Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline

Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation. We included 16,514 Nurses' Health Study participants aged 70-81 years who were followed since 1976 and completed up to 3 telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status; TICS), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants. Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was -0.04 (95% confidence interval, -0.07 to -0.004); for current estrogen + progestin users, the mean difference was -0.05 (95% confidence interval, -0.10 to -0.002). These differences were equivalent to those observed in women who are 1-2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p interaction, 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users. Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.     

APOE genotype and cognitive functioning in a large age-stratified population sample

There is evidence that the cognitive effects of Alzheimer's disease can be seen decades before disease diagnosis. If this is the case, then the apolipoprotein E (APOE) *E4 allele might be expected to have effects on cognitive functioning earlier in the life span. To assess such effects, the authors examined data on the *E4 allele and cognitive functioning from a population sample of 6,560 Caucasians covering the age groups of 20-24, 40-44, and 60-64 years. Participants were assessed on tests of episodic memory, working memory, mental speed, reaction time, and reading vocabulary. Although performance on all tests except reading vocabulary declined across age groups, there was no effect of the APOE *E4 allele at any age. These results indicate that APOE *E4 does not have preclinical effects early in the life span on these cognitive functions. Cognitive aging effects between the ages of 20 and 64 years must not be due to preclinical Alzheimer's disease.     

ACE genotype and cognitive decline in an African-Caribbean population

The insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is believed to influence risk of cerebrovascular disease. However, associations with cognitive outcomes remain controversial. As far as we are aware, all studies to date have been carried out in white American or European populations. African-Caribbean populations have high prevalence rates of hypertension, diabetes and cerebrovascular disease but risk factors for cognitive outcomes remain under-researched. In a UK community sample of 148 African-Caribbean people aged 55–75 years, we investigated the association between ACE genotype and cognitive decline over 3 years using a battery of repeated tests. No direct association was found between ACE genotype and decline. However, the association between increased age and cognitive decline was significantly stronger in people with the ACE DD genotype (odds ratio 3.6 per 5-year increase, 95% CI: 1.9–6.7) compared to those with ID/II genotype (odds ratio 0.7, 95% CI 0.4–1.2). This interaction was particularly strong for decline in verbal memory and was not apparently mediated by vascular risk factors measured at baseline.     

Sex steroids, APOE genotype and the innate immune system

Microglia are a primary cellular component of the CNS innate immune system. Their response to conserved pathogen motifs is inherent and leads to the release of cytoactive factors that impact surrounding neurons and glia. The microglial response is modified by the local tissue environment and by "global" factors such as gender. Exposure to estrogen and testosterone, in general, down regulate microglia and peripheral macrophage function, promoting an anti-inflammatory phenotype. Other global factors, however, can "override" the gender-based effects demonstrated by estrogen or testosterone. Apolipoprotein E (APOE) genotype and the expression of specific isoforms of apolipoprotein E differentially regulate microglial and peripheral macrophage function. Our studies have shown that the presence of the APOE4 gene, a known risk factor for AD and other neurodegenerative diseases, promotes a pro-inflammatory macrophage phenotype in neonatal microglia. However, in adult mice, the APOE genotype-specific effect depends on gender. Peritoneal macrophages from female adult APOE3 and APOE4 targeted replacement mice do not demonstrate an APOE genotype-specific response, whereas adult male APOE4 targeted replacement mice show enhanced macrophage responsiveness compared to adult male APOE3 mice. At least part of the altered macrophage response in APOE4 male mice may be due to differences in androgen receptor sensitivity to testosterone. These data re-enforce the concept that classical activation in macrophages has multiple levels of regulation, dictated by competing or synergistic factors and genotype.     

