Cholinesterase Inhibitor Therapy Research Articles

A Comparative Analysis on Alzheimer’s Medication

Alzheimer's disease (AD) is a neurodegenerative disorder in which brain cells, or neurons, slowly degenerate and die resulting in a gradual cognitive decline. AD does not have a known cure; this requires effective strategies to manage symptoms and slow its progression of this disease. This review paper delves into treatments, for Alzheimers disease (AD) such as cholinesterase inhibitors, NMDA antagonists and immunotherapies. The focus will be on exploring their effectiveness in early and mild to AD cases well as examining any potential side effects. This paper highlights the importance of treatment plans that take into account the nature of AD and emphasizes the significance of addressing both the underlying pathology and symptoms. After conducting an analysis on clinical trials, the conclusion is that cholinesterase inhibitor therapy stands out as the approach, for managing mild to moderate AD based on comprehensive clinical trial results and a comparative analysis.

Cholinesterase inhibitors associated with lower rate of mortality in dementia patients with heart failure: a nationwide propensity weighting study.

This study investigates the potential impact of cholinesterase inhibitors (ChEIs) on patients with heart failure (HF) and dementia. ChEIs are known to boost acetylcholine levels and benefit cognition in patients with dementia; however, their effect on patients with HF is uncertain. This study aimed to assess whether cardiovascular events and mortality among patients with HF and dementia are altered by ChEI therapy. Data from the National Health Insurance Research Database in Taiwan were retrospectively analyzed. Dementia patients diagnosed with HF were followed for 5years until all-cause mortality, cardiovascular mortality, hospitalization for worsening HF, or the end of the study. Multivariable Cox models and inverse probability of treatment weighting (IPTW) were employed. Out of 20,848 patients with dementia, 5138 had HF. Among them, 726 were ChEI users and 4412 were non-users. Based on IPTW, the ChEI users had significantly lower estimated risks of all-cause mortality [hazard ratio (HR) 0.43; 95% confidence interval (CI) 0.38-0.49, p < 0.001] and cardiovascular mortality (HR 0.41; 95% CI 0.33-0.53, p < 0.001) compared with the non-users, but there was no significant difference in hospitalization for worsening HF (HR 0.73; 95% CI 0.51-1.05, p = 0.091) after 5years. The survival benefits of ChEIs were consistent across subgroups. The results of this retrospective cohort study suggest that ChEIs may be beneficial in reducing all-cause and cardiovascular mortality in patients with dementia with HF. Further research is needed to validate these findings and explore the potential benefits of ChEIs in all patients with HF, including those without dementia.

Aphasic mild cognitive impairment in prodromal dementia with Lewy bodies.

This study aimed to determine the characteristics of aphasic mild cognitive impairment (aphasic MCI), which is characterized by a progressive and relatively prominent language impairment compared with other cognitive impairments, in the prodromal phase of dementia with Lewy bodies (DLB). Of the 26 consecutive patients with aphasic MCI who had been prospectively recruited at our hospital, 8 patients were diagnosed with prodromal DLB and underwent language, neurological, neuropsychological, and neuroimaging (N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography; IMP-SPECT) testing. Three of these patients also underwent cholinesterase inhibitor therapy with donepezil. In our aphasic MCI cohort, the clinical diagnosis of probable prodromal DLB accounted for more than 30% of cases; therefore, the presence of language impairment in prodromal DLB was not very uncommon. Five patients were diagnosed with progressive anomic aphasia and three with logopenic progressive aphasia. Anomic aphasia was characterized by apparent anomia but relatively preserved repetition and comprehension ability and logopenic progressive aphasia by anomia, phonemic paraphasia, and impaired repetition. IMP-SPECT revealed hypoperfusion of the temporal and parietal lobes in the left hemisphere in all but one patient. All patients who underwent cholinesterase inhibitor therapy with donepezil showed improvement in general cognitive function, including language function. The clinical and imaging features of aphasic MCI in prodromal DLB are similar to those observed in Alzheimer's disease. Progressive fluent aphasia, such as progressive anomic aphasia and logopenic progressive aphasia, is one of the clinical presentations in prodromal state of DLB. Our findings provide further insight into the clinical spectrum of prodromal DLB and may contribute to the development of medication for progressive aphasia caused by cholinergic insufficiency.

