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Postmenopausal hormone therapy and Alzheimer's disease, dementia, and Parkinson's disease: A systematic review and time-response meta-analysis

Wu M, Li M, Yuan J, Liang S, Chen Z, Ye M, et al.

Pharmacol Res, 2020 05;155:104693.
PMID: 32057896 DOI: 10.1016/j.phrs.2020.104693

Hormone therapy continues to be a favourable option in the management of menopausal symptomatology, but the associated risk-benefit ratios with respect to neurodegenerative diseases remain controversial. The study aim was to determine the relation between menopausal hormone therapy and Alzheimer's disease, dementia, and Parkinson's disease in human subjects. A literature search was performed in PubMed/Medline, Cochrane collaboration, and Scopus databases from onset of the database to September 2019. Random-effects model was used to estimate pooled odd ratio (OR) and 95 % confidence intervals (CI). Subgroup analysis was performed based on the type and formulation of hormone. In addition, the time-response effect of this relationship was also assessed based on duration of hormone therapy. Associations between hormone therapy and Alzheimer's disease, dementia, and Parkinson's disease in menopausal women were reported in 28 studies. Pooled results with random effect model showed a significant association between hormone therapy and Alzheimer's disease (OR 1.08, 95 % CI 1.03-1.14, I2: 69 %). This relationship was more pronounced in patients receiving the combined estrogen-progestogen formulation. Moreover, a significant non-linear time-response association between hormone therapy and Alzheimer's disease was also identified (Coef1 = 0.0477, p1<0.001; Coef2 = -0.0932, p2<0.001). Similarly, pooled analysis revealed a significant association between hormone therapy and all-cause dementia (OR 1.16, 95 % CI 1.02-1.31, I2: 19 %). Interestingly, no comparable relationship was uncovered between hormone therapy as a whole and Parkinson's disease (OR 1.14, 95 % CI 0.95-1.38, I2: 65 %); however, sub-group analysis revealed a significant relationship between the disease and progestogen (OR 3.41, 95 % CI 1.23-9.46) or combined estrogen-progestogen formulation use (OR 1.49, 95 % CI 1.34-1.65). Indeed, this association was also found to be driven by duration of exposure (Coef1 = 0.0626, p1 = 0.04). This study reveals a significant direct relationship between the use of certain hormonal therapies and Alzheimer's disease, all-cause dementia, and Parkinson's disease in menopausal women. However, the association appears to shift in direct after five years in the context of Alzheimer's disease, adding further weight to the critical window or timing hypothesis of neurodegeneration and neuroprotection.

Matched MeSH terms: Alzheimer Disease/epidemiology*
Beyond the Obvious: Smoking and Respiratory Infection Implications on Alzheimer's Disease

Wadhwa R, Paudel KR, Mehta M, Shukla SD, Sunkara K, Prasher P, et al.

CNS Neurol Disord Drug Targets, 2020;19(9):698-708.
PMID: 33109069 DOI: 10.2174/1871527319999200817112427

Tobacco smoke is not only a leading cause for chronic obstructive pulmonary disease, cardiovascular disorders, and lung and oral cancers, but also causes neurological disorders such as Alzheimer 's disease. Tobacco smoke consists of more than 4500 toxic chemicals, which form free radicals and can cross blood-brain barrier resulting in oxidative stress, an extracellular amyloid plaque from the aggregation of amyloid β (Aβ) peptide deposition in the brain. Further, respiratory infections such as Chlamydia pneumoniae, respiratory syncytial virus have also been involved in the induction and development of the disease. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. The review article sheds light on the role of smoking and respiratory infections in causing oxidative stress and neuroinflammation, resulting in Alzheimer's disease (AD). This review will be of interest to scientists and researchers from biological and medical science disciplines, including microbiology, pharmaceutical sciences and the translational researchers, etc. The increasing understanding of the relationship between chronic lung disease and neurological disease is two-fold. First, this would help to identify the risk factors and possible therapeutic interventions to reduce the development and progression of both diseases. Second, this would help to reduce the probable risk of development of AD in the population prone to chronic lung diseases.

Matched MeSH terms: Alzheimer Disease/epidemiology*
Mutations, associated with early-onset Alzheimer's disease, discovered in Asian countries

Bagyinszky E, Youn YC, An SS, Kim S

Clin Interv Aging, 2016;11:1467-1488.
PMID: 27799753

Alzheimer's disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD patients are growing rapidly, and the genetics of AD has been extensively studied, except in Japan. However, recent studies have been started to investigate the genes and mutations associated with AD in Korea, the People's Republic of China, and Malaysia. This review describes all of the known mutations in three early-onset AD (EOAD) causative genes (APP, PSEN1, and PSEN2) that were discovered in Asian countries. Most of the EOAD-associated mutations have been detected in PSEN1, and several novel PSEN1 mutations were recently identified in patients from various parts of the world, including Asia. Until 2014, no PSEN2 mutations were found in Asian patients; however, emerging studies from Korea and the People's Republic of China discovered probably pathogenic PSEN2 mutations. Since several novel mutations were discovered in these three genes, we also discuss the predictions on their pathogenic nature. This review briefly summarizes genome-wide association studies of late-onset AD and the genes that might be associated with AD in Asian countries. Standard sequencing is a widely used method, but it has limitations in terms of time, cost, and efficacy. Next-generation sequencing strategies could facilitate genetic analysis and association studies. Genetic testing is important for the accurate diagnosis and for understanding disease-associated pathways and might also improve disease therapy and prevention.