Effect of sesamol on diabetes-associated cognitive decline in rats

Emerging epidemiologic data indicates that diabetes is a potential predisposing factor for neuropsychiatric deficits as stroke, cerebrovascular diseases, diabetes-associated cognitive decline, depression and anxiety. Diabetes-associated cognitive decline, characterized by impaired cognitive functions and neurochemical and structural abnormalities, involves direct neuronal damage caused by intracellular glucose. The present study was designed to investigate the effect of sesamol (3,4-methylenedioxyphenol), a phenolic antioxidant and anti-inflammatory molecule, on cognitive functions, oxidative stress and inflammation in diabetic rats. Learning and memory behaviors were investigated using a spatial version of the Morris water maze test. Acetylcholinesterase activity, a marker of cholinergic dysfunction, was increased by 80% in the cerebral cortex of diabetic rats. There was 107 and 121% rise in thiobarbituric acid reactive substance levels in cerebral cortex and hippocampus of diabetic rats, respectively. Reduced glutathione levels and enzymatic activities of superoxide dismutase and catalase were decreased in both cerebral cortex and hippocampal regions of diabetic rat brain. Nitrite levels in cerebral cortex and hippocampus was increased by 138 and 109%, respectively. Serum tumor necrosis factor-alpha, a marker for inflammation, was found to increase by 1,100% in diabetic rats. Chronic treatment with sesamol (2, 4 and 8 mg/kg; p.o.) significantly and dose-dependently attenuated cognitive deficit, reduced acetylcholinesterase, oxidative stress and inflammation in diabetic rats. The results emphasize the involvement of oxidative stress and inflammation in the development of cognitive impairment in diabetic animals and point towards the therapeutic potential of sesamol in diabetes-associated cognitive decline.     

Diabetes, aging, and cognitive decline

Type 1 diabetes is associated with cognitive changes in children and adults, but the extent to which cognition declines with increasing age, and increasing duration of diabetes, remains poorly understood. This cross-sectional study assessed neuropsychological performance on 200 diabetic and 175 nondiabetic adults, 18-64 years of age, stratified into five age bands. Similar age-related cognitive declines were seen on measures of problem-solving, learning and memory, and psychomotor speed, but it was only on the latter measure that diabetic and nondiabetic subjects differed significantly. The best predictor of psychomotor slowing was the presence of clinically significant biomedical complications, particularly proliferative retinopathy, peripheral neuropathy, and peripheral vascular disease (PVD). It now appears that psychomotor slowing is the fundamental cognitive deficit associated with diabetes mellitus; why other cognitive skills are relatively unaffected remains poorly understood.     

COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.     

Interaction of herpesviridae, APOE gene, and education in cognitive impairment

While high age, low level of education and APOE epsilon4 allele are known to predict dementia, there is recent data suggesting that certain viruses and subtypes of APOE epsilon3 could be involved, too. We investigated these relationships in a home-dwelling cohort of 357 elderly people with various cardiovascular diseases (DEBATE study). MMSE score below 24 was used to define cognitive impairment (n = 58). When adjusted for age and the presence of diabetes, multivariate analysis demonstrated maximally increased risk of cognitive impairment in association with a combination of three factors: seropositivity for herpesviridae, presence of APOE epsilon4, and low education (risk ratio 6.1, 95% CI 2.4-15.2). In the subcohort of APOE3/3 individuals (n = 216) homozygosity for the -219G epsilon3 haplotype showed a similar association (risk ratio 8.8, 95% CI 2.6-29.8). These results demonstrate an interaction of specific genetic (APOE) and environmental (education and herpesviridae) risk factors in the development of cognitive impairment and indicate that not only the epsilon4 allele of APOE but also the epsilon3 haplotype is a risk factor for dementia.     

Influence of apolipoprotein E genotype variation on the means, variances, and correlations of plasma lipids and apolipoproteins in children

The impact of the three most common apolipoprotein E ( APOE ) genotypes (ε32, ε33, and ε43) on means, variances, and correlations of nine plasma lipid and apolipoprotein traits (total cholesterol, lnTriglycerides, HDL cholesterol, and apolipoproteins AI, AII, B, CII, CIII, and lnE) was studied in 212 unrelated female and 219 unrelated male children aged 5–21.5 years from 278 pedigrees ascertained without regard to health status from Rochester, Minnesota. There was significant heterogeneity ( p ≤ 0.05) among genotypes for the mean plasma levels of lnApo E, Apo CII, Apo CIII, and lnTriglycerides (lnTrig) in females, and for the means of lnApo E, Apo B, and total cholesterol (Total-C) in males. Significant heterogeneity of intragenotypic variance was observed in males for Apo CII, lnTrig, and HDL-C; no significant heterogeneity was observed in females. Pairwise correlations between traits differed significantly among APOE genotypes in both females (6 of 36 pairs) and males (5 of 36 pairs). These results differ from those obtained from studies of the parental generation from the same sample of pedigrees. Our study further demonstrates that, with the exception of mean lnApo E levels, the univariate and bivariate distributions of traits that are measures of lipoprotein metabolism are influenced by variation in the APOE gene in a gender- and generation-dependent manner.     