Alzheimer’s Disease and Stem Cell Therapy

Alzheimer’s disease is a neurodegenerative disorder mainly caused by aggregation of neurofibrillary tangles and beta-amyloid plaques. As the most common cause of dementia, the population of AD patients has risen significantly in recent years. Due to the difficulty to diagnose AD at its early stage and the rapid development of the disease, AD is still an unsolved puzzle in the medical world. Though there are treatments for delaying symptoms of AD such as anti-amyloid therapy and medicine treatments that contain Cholinesterase inhibitors therapy, efficient therapies which treat AD fundamentally are yet to be discovered. The review paper will focus on one of the most promising therapies for AD, stem cell therapy. Compared to slowing down the disease, stem cell therapy can actually help the patients to grow brand-new neurons hence the treatment is pretty worthy to be studied. Stem cells are undifferentiated cells that are able to develop into new brain cells. There are four types of stem cell therapies for Alzheimer’s Disease: Mesenchymal Stem Cells therapy, Neural Stem Cell therapy, Embryonic Stem Cell therapy, and Induced Pluripotent stem Cell therapy. Among all the stem cell therapies, induced pluripotent stem cells (iPSC) therapy has the most potential to work out due to the successful trials upon rodent animal models. Nevertheless, no stem cell therapy for AD succeeds in human trials so far. Besides, the likelihood of cancer and tumor should also be taken into consideration.

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration

The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.

Reimagining cholinergic therapy for Alzheimer's disease.

Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms of the early as well as late stages of Alzheimer's disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer's disease, as four of the six approved therapies are acetylcholinesterase inhibitors. Memantine is an N-methyl-d-aspartate antagonist with a well-documented clinical effect on behavioural symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targeting the amyloid pathology, has recently been approved. The early, progressive and selective degeneration of the cholinergic system together and its close relation to cognitive deficits supports the use of cholinergic therapy for Alzheimer's disease. This review provides an updated view of the basal forebrain cholinergic system, its relation to cognition and its relevance for therapy of Alzheimer's disease. It deals with the three main aspects that form the basis of the cholinergic-oriented therapy of Alzheimer's disease, its origin, its mechanism of action, its clinical effects, advantages and limits of a cholinergic therapeutic approach. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer's disease as well as the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. It also addresses the discovery of a novel nerve growth factor metabolic pathway responsible for the trophic maintenance of the basal forebrain system and its deregulation in Alzheimer's disease. It discusses new clinical studies and provides evidence for the long-term efficacy of cholinesterase inhibitor therapy suggesting a disease-modifying effect of these drugs. The classical symptomatic cholinergic therapy based on cholinesterase inhibitors is judiciously discussed for its maximal efficacy and best clinical application. The review proposes new alternatives of cholinergic therapy that should be developed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.

Drug cost optimization of cholinesterase inhibitor therapy in advanced dementia: Results of a prospective study of discontinuation

Purpose: To investigate the effect of discontinuing treatment with cholinesterase inhibitors (ChEIs) on drug costs in patients with advanced dementia.&#x0D; Methods: Severe dementia patients receiving ChEI treatment for over 12 months (n = 43) aged over 65 years (mean age = 82.6 ± 7.5 years) were recruited from 8 nursing homes located in Alicante, Spain. ChEI treatment was discontinued in 23 patients. Here, we report the results from a cost-minimization analysis to evaluate the drug costs with a follow-up period of three months. The drug costs were prospectively analyzed based on drug acquisition costs.&#x0D; Results: At the end of the follow-up, the mean monthly drug costs were €52.68 ± 22.48 in the discontinuation group and €122.54 ± 44.74 in the continuation group - a significant difference of means of -€69.86 (95 % CI, -91.24 to -48.48; p = 0.000). The monthly drug cost reduction for the ChEI discontinuation group was €1,533.35.&#x0D; Conclusion: ChEI discontinuation appears to be a possible option for minimizing treatment costs in institutionalized patients with advanced dementia.

Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer's Disease.

