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Highly prevalent geriatric medications and their effect on β-amyloid fibril formation

BMC Neurology volume 24, Article number: 445 (2024) Cite this article

Abstract

Background

The unprecedented increase in the older population and ever-increasing incidence of dementia are leading to a “silver tsunami” in upcoming decades. To combat multimorbidity and maintain daily activities, elderly people face a high prevalence of polypharmacy. However, how these medications affect dementia-related pathology, such as Alzheimer’s β-amyloid (Aβ) fibrils formation, remains unknown. In the present study, we aimed to analyze the medication profiles of Alzheimer’s disease (AD; n = 124), mild cognitive impairment (MCI; n = 114), and non-demented (ND; n = 228) patients to identify highly prevalent drugs and to determine the effects of those drugs on Aβ fibrils formation.

Methods

Study subjects (≥ 65 years) were recruited from an academic geriatric practice that heavily focuses on memory disorders. The disease state was defined based on the score of multiple cognitive assessments. Individual medications for each subject were listed and categorized into 10 major drug classes. Statistical analysis was performed to determine the frequency of individual and collective drug classes, which are expressed as percentages of the respective cohorts. 10 µM monomeric β-amyloid (Aβ) 42 and fibrillar Aβ (fAβ) were incubated for 6–48 h in the presence of 25 µM drugs. fAβ was prepared with a 1:10 ratio of Aβ42 to Aβ40. The amount of Aβ fibrils was monitored using a thioflavin T (Th-T) assay. Neuronal cells (N2A and SHSY-5Y) were treated with 25 µM drugs, and cell death was measured using a lactose dehydrogenase (LDH) assay.

Results

We noticed a high prevalence (82–90%) of polypharmacy and diverse medication profiles including anti-inflammatory (65–77%), vitamin and mineral (64–72%), anti-cholesterol (33–41%), anti-hypersensitive (35–39%), proton pump inhibitor (23–34%), anti-thyroid (9–21%), anti-diabetic (5–13%), anti-constipation (9–11%), anti-coagulant (10–13%), and anti-insomnia (9–20%) drugs in the three cohorts. Our LDH assay with 18 highly prevalent drug components showed toxic effects of Norvasc, Tylenol, Colace, and Plavix on N2A cells, and of vitamin D and Novasc on SH-SY5Y cells. All these drugs except Colace significantly reduced the amount of Aβ fibril when incubated with Aβ42 for a short period (6 h). However, Lipitor, vitamin D, Levothyroxine, Prilosec, Flomax, and Norvasc prominently reduce the amount of fibrils when incubated with monomeric Aβ42 for a longer period (48 h). Furthermore, our disaggregation study with fAβ showed consistent results for cholecalciferol (vitamin D), omeprazole (Prilosec), clopidogrel hydrogensulfate (Flomax), levothyroxine, and amlodipine (Norvasc). The chemical structures of these four efficient molecules contain polyphenol components, a characteristic feature of the structures of polyphenolic inhibitors of Aβ fibrillation.

Conclusion

A higher polypharmacy incidence was observed in an elderly population of 228 ND, 114 MCI, and 124 AD patients. We found that several highly recommended drug components, including vitamin D3, Levothyroxine, Prilosec, Flomax, and Norvasc, efficiently reduce the amount of fibrils formed by monomeric Aβ42 and existing preformed Aβ fibrils in vitro. However, only Levothyroxine was able to prevent Aβ-mediated toxicity to SH-SY5Y cells. Our study suggested that these drugs likely function as polyphenolic inhibitors of Aβ.

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Introduction

With the steady increase in life expectancy and rapid decrease in the birth rate, the growth of the aging population is increasing at an unprecedented rate [1, 2]. Despite 16% of the projected growth in the overall world population by 2050, the increase in the elderly population during this period is estimated to be 300% [1, 3]. Due to the aging-associated decline in physical and cognitive functions, the elderly population faces challenges in maintaining independence in their daily activities [1]. Normal debility during aging includes hearing loss, vision loss, decreased walking speed, mobility disabilities, and urinary incontinence [4]. A decrease in age-related cognitive functions is characterized by short-term memory loss, difficulties in word retrieval, and slower cognitive processing. In addition to such aging-associated physical and cognitive decline, the elderly population suffers from acute and chronic diseases, such as hypertension, cardiovascular disease, cancer, depression, dementia, diabetes mellitus, and osteoporosis [4, 5]. Most elderly people experience multimorbidity, two or more chronic diseases. While nonpharmacologic treatments are encouraged to combat such acute and chronic conditions, pharmacologically prescribed or nonprescribed medications are common practices for maintaining daily activities and a comfortable life in the geriatric population [6]. In addition to vitamin and mineral supplements, antiplatelet, and anticoagulant drugs are often prescribed to reduce the risk of atherosclerotic cardiovascular disease and atrial fibrillation in elderly people [7]. Similarly, dementia patients are prescribed antipsychotic drugs to treat severe psychotic symptoms [3]. However, the side effects or adverse reactions of these drugs  predispose the aging population to be at an increased risk for further illness [8]. For instance, anticoagulant drugs prescribed to aged people include aspirin, P2Y12 receptor blockers, low molecular weight heparin, warfarin, and DOAC, which have significant side effects, such as an increased risk of bleeding with aging [7]. Additionally, polypharmacy (prescribing five or more medications per day) is frequently seen in the elderly population as they often suffer from multimorbidity [9]. As different medications are prescribed for each chronic condition or disease, a prescribing cascade can develop, further increasing the risk for adverse drug reactions in the geriatric population [8].