Effect of interactions between APOE and ESR1 polymorphisms on cognitive functions in postmenopausal women

IntroductionDuring menopause the level of estrogens is decreased, which may lead to cognitive impairment or dementia. Some forms of genetic polymorphism were found to be related to cognitive functions, including APOE and ESR1 (PvuII and XbaI) polymorphisms. In the present study we aimed to analyze the impact of interactions between APOE and ESR1 polymorphisms on cognitive functions in the group of postmenopausal women.Material and methodsThe study group consisted of 266 postmenopausal women aged 50–65 years without symptoms of dementia. A computerized battery of the Central Nervous System Vital Signs (CNS VS) test was used to diagnose cognitive functions. APOE and ESR1 polymorphisms were genotyped using multiplex PCR and PCR-RFLP methods, respectively. Statistical analysis was performed using two-way analysis of variance in Statistica software.ResultsThe best memory, visual memory, processing and psychomotor speeds were found in women carrying the C allele of the PvuII polymorphism (TC + CC genotypes) in the presence of the APOE ε2/ε3 genotype, while a lower outcome was noted in women with ε3/ε3, and the lowest if they had the ε4 allele. In the case of women with TT genotype of the PvuII polymorphism, cognitive functioning did not decrease in women with the ε4 allele. A similar effect on cognitive functions was observed for AG + GG genotypes of the XbaI and APOE polymorphisms. Women who simultaneously carried CC PvuII and GG XbaI genotypes had the lowest cognitive functions.ConclusionsInteractions of polymorphic variants of APOE and ESR1 genes influenced cognitive functions in postmenopausal women.     

Hippocampal apolipoprotein D level depends on Braak stage and APOE genotype

Apolipoprotein (APO, gene; apo, protein) D, a member of the lipocalin family, has been implicated in several, pathological conditions but neither its physiologic function(s) nor ligand(s) has been clearly identified so far. Presuming a role in nerve de- and regeneration, several groups investigated apoD alterations in Alzheimer's disease (AD). Reported data, however, were not unanimous. We determined apoD protein levels in the hippocampus in a large, carefully matched autopsy case sample. ApoD levels were compared with the severity of neuropathological changes as determined by the Braak classification and with APOE genotype, a major risk factor for developing AD. ApoD was found to be related to the severity of AD-related neurofibrillary (NF) changes and not to old age alone. No correlation was found to amyloid deposits. Brain samples with widespread NF changes showed significantly higher apoD than cases with low Braak stages. This increase, however, was restricted to the APOE epsilon3/3 group, whereas the APOE epsilon4 group did not show significant variations in hippocampal apoD.     

ESR1 and APOE gene polymorphisms, serum lipids, and hormonal replacement therapy

OBJECTIVES: The risks and benefits of hormone replacement therapy (HRT) are, at least in part, mediated by the metabolic individuality of women. Therefore, we investigated the association between polymorphisms at the estrogen receptor 1 gene (ESR1) and at the apolipoprotein E gene (APOE) with lipid and lipoprotein levels in order to verify whether these concentrations are modulated by these gene variants in women with different hormonal status. METHODS: One hundred and eighteen postmenopausal women using oral HRT with estrogen or estrogen plus progestagen (HRT+, mean age=56+/-6.7 years, 39-75 years) and 167 postmenopausal women that were not on HRT (HRT-, mean age=58+/-9.8 years, 38-85 years) participated in the study. The polymorphisms were genotyped by PCR-RFLP methods. RESULTS: No significant effect of ESR1 genotypes or haplotypes and ESR1*HRT interactions were detected on lipid levels in two-way analysis of variance. Postmenopausal women HRT nonusers carriers of the APOE*4 allele had higher T-chol and LDL-C levels than postmenopausal women HRT nonusers carriers of the APOE*3 and APOE*2 allele. T-chol and LDL-C concentrations in postmenopausal users of HRT that were APOE*4 carriers were similar to those in postmenopausal women nonusers of HRT homozygotes for APOE*3 and APOE*2 carriers. A significant APOE*4/HRT interaction was detected on T-chol and LDL-C levels by multiple regression analysis. CONCLUSION: The results from this study suggest that the HRT influence on T-chol and LDL-C levels is modulated by APOE isoforms but not by ESR1 polymorphisms.     

Relationship between plasticity, mild cognitive impairment and cognitive decline.