Background: Whether gender differences exist in late-onset of Alzheimer’s disease (LOAD) treated with cholinesterase inhibitors (ChEIs) is not fully understood. This study investigated demographic and pharmacological characteristics in LOAD patients to determine gender differences in LOAD patients treated with ChEIs alone and ChEIs with other medications. Methods: This 5-year retrospective data analysis included 9290 LOAD AD patients with 2949 men patients and 6341 women. Potential predictors of demographic and pharmacological characteristics associated gender differences in patients treated with and without ChEIs therapy were determined using univariate analysis, while multivariable models adjusted for demographic and pharmacological variables. Results: In the adjusted analysis, men patients with LOAD that presented with a history of alcohol use (ETOH) (OR = 1.339, 95% CI, 1.072–1.672, p = 0.010), treated with second generation antipsychotics (SGAs) (OR = 1.271, 95% CI, 1.003–1.610, p = 0.047), citalopram (OR = 5.103, 95% CI, 3.423–7.607, p < 0.001), memantine (OR = 4.409, 95% CI, 3.704–5.249, p < 0.001), and buspirone (OR = 2.166, 95% CI, 1.437–3.264, p < 0.001) were more likely to receive ChEIs therapy, whereas older men were less likely to be treated with ChEIs therapy. Women who were African Americans (OR = 1.387, 95% CI, 1.168–1.647, p < 0.001), that received memantine (OR = 3.412, 95% CI, 3.034–3.837, p < 0.001), selective serotonin reuptake inhibitor (SSRIs) (OR = 1.143, 95% CI, 1.016–1.287, p = 0.026), and a history of ETOH (OR = 2.109, 95% CI, 1.724–2.580, p < 0.001) were more likely to receive ChEIs therapy, whereas older women were less likely to receive ChEIs therapy. Conclusion: In both men and women patients, those with increasing age were less likely to be treated with ChEI therapy, while patients treated with memantine were also likely to receive ChEI therapy. Our findings highlight the importance for clinicians to optimize ChEI in LOAD to improve treatment effectiveness and eliminate gender differences in ChEI therapy.

Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial.

Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica improve cognition in mouse models of aging and Alzheimer’s disease (AD) through the modulation of mitochondrial biogenesis and nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response genes. This randomized, double-blind, crossover Phase I trial explored the oral bioavailability and pharmacokinetics of key compounds from two doses (2 g and 4 g) of a standardized C. asiatica aqueous extract product (CAP), over 10 h, in four mildly demented older adults on cholinesterase inhibitor therapy. The analysis focused on triterpenes (TTs) and caffeoylquinic acids (CQAs), which are known to contribute to C. asiatica’s neurological activity. The acute safety of CAP and the effects on NRF2 gene expression in peripheral blood mononuclear cells were evaluated. Single administration of 2 g or 4 g of CAP was safe and well-tolerated. The TT aglycones, asiatic acid and madecassic acid, were identified in plasma and urine, while the parent glycosides, asiaticoside and madecassoside, although abundant in CAP, were absent in plasma and had limited renal excretion. Similarly, mono- and di-CQAs showed delayed absorption and limited presence in plasma or urine, while the putative metabolites of these compounds showed detectable plasma pharmacokinetic profiles and urinary excretion. CAP elicited a temporal change in NRF2 gene expression, mirroring the TT aglycone’s pharmacokinetic curve in a paradoxical dose-dependent manner. The oral bioavailability of active compounds or their metabolites, NRF2 target engagement, and the acute safety and tolerability of CAP support the validity of using CAP in future clinical studies.

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.

Cholinesterase inhibitor to prevent falls in Parkinson\u2019s disease (CHIEF-PD) trial: a phase 3 randomised, double-blind placebo-controlled trial of rivastigmine to prevent falls in Parkinson\u2019s disease