Cognitive ability is maintained by integral neuronal synaptic plasticity to process sensory information and is critical for functional independence, learning, and effective communication during the human life span. Age-associated declines in cognitive function correlate with structural and functional changes in the brain, such as dysfunction of the neuronal network, reduced synaptic plasticity, and structural alterations in neurons without neuronal death [10, 11]. However, in age-associated brain diseases, the development of certain pathologic conditions accelerates neuronal dysfunction and neuronal loss that leads to cognitive impairment, which severely impacts a person’s memory of everyday functional activity and leads to the development of dementia [12]. Alzheimer’s disease (AD) is the most common form of aging-associated dementia and the 5th leading cause of death among people aged 65 and older [3]. Early-onset AD, i.e., earlier than age 65, is rare and constitutes approximately 5% of all AD cases. Genetic, neuroimaging, and biomarker data demonstrate that pathology onset in patients’ brains begins more than 15–20 years before the emergence of clinical symptoms [13,14,15]. During this preclinical phase, pathology onset is initiated by the generation of β-amyloid (Aβ) peptides, which subsequently undergo conformational changes from monomeric to fibrillar (f) forms in a series of aggregation steps and are eventually deposited as Aβ plaques in the brain [13,14,15]. The deposited fAβ and soluble Aβ aggregates advance other intra- and extraneuronal pathologies, including the formation of neuritic/senile plaques, neurofibrillary tangles, dystrophic neurites, and glia-activated neuroinflammation, which ultimately leads to the development of dementia [13, 16,17,18,19,20,21,22,23,24]. Hence, inhibiting Aβ aggregation or fibril formation is one of the critical targets for achieving therapeutic goals in AD patients [13, 25]. Enormous studies have shown that small molecules can interfere with Aβ aggregation and inhibit fibril formation that generates various types of aggregates including non-toxic oligomers [26,27,28,29,30]. While, polypharmacy is a common practice in the elderly population due to polymorbidity, whether those drugs have potential effects on Aβ related pathology is not known yet. In this study, we analyzed the medication profiles of AD (n = 124), mild cognitive impairment (MCI; n = 114), and nondemented (n = 228) patients and identified 18 frequently recommended drugs from 10 drug classes. To determine the potential effects of these drugs on Aβ fibril formation, the ability of each drug to reduce the amount of Aβ fibrils in reaction mixtures was investigated. Our results showed that vitamin D3 (cholecalciferol), Levothyroxine (levothyroxine), Prilosec (omeprazole), Flomax (Clopidogrel hydrogensulfate), and Norvasc (amlodipine) significantly reduced the amount of fibrils in reaction mixtures when incubated with monomeric Aβ42 and prefibrillar Aβ40/42 fibrils. However, vitamin D3 and Norvasc also showed toxicity to neuronal cells. We noticed that some drug components including acetylsalicylic acid (Aspirin), dioctyl sulfosuccinate (Colace), L-ascorbic acid (vitamin C), and metoprolol (Lopressor) increased the fibrils amount in the reaction. The components of several drugs including Levothyroxine, vitamin C, and Lopressor were able to prevent Aβ induced toxicity to human neuroblastoma cells. Our results revealed that the drug components of highly prevalent medication among the geriatric population have differential effects on Aβ fibril formation.

Materials and methods

Materials

1,1,1,3,3,3, Hexafluoro-2-propanol-treated Aβ42 peptide was purchased from Millipore Sigma, MA, USA (Cat# AG698). Aβ40 was purified in the laboratory following a modified protocol used previously [28,29,30]. The fine-grade drug components were obtained from Sigma or Fisher Scientific (USA).