A topic of great interest in gerontology research is the prediction of cognitive deterioration which marks the transition from mild cognitive impairment (MCI) to dementia. In this area the term plasticity is a construct of prime importance. Previous studies have demonstrated the existence of plasticity in healthy older persons, and it is thought that this is what discriminates between healthy individuals and those at risk for dementia. The aim of the present study is to demonstrate that plasticity exists in persons with MCI, and that a lack of plasticity may be one of the risk factors related to cognitive decline. An adapted version of the Auditory Verbal Learning Test-the AVLT of Learning Potential-was used to assess plasticity. Participants in the research were 203 older persons whose cognitive status had previously been determined using a cognitive screening test. The results show that plasticity exists in persons with MCI and that its presence is associated with less marked cognitive decline.     

Effect of the angiotensinogen genotype on experimental hypertension in mice

Polymorphisms of the angiotensinogen (Agt) gene may affect blood pressure. We used a mouse model to test for the role of the Agt genotype in low-renin or high-renin forms of hypertension. Mice bearing one, two, three, or four copies of the Agt gene underwent renal artery clipping to induce high-renin two-kidney, one-clip renovascular hypertension (2K1C), or uninephrectomy, salt loading, and application of deoxycorticosterone-acetate (DOCA) pellets to induce low-renin mineralocorticoid hypertension. Appropriate control animals were also studied. Blood pressure was measured by tail cuff as well as by direct intra-arterial recordings. There was a small effect of the Agt genotype on baseline blood pressure before induction of hypertension. The extent of 2K1C hypertension was not affected by the genotype. In contrast, there was a marked gene-dose effect on DOCA-hypertension (21.2 mmHg over all genotypes). Treatment of DOCA mice with the angiotensin II type 1 receptor antagonist abolished the genotype effect on blood pressure and left ventricular hypertrophy. There was a trend towards less suppression of endogenous aldosterone by DOCA treatment with increasing number of Agt gene copies. We conclude that the Agt genotype exerts a marked effect on blood pressure in a low-renin form of hypertension but no effect in the face of stimulated renin, at least in mice.     

Effect of continuous oestradiol-medroxyprogesterone administration on plasma lipids and lipoproteins

Plasma lipids and lipoproteins were measured in 21 post-menopausal women after 4 and 8 months of continuous treatment with an orally administered combination of oestradiol and medroxyprogesterone acetate. The mean concentrations of cholesterol and low-density-lipoprotein (LDL) cholesterol were reduced by 12% (P less than 0.001) and 11% (P less than 0.01), respectively, after 4 months of treatment and by 9% (P less than 0.05) and 12% (P less than 0.05) after 8 months. The mean level of high-density-lipoprotein (HDL) cholesterol showed an initial fall of 5% (P less than 0.05) after 4 months and then increased by 13% (P less than 0.05) after 8 months of treatment. The plasma triglycerides level oscillated around the baseline value, but the changes were not statistically significant. Indexes such as the HDL-cholesterol/LDL-cholesterol and cholesterol/HDL-cholesterol ratios, which are considered to be good indicators of atherogenic risk, showed changes towards patterns considered to be beneficial. Although the clinical significance of these changes remains uncertain at present, it seems clear that an oestradiol and medroxyprogesterone combination administered continuously produces biochemical changes which are regarded as protective against cardiovascular disease. Additionally, the endometrial inertness attributed to the continuous oestrogen-progestogen therapy would warrant its use as a good alternative in post-menopausal replacement therapy.     

Age-related neuropathology, cognitive decline, and Alzheimer's disease

In the last 20 years, there have been tremendous strides made in the understanding of the molecular and cellular processes that occur during brain aging, as well as our understanding of age-related disorders of the central nervous system (CNS). Aging is associated with a decline in cognitive performance, and is the biggest risk factor for the development of Alzheimer's disease (AD), although the underlying basis for both of these observations is poorly defined. Both normal aging and AD are associated with overlapping and increased levels of pathology. Numerous reports have now linked elevations in pathology as potential mediators of cognitive decline in the elderly, with most studies focusing on the role of AD-related pathology. However, it is important to point out that there are numerous other pathological features observed in the aging brain including corpora amylacea, argyrophilic grains, neuromelanin, and lipofuscin. In this review, I discuss the decreased cognitive performance observed during normal aging, the potential for pathology to alter neuronal function and neuronal viability during normal brain aging, and the potential for common pathologies to either inhibit or promote the development of age-related disorders such as AD.