BackgroundFalls are a common complication of Parkinson’s disease. There is a need for new therapeutic options to target this debilitating aspect of the disease. Cholinergic deficit has been shown to contribute to both gait and cognitive dysfunction seen in the condition. Potential benefits of using cholinesterase inhibitors were shown during a single centre phase 2 trial. The aim of this trial is to evaluate the effectiveness of a cholinesterase inhibitor on fall rate in people with idiopathic Parkinson’s disease.MethodsThis is a multi-centre, double-blind, randomised placebo-controlled trial in 600 people with idiopathic Parkinson’s disease (Hoehn and Yahr stages 1 to 4) with a history of a fall in the past year. Participants will be randomised to two groups, receiving either transdermal rivastigmine or identical placebo for 12 months. The primary outcome is the fall rate over 12 months follow-up. Secondary outcome measures, collected at baseline and 12 months either face-to-face or via remote video/telephone assessments, include gait and balance measures, neuropsychiatric indices, Parkinson’s motor and non-motor symptoms, quality of life and cost-effectiveness.DiscussionThis trial will establish whether cholinesterase inhibitor therapy is effective in preventing falls in Parkinson’s disease. If cost-effective, it will alter current management guidelines by offering a new therapeutic option in this high-risk population.Trial registrationREC reference: 19/SW/0043.EudraCT: 2018–003219-23.ISCRTN: 41639809 (registered 16/04/2019).ClinicalTrials.gov Identifier: NCT04226248Protocol at time of publicationVersion 7.0, 20th January 2021.

Potential synergistic effect between Fortasyn Connect and cholinesterase inhibitors in patients with early stages (very mild and mild) of dementia due to Alzheimer disease in common medical practice: An observational, non‐interventional study

AbstractBackgroundDetails implementation of an innovative care program or practice: Fortasyn connect medical food, approved for early stages of Alzheimer dementia, can have a synergistic effect with cholinesterase inhibitors drugs.ObjectivesTo analyse the possible synergistic effect between Fortasyn Connect medical food and Cholinesterase Inhibitors drugs in Alzheimer disease patients in a common medical practice.Patients and Methods60 patients at early stages of dementia due to Alzheimer disease were followed. CDR (Clinical Dementia Rating) scale was administered at the beginning and at the end of the follow‐up period. The rate of change of CDR‐SB (sum of Blocks) was chosen as a efficacy criteria. Informed Consent was aquired. An approval of the Ethical Committee of the protocol was obtained. SSPS (v20) was used as a Statistical Software.ResultsThe combination therapy with Fortasyn Connect and Cholinesterase inhibitors was well tolerated. There were no significative advers effect. The patients were distribute at the final visit in 4 groups: Those who had taken both Fortasyn Connect and Cholinesterase inhibitors (Group 1), those who had taken Fortasyn Connect and no Cholinesterase inhibitors (Group 2), those who had taken Cholinesterase inhibitors and non Fortasyn Connect (Group 3), those who had not taken neither Fortasyn Connect nor Cholinesterase inhibitors (Group 4). There was a statistical difference between the Group 1 with the Group 3 and Group 4, indicating a potential synergistic effect between both therapies.ConclusionsThe combination therapy with Fortasyn Connect medical food and Cholinesterase inhibitors was well tolerated. It seem to be a potential synergistic efect between Fortasyn Connect medical food and Cholinesterase inhibitors Drugs. An statistical difference between the Group 1 (Fortasyn Connect medical food and Cholinesterase inhibitors therapy) with the Group 3 (Cholinesterase Inhibitor alone) and Group 4 (Fortasyn Connect medical food and Cholinesterase inhibitors therapy), indicating a potential synergistic effect between both therapies. Due to the limitations of this preliminary study (non‐blinded, non randomized, small sample of patients, non placebo control), more studies are needed.

Re-pigmentation of hair after prolonged cholinesterase inhibitor therapy in a Chinese population.

Eighty consecutive Chinese patients diagnosed with Alzheimer disease were assessed for darkening of grey hair. Of the 62 eligible patients (mean age=79.3±7.9years; male: female=1:1.48), 24/62 (38.7%, 95%CI: 26.6 - 51.9) reported hair darkening after prolonged usage of cholinesterase inhibitor for at least 6months. Of the 24 patients with hair darkening, 17 (70.9%) experienced hair darkening in the occipital region, 3 (12.5%) in the parietal region, 2 (8.3%) patients in the frontal region and 2 (8.3%) patients experienced hair darkening in multiple regions. Analysis of melanin concentration showed no significant difference between darkened hair of patients after prolonged drug use and the dark hair of controls (P=0.381).