Study subjects and data collection

The study was approved by the Human Investigation Committee of Corewell Health East (CHE) (formally William Beaumont Hospital), Royal Oak, MI, USA (IRB#2017 − 214). The CHE Institutional Review Board is accredited by the Association for the Accreditation of Human Research Protection Programs and complies with Good Clinical Practice Guidelines as defined by the U.S. Food and Drug Administration under the Code of Federal Regulations (21 CFR Parts 50 and 56; 45 CFR Part 46) and International Conference on Harmonization (ICH) Guidelines (Section E6). Written consent was obtained from study participants or their legal representatives prior to obtaining medication information or any samples. We collected medication data from AD patients (n = 124), MCI patients (n = 114), and cognitively normal controls/ND people (n = 228). The diagnosis of AD was based on existing clinical and laboratory criteria according to NINCDS-ADRDA [31]. Only, the medication data from each individual in three cohorts were extracted and analyzed for this study.

Drug profiling and classification

The recommended/prescribed drugs were listed for each patient from their medication profile. The drugs recommended for more than 1% of the people in each cohort were categorized into 10 major drug classes. For each cohort, the frequencies of individual drugs and drug classes were expressed as percentages of the total number of subjects in that cohort. Polypharmacy was determined by counting at least 5 medications recommended for a subject. Vitamins and minerals were not counted in determining the polypharmacy.

Drug selection and the preparation of drug components

Based on the higher frequency of individual drugs in the three cohorts, 18 highly prevalent drugs were selected by choosing at least one drug from each group (Table 1). The drug components were purchased from Millipore Sigma and Fisher Scientific. Each compound (powder) was dissolved in Dimethylsulfoxide (DMSO) at 25mM concentration and stored at -20°C. The stock solutions of drugs were then diluted to the desired concentration either in PBS or culture medium.

Table 1 The drugs/drug components with their molecular weight, drug class, and prescription prevalence in each cohort
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Preparation of Aβ peptides

Immediately before use, Aβ peptides were dissolved in 0.1% NH4OH at a concentration of 2 mg/ml, followed by bath sonication for 10 min at 4 °C. Then, the solution was diluted to the desired concentration with PBS. Preformed fAβ was prepared by incubating Aβ42 and Aβ40 at a 1:10 ratio for 72 h at 37 °C [28, 29]. fAβ was precipitated by centrifugation and washed 2 times with PBS. The concentration of fAβ was measured, and the samples were then stored at -80 °C until use in the experiments.

Thioflavin T (ThT) assay

For the assessment of fibril formation by monomeric Aβ42, 10 µM peptide was incubated in PBS at 37 °C in the presence or absence of each drug (25 µM) in a final volume of 30 µl without shaking. Similarly, for the disaggregation assay, 5 µM fAβ was incubated with 25 µM drug. Then, 20 µl from each reaction was mixed with 80 µl of 6 µM Th-T in PBS. The fluorescence was measured on a Gemini-XS microplate spectrofluorometer (Molecular Devices CA, USA) using excitation at 440 nm and emission at 490 nm [29].

Cell culture, cell death and cell viability assays

Mouse neuronal N2A and Human neuroblastoma SH-SY5Y cells were cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% (v/v) fetal bovine serum (FBS) and 1% antibiotics at 37 °C with 5% CO2 flow. Cells were seeded at a density of 15,000 cells/well in 96-well plates (Nunc, Denmark) and incubated for 24 h. The media were replaced with new media containing 25 µM of each drug. After 24 h of incubation, cytotoxicity was measured with lactate dehydrogenase (LDH) or tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assays. LDH activity was measured using the Pierce LDH Cytotoxicity Assay Kit following the manufacturer’s protocol (Thermo Fisher Scientific, Waltham, MA). Briefly, 50 µl of conditioned medium was collected from each sample and mixed with the reaction solution. The reaction mixtures were incubated for 30 min at 37 °C and then the stop solution was added. The absorbance was measured at 490 and 680 nm on a SpectraMax (Molecular Devices, San Jose, CA). Cell survival was measured using MTT assay kit (abcam, Waltham, MA). Briefly, 50 µl of MTT reagent solution in 50µM FBS free medium was added to each well and incubated for 3 h. Then, 150 µl of solubilizing solution was added to each well and mixed on an orbital rocker for 15 min at room temperature. Then the absorbance was recorded at 590 nm using a microplate reader.