Matched MeSH terms: Alzheimer Disease/epidemiology
Peripheral cytokines, C-X-C motif ligand10 and interleukin-13, are associated with Malaysian Alzheimer's disease

Mohd Hasni DS, Lim SM, Chin AV, Tan MP, Poi PJH, Kamaruzzaman SB, et al.

Geriatr Gerontol Int, 2017 May;17(5):839-846.
PMID: 27215446 DOI: 10.1111/ggi.12783

AIM: Cytokines released from chronically-activated microglia could result in neuroinflammation. An accurate profile of the relationship between cytokines and Alzheimer's disease (AD) pathogenesis, as well as the patterns of these inflammatory mediators in AD patients could lead to the identification of peripheral markers for the disease. The present study was undertaken to identify pro- and anti-inflammatory cytokines associated with AD in the Malaysian population.
METHODS: Further to informed consent from 39 healthy subjects and 39 probable AD patients, 8.5 mL of peripheral blood was collected and serum was extracted. The differential levels of 12 serum cytokines extracted from peripheral blood samples were measured using Procarta Multiplex Cytokine and enzyme-linked immunoassay kits. Concentrations of cytokines were measured at 615 nm using a fluorometer.
RESULTS: Except for tumor necrosis factor-α, all classical pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-12 and interferon-γ) were found to be significantly upregulated (P 53.65 ρg/mL and <9.315 ρg/mL, respectively).
CONCLUSIONS: Both the non-classical pro-inflammatory CXCL-10 and anti-inflammatory IL-13 cytokines showed promising potential as blood-based cytokine biomarkers for AD. This is the first study of non-classical cytokine profiles of Malaysian AD patients. Geriatr Gerontol Int 2017; 17: 839-846.

Matched MeSH terms: Alzheimer Disease/epidemiology
Fulltext The effects of sleep quality, physical activity, and environmental quality on the risk of falls in dementia

Eshkoor SA, Hamid TA, Nudin SS, Mun CY

Am J Alzheimers Dis Other Demen, 2013 Jun;28(4):403-7.
PMID: 23698600 DOI: 10.1177/1533317513488921

OBJECTIVES: This study aimed to identify the effects of sleep quality, physical activity, environmental quality, age, ethnicity, sex differences, marital status, and educational level on the risk of falls in the elderly individuals with dementia.
METHODOLOGY: Data were derived from a group of 1210 Malaysian elderly individuals who were noninstitutionalized and demented. The multiple logistic regression model was applied to estimate the risk of falls in respondents.
RESULTS: Approximately the prevalence of falls was 17% among the individuals. The results of multiple logistic regression analysis revealed that age (odds ratio [OR] = 1.03), ethnicity (OR = 1.76), sleep quality (OR = 1.46), and environmental quality (OR = 0.62) significantly affected the risk of falls in individuals (P < .05). Furthermore, sex differences, marital status, educational level, and physical activity were not significant predictors of falls in samples (P > .05).
CONCLUSION: It was found that age, ethnic non-Malay, and sleep disruption increased the risk of falls in respondents, but high environmental quality reduced the risk of falls.

Matched MeSH terms: Alzheimer Disease/epidemiology*
Fulltext APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Giau VV, Bagyinszky E, Youn YC, An SSA, Kim S

Int J Mol Sci, 2019 Sep 25;20(19).
PMID: 31557888 DOI: 10.3390/ijms20194757

The number of patients with Alzheimer's disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (EOAD). Although these genes have been extensively studied, variant classification remains a challenge, highlighting the need to colligate mutations across populations. In this study, we performed a genetic screening for mutations in the APP, PSEN1, and PSEN2 genes in 200 clinically diagnosed EOAD patients across four Asian countries, including Thailand, Malaysia, the Philippines, and Korea, between 2009 and 2018. Thirty-two (16%) patients presented pathogenic APP, PSEN1, or PSEN2 variants; eight (25%), 19 (59%), and five (16%) of the 32 patients presented APP, PSEN1, and PSEN2 variants, respectively. Among the 21 novel and known non-synonymous variants, five APP variants were found in Korean patients and one APP variant was identified in a Thai patient with EOAD. Nine, two, and one PSEN1 mutation was found in a Korean patient, Malaysian siblings, and a Thai patient, respectively. Unlike PSEN1 mutations, PSEN2 mutations were rare in patients with EOAD; only three variants were found in Korean patients with EOAD. Comparison of AD-causative point mutations in Asian countries; our findings explained only a small fraction of patients, leaving approximately 84% (p = 0.01) of autosomal dominant pedigrees genetically unexplained. We suggest that the use of high-throughput sequencing technologies for EOAD patients can potentially improve our understanding of the molecular mechanisms of AD.