Cerebro-spinal fluid biomarker levels: phosphorylated tau (T) and total tau (N) as markers for rate of progression in Alzheimer\u2019s disease

BackgroundWe investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer’s disease (AD).MethodsThis prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-β1–42 (Aβ42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated.ResultsAll patients had abnormal Aβ42 (A+). Fifty-eight individuals (45%) exhibited normal P-tau and T-tau (A+ T– (N)–), 12 (9%) abnormal P-tau/normal T-tau (A+ T+ (N)–), 17 (13%) normal P-tau/abnormal T-tau (A+ T– (N)+) and 42 (33%) abnormal P-tau and T-tau (A+ T+ (N)+). The participants with A+ T+ (N)+ were younger than A+ T– (N)+ at the estimated onset of AD and the initiation of ChEIs. The proportion of 6-month responders to ChEI and deterioration/year after start of treatment did not differ between the AT(N) profiles in any scales. A higher percentage of globally improved/unchanged patients was exhibited in the A+ T– (N)– group after 12, 30 and 36 months of ChEI therapy but not at other assessments. In apolipoprotein E (APOE) ε4-carriers, linear relationships were found between greater cognitive decline/year and higher tau; Mini-Mental State Examination score – T-tau (rs = − 0.257, p = 0.014) and Alzheimer’s Disease Assessment Scale–cognitive subscale – P-tau (rs = − 0.242, p = 0.022). A correlation between faster progression in instrumental ADL (IADL) and higher T-tau was also detected (rs = − 0.232, p = 0.028). These associations were not demonstrated in non-ε4-carriers.ConclusionsYounger age and faster global deterioration were observed in AD patients with pathologic tau and neurodegeneration, whereas more rapid cognitive and IADL decline were related to higher P-tau or T-tau in APOE ε4-carriers only. The results might indicate an association between more pronounced tau pathology/neuronal injury and the APOE ε4-allele leading to a worse prognosis. Our findings showed that the AT(N) biomarker profiles have limited utility to predict AD progression rates and, thus, measure change and interpreting outcomes from clinical trials of future therapies.

Use of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Risk in Mild Cognitive Impairment and Subjective Cognitive Decline in Routine Clinical Care in Germany.

The National Institute of Aging and Alzheimer's Association's diagnostic recommendations for preclinical Alzheimer's disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in Germany. From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42, tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p = 0.006), given that all CSF biomarkers were in the pathological range. Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed.

Prognostic regression models of life expectancy after diagnosis of Alzheimer’s disease – a 20-year follow-up

Background: To determine characteristics that might affect survival times in Alzheimer’s disease (AD) patients treated with cholinesterase inhibitors (ChEI) in clinical practice, and create statistical models of estimated life-span after AD diagnosis. Method: The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicenter study to evaluate the use of long-term ChEI therapy. The SATS enrolled 1,021 participants with a clinical diagnosis of mild-to-moderate AD (Mini-Mental State Examination (MMSE) score, 10–26) at the start of ChEI treatment (shortly after AD diagnosis). Cognitive ability, instrumental and basic activities of daily living (ADL) were evaluated at baseline and semiannually over 3 years, and the date of death was recorded. Result: After up to 20 years of follow-up, 966 patients (95%) were deceased. Two types of multivariate linear regression models were created, one using only sociodemographic and clinical characteristics at baseline, and another model including baseline and longitudinal measures. Both main models included cognitive ability, and the extended models also included ADL capacities, as well as aspects of ChEI therapy in the longitudinal model. Significant independent predictors of longer life expectancy in all models were female sex, younger age, no use of antihypertensive/cardiac therapy or antidiabetics, (but not the specific apolipoprotein E genotype or solitary living), indicating the stability and validity of our regression models. A higher education level predicted shorter survival time in both baseline models (with and without ADL) and in the longitudinal model including cognition only. In the baseline model including ADL capacities, instrumental ADL (IADL) and basic ADL scores were stronger predictors of mortality than cognition. In the longitudinal model including ADL capacities, IADL and basic ADL scores (but not MMSE score) at baseline, progression rates in cognition and basic ADL predicted survival independently. A longer period of ChEI treatment in the study was also a strong predictor of longer life-span of up to ~2 years. Conclusion: The survival time after a diagnosis of AD could be predicted with a high degree of explanation using multivariate regression models including sociodemographic and clinical factors. These clinically relevant prognostic models can be used to estimate life expectancy for AD patients.

