholinesterase inhibitor therapy, we found significantly reduced TBARS levels, and elevated mtCN in AD patients receiving rivastigmine and galantamine therapy. Our study demonstrates associations between the APOE4 allele and oxidative stress biomarkers and mtCN. Using cholinesterase inhibitor therapy may benefit AD patients through attenuation of oxidative stress and manipulation of the mtCN.

Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairments

Alzheimer's disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking APOE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered significantly increase in the ApoE4 contents of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with adult healthy subjects. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum thyroid hormones level and cognitive function. We analysed effects of ApoE4 in peripheral exosomes on the neurological disorders in aged or thyroidectomied young mice. Ageing-associated hypothyroidism as well as acute thyreoidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activates NLRP3 inflammasome by increasing cholesterol level in neural cells. This, in turn, affects cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, which process can represent potential therapeutic target.

Mild Cognitive Impairment is not a Valid Concept and Should be Replaced by a More Restrictive, Biologically Validated Class, Named Mild Cognitive Dysfunctions (MCD): A Nomothetic Network Approach

Background: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Aims: To clinically define and biologically validate a subgroup of aMCI subjects that take up an intermediate position between controls and AD patients. Methods: In 61 healthy controls, 60 subjects with aMCI, and 60 AD patients we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimer&rsquo;s Disease (CERAD). A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose (FBG), atherogenic index of plasma (AIP), T2DM and hypertension. Results: Clustering and nearest neighbour analyses were unable to validate the aMCI subgroup. We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioural deterioration (OBD), and a second reflecting the interactions between ApoE4, all other biomarkers, hypertension and T2DM (BIORISK). We found that 40.2% of the variance in the OBD score was explained by BIORISK, ApoE4, age and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n=45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD.Conclusions: Petersen&rsquo;s aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.

Mild cognitive impairment is not a valid concept and should be replaced by a more restrictive, biologically validated class, named Mild Cognitive Dysfunctions (MCD): a nomothetic network approach.

Background: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Aims: To clinically define and biologically validate a subgroup of aMCI subjects that take up an intermediate position between controls and AD patients. Methods: In 61 healthy controls, 60 subjects with aMCI, and 60 AD patients we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimer s Disease (CERAD). A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose (FBG), atherogenic index of plasma (AIP), T2DM and hypertension. Results: Clustering and nearest neighbour analyses were unable to validate the aMCI subgroup. We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioural deterioration (OBD), and a second reflecting the interactions between ApoE4, all other biomarkers, hypertension and T2DM (BIORISK). We found that 40.2 % of the variance in the OBD score was explained by BIORISK, ApoE4, age and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n=45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD. Conclusions: Petersen s aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.

Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.