Matched MeSH terms: Alzheimer Disease/epidemiology*
Alzheimer's Disease and Related Dementia in Indigenous Populations: A Systematic Review of Risk Factors

Walker JD, Spiro G, Loewen K, Jacklin K

J Alzheimers Dis, 2020;78(4):1439-1451.
PMID: 33185601 DOI: 10.3233/JAD-200704

BACKGROUND: There remains a lack of information and understanding of the prevalence and incidence of Alzheimer's disease and related dementia in Indigenous populations. Little evidence available suggests that Indigenous peoples may have disproportionately high rates of Alzheimer's disease and related dementia (ADRD).
OBJECTIVE: Given this information, this study systematically explores what risk factors may be associated with ADRD in Indigenous populations.
METHODS: A search of all published literature was conducted in October 2016, March 2018, and July 2019 using Medline, Embase, and PsychINFO. Subject headings explored were inclusive of all terms related to Indigenous persons, dementia, and risk. All relevant words, phrases, and combinations were used. To be included in this systematic review, articles had to display an association of a risk factor and ADRD. Only studies that reported a quantifiable measure of risk, involved human subjects, and were published in English were included.
RESULTS: Of 237 articles originally identified through database searches, 45 were duplicates and 179 did not meet a priori inclusion criteria, resulting in 13 studies eligible for inclusion in this systematic review.
CONCLUSION: The large number of potentially modifiable risk factors reported relative to non-modifiable risk factors illustrates the importance of socioeconomic context in the pathogenesis of ADRD in Indigenous populations. The tendency to prioritize genetic over social explanations when encountering disproportionately high disease rates in Indigenous populations can distract from modifiable proximal, intermediate, and distal determinants of health.

Matched MeSH terms: Alzheimer Disease/epidemiology
Fulltext A Review on the Relationship between Tocotrienol and Alzheimer Disease

Chin KY, Tay SS

Nutrients, 2018 Jul 09;10(7).
PMID: 29987193 DOI: 10.3390/nu10070881

Alzheimer’s disease (AD) is plaguing the aging population worldwide due to its tremendous health care and socioeconomic burden. Current treatment of AD only offers symptomatic relief to patients. Development of agents targeting specific pathologies of AD is very slow. Tocotrienol, a member of the vitamin E family, can tackle many aspects of AD, such as oxidative stress, mitochondrial dysfunction and abnormal cholesterol synthesis. This review summarizes the current evidence on the role of tocotrienol as a neuroprotective agent. Preclinical studies showed that tocotrienol could reduce oxidative stress by acting as a free-radical scavenger and promoter of mitochondrial function and cellular repair. It also prevented glutamate-induced neurotoxicity in the cells. Human epidemiological studies showed a significant inverse relationship between tocotrienol levels and the occurrence of AD. However, there is no clinical trial to support the claim that tocotrienol can delay or prevent the onset of AD. As a conclusion, tocotrienol has the potential to be developed as an AD-preventing agent but further studies are required to validate its efficacy in humans.

Matched MeSH terms: Alzheimer Disease/epidemiology
Type 3 diabetes (Alzheimer's disease): new insight for promising therapeutic avenues

Candasamy M, Mohamed Elhassan SA, Kumar Bhattamisra S, Hua WY, Sern LM, Binti Busthamin NA, et al.

Panminerva Med, 2020 Sep;62(3):155-163.
PMID: 32208408 DOI: 10.23736/S0031-0808.20.03879-3

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) are two of the most commonly occurring diseases worldwide, especially among the elderly population. In particular, the increased prevalence of AD has imposed tremendous psychological and financial burdens on society. Growing evidence suggests both AD and T2D share many similar pathological traits. AD is characterized as a metabolic disorder whereby the glucose metabolism in the brain is impaired. This closely resembles the state of insulin resistance in T2D. Insulin resistance of the brain has been heavily implicated two prominent pathological features of AD, Aβ plaques and neurofibrillary tangles. Brain insulin resistance is known to elicit a positive feed-forward loop towards the formation of AD pathology in which they affect each other in a synergistic manner. Other physiological traits shared between the two diseases include inflammation, oxidative stress and autophagic dysfunction, which are also closely associated with brain insulin resistance. In this review and depending on these underlying pathways that link these two diseases, we have discussed the potential therapeutic implications of AD. By expanding our knowledge of the overlapping pathophysiology involved, we hope to provide scientific basis to the discovery of novel therapeutic strategies to improve the clinical outcomes of AD in terms of diagnosis and treatment.

Matched MeSH terms: Alzheimer Disease/epidemiology