Butyrylcholinesterase Protein Ends in the Pathogenesis of Alzheimer's Disease-Could BCHE Genotyping Be Helpful in Alzheimer's Therapy?

Late-onset Alzheimer’s disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century since the first AD patient was diagnosed. Drugs increasing the availability of neurotransmitters at synapses in the brain are used clinically in the treatment of AD dementia, and cholinesterase inhibitors (ChEIs) are the mainstay of the therapy. A detrimental effect on cognitive function has been reported in patients with pharmacological inhibition of acetylcholinesterase (AChE) by ChEIs and reduced butyrylcholinesterase (BChE) activity due to the single nucleotide polymorphisms. The BChE K-variant (rs1803274), the most common genetic variant of the BCHE gene, was thought to reduce enzyme activity reflecting the lower clinical response to rivastigmine in AD patients. During ChEIs therapy, patients carrying reduced-activity BChE do not present such improved attention like patients with the wild-type enzyme. On the other hand, alterations in the BCHE gene causing enzyme activity reduction may delay AD onset in patients at risk by preserving the level of cortical acetylcholine (ACh). Based on our previous results, we conclude that SNPs localized outside of the coding sequence, in 5’UTR (rs1126680) and/or intron 2 (rs55781031) of the BCHE gene, but not solely K-variant alteration (p.A539T) itself, are responsible for reduced enzyme activity. Therefore, we suspect that not BChE-K itself, but these coexisting SNPs (rs1126680 and rs55781031), could be associated with deleterious changes in cognitive decline in patients treated with ChEIs. Based on the results, we suggest that SNPs (rs1126680) and/or (rs55781031) genotyping should be performed to identify subjects at risk for lowered efficacy ChEIs therapy, and such patients should be treated with a lower rivastigmine dosage. Finally, our sequence analysis of the N-terminal end of N-BChE revealed evolutionarily conserved amino acid residues that can be involved in disulfide bond formation and anchoring of N-BChE in the cell membrane.

Sex Differences in the Prevalent Use of Oral Formulations of Cholinesterase Inhibitors in Older Adults with Dementia.

Cholinesterase inhibitors (ChEIs) are one of only two drug therapies available to manage cognitive decline in dementia. Given sex-specific differences in medication access and effects, it is important to understand how ChEIs are used by women and men. The objective of this study was to provide contemporary sex-stratified evidence on patterns of ChEI use by community-dwelling older adults with dementia to inform opportunities to optimize drug prescribing. We conducted a population-based cross-sectional study examining ChEI use in older adults with dementia in Ontario, Canada. We identified all community-dwelling individuals aged 66 years and older with a pre-existing diagnosis of dementia as of 1 April, 2016. We examined the prevalence of ChEI use among women and men separately, and explored the association between ChEI use and age, sex, income status, geographic location of residence, use of palliative care services, comorbidity, and polypharmacy. Concurrent use of drugs known to impair cognition (including antipsychotics, benzodiazepines, and medications with strong anticholinergic properties) was separately assessed among women and men using multivariable analyses and prevalence risk ratios. Of 74,799 women and 52,231 men living with dementia in the community, nearly 30% currently were using a ChEI (29.3% women, 28.6% men). Close to 70% of users were receiving the target therapeutic dose. Compared to men, women were less often taking the target therapeutic dose (67.8% women vs. 71.6% men, p < 0.001). Over 20% of users also were using drugs known to impair cognition, while being treated for cognitive decline using ChEIs. Compared to men, women were more often concurrently using drugs known to impair cognition (23.9% women vs. 21.8% men, p < 0.001). This is one of the first studies of ChEI use to account for important sex differences. The results remind clinicians and researchers that patterns of ChEI therapy use differ by sex, as women were less likely to receive target therapeutic doses and more vulnerable to potentially problematic polypharmacy than men.

