Regular proton pump inhibitor use and incident dementia: population-based cohort study.

BACKGROUND: To examine the association between regular use of proton pump inhibitors and the risk of incident dementia, including dementia subtypes, and whether the association differs between APOE genotypes. METHODS: Based on a prospective analysis of data from the UK Biobank, 501,002 individuals (female, 54.4%) aged between 40 and 70 years, who had no prevalent dementia at baseline, were enrolled between 2006 and 2010 and followed up to 2018. We compared all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) incidence rates between proton pump inhibitor users and non-users by the Cox proportional hazard model. RESULTS: During 4,438,839 person-years of follow-up (median length of follow-up, 9.0 years), there were 2505 incident cases of all-cause dementia, including 932 cases of AD and 524 cases of VaD. The incident rate of all-cause dementia among proton pump inhibitor users was 1.06 events per 1000 person-years, compared with 0.51 events per 1000 person-years among non-users. After adjustment for multiple confounders and indications, the hazard ratios (HRs) of the proton pump inhibitor users were 1.20 (95% CI, 1.07-1.35) for incident all-cause dementia, 1.23 (95% CI, 1.02-1.49) for incident AD, and 1.32 (95% CI, 1.05-1.67) for incident VaD. In addition, the association between proton pump inhibitor use and all-cause dementia differed by APOE genotype (P for interaction = 0.048). Among APOE ε4 heterozygotes, the fully adjusted HR of proton pump inhibitor use was 1.46 (95% CI, 1.22-1.75) and 1.68 (95% CI, 1.36-2.07), especially for individuals aged 65 years and older. CONCLUSIONS: The finding of this large population-based cohort study indicates that the use of proton pump inhibitors is associated with an increased risk of incident dementia, particularly among APOE ε4 heterozygotes.

The anti-aging effect of velvet antler polypeptide is dependent on modulation of the gut microbiota and regulation of the PPARα/APOE4 pathway.

We investigated the anti-aging effects of velvet antler polypeptide on D-galactose (D-gal)-induced aging mice. D-gal-induced aging mice were established and randomly divided into five groups, the control, model, vitamin E (VE), velvet antler polypeptide low-dose and velvet antler polypeptide high-dose groups. The Morris water maze test was used to evaluate the learning and memory abilities of aging mice. Hippocampal neurons were observed via hematoxylin-eosin staining and transmission electron microscopy. Biochemical methods were used to detect the activities of superoxide dismutase, malonaldehyde and other enzymes and evaluate the influence of velvet antler polypeptide on the antioxidant capacity of aging mice. Using 16S rRNA gene sequencing and meristem technology, we assessed the effect of velvet antler polypeptide on aging mice's intestinal flora and fatty acid metabolism. The experimental results showed that velvet antler polypeptide could significantly improve aging mice's learning and cognitive abilities, increase the activities of superoxide dismutase, glutathione peroxidase, and catalase in the serum decrease the malonaldehyde content. Intestinal microecological analysis showed that velvet antler polypeptide could significantly increase the beneficial bacterial genus Lactobacillus abundance. Western blot analysis further demonstrated that velvet antler polypeptide could promote fatty acid metabolism by activating peroxisome proliferator-activated receptor α (PPARα) and upregulating the expression of the downstream enzymes carnitine-palmitoyl transferase-1 A and acyl-CoA oxidase 1 while downregulating that of apolipoprotein E4 (APOE4), thereby reducing fatty acid accumulation and increasing adenosine-triphosphate (ATP) production. Therefore, velvet antler polypeptide improves the intestinal microecology and activates the PPARα/APOE4 pathway to regulate fatty acid metabolism.

Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil.

OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice weekly), or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-for-height z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6) later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+), with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+) children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+) children and improved delta lactulose/mannitol. Apolipoprotein E4(-) children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may function concomitantly with gut-tropic nutrients to benefit immediate nutritional status, which can translate into better long-term cognitive outcomes.

Isoform-specific proteolysis of apolipoprotein-E in the brain.

Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE peptides are biologically active and may be produced in the brain. It is unclear if apoE proteolysis is dependent on isoform or AD status and this was addressed here. Hippocampus, frontal cortex, occipital lobe and cerebellum samples were homogenized into fractions that were soluble in Tris-buffered saline (TBS), Triton X-100 or guanidine hydrochloride and analysed for apoE fragmentation by Western blotting. Approximately 20% of apoE3 was detected as fragments and this was predominantly as a 25 kDa peptide in TBS-soluble fractions. The concentration of TBS-soluble apoE fragments was two- to three-fold higher in apoE3 compared to apoE4 subjects. This difference was observed in all areas of the brain examined and was not related to AD status. Cathepsin-D treatment generated apoE fragments that were very similar to those detected in brain, however, no apoE isoform-specific differences in susceptibility to cathepsin-D proteolysis were detected. This indicates that proteolytic processing of apoE to form soluble fragments in the human brain is dependent on apoE isoform but not AD status.

Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults.

Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.

Molecular pathology and pharmacogenomics in Alzheimer's disease: polygenic-related effects of multifactorial treatments on cognition, anxiety and depression.

Alzheimer's disease (AD) is a major problem of health in developed societies together with cardiovascular disorders and cancer. The lack of accurate diagnostic markers for early prediction and an effective therapy are the two most important problems to efficiently halt disease progression. The pharmacological treatment in AD accounts for 10-20% of direct costs, and less than 20% of AD patients are moderate responders to conventional drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. The neuropathological hallmark of AD (amyloid deposition in senile plaques, neurofibrillary tangle formation, and neuronal loss) are buth the phenotypic expression of a pathogenic process in which more than 200 genes and their products are potentially involved. Drug metabolism, and the mechanisms underlying drug efficacy and safety, are also genetically regulated complex traits in which hundreds of genes cooperatively participate. Structural and functional genomics studies demonstrate that genomic factors, probably induced by environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, might be responsible for AD pathogenic events leading to premature neuronal death. The AD population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. AD patients also differ in their genomic architecture from patients with other forms of dementia. Functional genomics studies in AD reveal that age of onset, brain atrophy, cerebrovascular hemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function, lipid metabolism dyshomeostasis, and amyloid deposition are associated with AD-related genes. Pioneering pharmacogenomics studies also demonstrate that the therapeutic response in AD is genotype-specific, with APOE-4/4 carriers as the worst responders to conventional treatments. About 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. There is a moderate accumulation of AD-related genetic variants of risk in CYP2D6 poor metabolizers and ultra-rapid metabolizers, which are the worst responders to conventional drugs. With diverse multifactorial therapies, combining different types of drugs and metabolic factors, it is partially possible to slow-down cognitive deterioration, improving non-cognitive symptoms, such as anxiety and depression, which currently aggravate cognition and increase the difficulties in disease management; however, the association of the APOE-4 allele with specific genetic variants of other genes (e.g., CYP2D6, ACE) negatively modulate the therapeutic response to multifactorial treatments affecting cognition, mood and behaviour. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic/pharmacogenomic protocols to AD research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety.

Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease.

As the major genetic risk factor for Alzheimer's disease, the apolipoprotein (apo) E4 isoform is a promising therapeutic target. ApoE4 likely contributes to Alzheimer's disease pathology by interacting with multiple factors through various pathways. Interactions with the amyloid beta peptide and the amyloid cascade, for example, may lead to cognitive decline and neurodegeneration. Alternatively, apoE4 might act independently of the amyloid beta peptide. Our working hypothesis is that apoE has isoform-specific effects on neuronal repair and remodeling. One or more injurious agents could result in neuronal damage, requiring neuronal repair or remodeling. The injurious agents (or "second hits") may be genetic, metabolic, or environmental. Potential therapeutic strategies include changing the structure of apoE4 to be more apoE3-like, inhibiting the protease that cleaves apoE4 into toxic fragments, and protecting mitochondria from apoE4 toxicity. Structural features that distinguish apoE4 and apoE3 determine their functional differences and hold the key to understanding how apoE4 is involved in Alzheimer's disease.