P2‐282: PROGNOSTIC REGRESSION MODELS OF LIFE EXPECTANCY AFTER DIAGNOSIS OF ALZHEIMER'S DISEASE: A 20‐YEAR FOLLOW‐UP

To determine characteristics that might affect survival times in Alzheimer's disease (AD) patients treated with cholinesterase inhibitors (ChEI) in clinical practice, and create statistical models of estimated life-span after AD diagnosis. The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicenter study to evaluate the use of long-term ChEI therapy. The SATS enrolled 1,021 participants with a clinical diagnosis of mild-to-moderate AD (Mini-Mental State Examination (MMSE) score, 10–26) at the start of ChEI treatment (shortly after AD diagnosis). Cognitive ability, instrumental and basic activities of daily living (ADL) were evaluated at baseline and semiannually over 3 years, and the date of death was recorded. After up to 20 years of follow-up, 966 patients (95%) were deceased. Two types of multivariate linear regression models were created, one using only sociodemographic and clinical characteristics at baseline, and another model including baseline and longitudinal measures. Both main models included cognitive ability, and the extended models also included ADL capacities, as well as aspects of ChEI therapy in the longitudinal model. Significant independent predictors of longer life expectancy in all models were female sex, younger age, no use of antihypertensive/cardiac therapy or antidiabetics, (but not the specific apolipoprotein E genotype or solitary living), indicating the stability and validity of our regression models. A higher education level predicted shorter survival time in both baseline models (with and without ADL) and in the longitudinal model including cognition only. In the baseline model including ADL capacities, instrumental ADL (IADL) and basic ADL scores were stronger predictors of mortality than cognition. In the longitudinal model including ADL capacities, IADL and basic ADL scores (but not MMSE score) at baseline, progression rates in cognition and basic ADL predicted survival independently. A longer period of ChEI treatment in the study was also a strong predictor of longer life-span of up to ∼2 years. The survival time after a diagnosis of AD could be predicted with a high degree of explanation using multivariate regression models including sociodemographic and clinical factors. These clinically relevant prognostic models can be used to estimate life expectancy for AD patients.

ASSOCIATION WITH REDUCED MORTALITY USING CHOLINESTERASE INHIBITORS IN PATIENTS WITH DEMENTIA: DATA FROM SVEDEM, THE SWEDISH DEMENTIA REGISTRY

Recent studies have shown that cholinesterase inhibitors (ChEIs) associate with a reduced risk of death among patients with mild-to-moderate Alzheimer's disease, but it is not known whether the associations exist for other types of dementia or varies with stage of dementia. Registrants of Swedish dementia registry between 2008 and 2015 were linked to national death and drug registries. ChEIs treatment duration and dosages were obtained from complete collection of pharmacy dispensations in the national drug prescription registry (Läkemedelsregistret). The association between the use of ChEIs and death was examined by Cox proportional hazards model. Propensity score adjusted for age, sex, comorbidity and medications. Stages in the dementia course were defined using Mini Mental State Examination (MMSE) assessments. The cohort included 31,794 patients with a diagnoses of Alzheimer's dementia or mixed or vascular or Lewy body dementia. Of these, 8,901 had very mild dementia (MMSE score 25-30), 12,665with mild dementia (MMSE 20-24), and 10,228 with moderate to severe dementia (MMSE 0-19) at the start of ChEI treatment or dementia diagnosis. Mean age was 79±7.6 years and 59% was female. The proportions of ChEIs treatment were 83%, 62%, 16% and 87% among the patients with Alzheimer's, mixed, vascular and Lewy body dementia separately. During an average of 3.2 (range 0.1-9) years of follow up, 12,850 (40%) of cases died. After adjustment for age, sex, comorbidity and medications, ChEIs users had a 22% lower risk of death (adjusted hazard ratio [HR], 0.78; 95% confidence interval, 0.73-0.84) in Alzheimer's dementia compared with non-users. Effect sizes were similar in mixed [0.78 (0.72-0.83)] and vascular dementia [0.76 (0.69-0.84)], but not in Lewy body dementia [0.93 (0.71-1.22)]. ChEIs users also associated with lower risk of death in patients with very mild [0.71(0.65-0.76)], mild [0.75 (0.72-0.79)] and moderate to severe dementia stages [0.80 (0.75-0.85)] separately. There was also a graded association between cumulative exposure to ChEIs and death. Propensity score matched analyses showed similar results. Initiation of ChEIs therapy and cumulative ChEIs exposure are associated with decreased risk of mortality in Alzheimer's, mixed and vascular dementia patients, irrespective of dementia stage.