Statistical analysis

The medication profile data for each cohort and each drug class or individual drug are expressed as percentages. All other experiments were performed in triplicate, the data are expressed as the mean ± standard error (SE, n = 3), and statistical significance was assessed by Student’s t-tests. A p-value of < 0.05 was considered significant.

Results

High prevalence of medications and polypharmacy in AD, MCI, and ND cohorts

For acute and chronic illnesses, elderly people are often treated with medications. To determine the composition of medication profiles in the elderly population, we listed all the medications recommended for the total population (466 subjects) and found 453 individual drugs recommended for at least one patient in either the AD, MCI, or ND cohort. We sorted the drugs that have greater than 1% prevalence in all three cohorts and grouped those medications into 10 major drug classes. Then, the frequency of each drug class in the three cohorts was calculated as a whole (Fig. 1A) or separately (Fig. 1B). The medication profiles of the geriatric population primarily consisted of 24% anti-inflammatory, 22% vitamin and mineral, 13% anti-cholesterol, 12% anti-hypertensive , 10% proton pump inhibitor, 5% anti-thyroid, 4% anti-coagulant, 4% melatonin, 3% anti-diabetic, and 3% anti-constipation drugs (Fig. 1A). AD drugs were not included in this class because the prescription frequency was not 1% in the ND cohort. Next, we calculated the prescription or recommendation prevalence of each drug class in each cohort and found that 65–77% of subjects were prescribed anti-inflammatory drugs, 64–72% were recommended for vitamins and minerals, 33–41% of subjects were prescribed anti-cholesterol, 35–39% were advised for anti-hypertensive drugs, 23–34% were prescribed for proton pump inhibitors, 9–21% were given anti-thyroids, 5–13% were recommended for anti-diabetic drugs, 9–11% were prescribed for anti-constipation drugs, 10–13% were recommended for anti-coagulant drugs, and 9–20% were prescribed for anti-insomnia drugs (Fig. 1B). There was approximately 8–10% variation between cohorts for anti-inflammatory and vitamin and mineral drugs, with a greater tendency toward anti-inflammatory drug use by people with AD and increased vitamin and mineral intake by patients with MCI (Fig. 1B). We noticed a reduced tendency for prescription of proton pump inhibitors, anti-thyroids, and anti-diabetic drugs in MCI and AD patients compared to ND patients. ∼20% of AD patients were taking anti-insomnia drugs, and this percentage was reduced to ∼ 10% in the other two cohorts. Over 60% of AD patients were prescribed either an NMDA receptor agonist or a cholinesterase inhibitor, and this percentage was ∼ 15% for MCI patients (Fig. 1B).

Fig. 1
figure 1

The drugs with over 1% prevalence in the three cohorts were classified into 10 groups. (A) The frequency of each drug class was calculated as the percentage of all drugs in the total population (466 subjects in three cohorts). (B) The prevalence of each drug class in the ND (N = 228), MCI (N = 114), and AD (N = 124) cohorts is expressed as a percentage of the total patient cohort. (C) The polypharmacy in each cohort was expressed as the percentage of total patients in the respective cohort

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Polypharmacy is defined as the use of five or more medications for a patient per day [9, 32,33,34]. We counted the number of medications for every patient and the subjects having at least five recommended drugs were noted to determine polypharmacy in each cohort. We found a polypharmacy prevalence of ∼ 91% in the ND cohort, ∼ 82% in the MCI cohort and ∼ 85% in the AD cohort (Fig. 1C). Although polypharmacy rates ranging from 30 to 60% have previously been reported [9], our data suggests a much higher prevalence of polypharmacy in the geriatric population.

Based on the higher frequency of individual drugs in the three cohorts, we identified 18 highly prevalent drugs by choosing at least one drug from each group (Table 1) to study the effects of these drug components on cell survival and Aβ fibril formation. AD drugs were not included in this list.

Cytotoxic effects of frequently recommended drug components

The frequently prescribed brain-penetrating drugs may affect neuronal survival. To determine whether the recommended drugs have toxic effects on neuronal cells, we incubated 25 µM of each of the 18 drugs (Table 1) with mouse neuronal N2A and human neuroblastoma SHSY-5Y cells for 24 h (h). Then, the lactose dehydrogenase (LDH) assay was performed to determine the cytotoxicity [35]. DMSO was treated as a control. We found that several drug components, including 4-acetamidophenol (Tylenol), dioctyl sulfosuccinate (Colace), clopidogrel sulfate (Plavix), and amlodipine (Norvasc), significantly increased LDH activity at a concentration of 25 µM in N2A cells (Fig. 2A). On the other hand, only vitamin D and amlodipine were toxic to SH-SY5Y cells (Fig. 2B). However, levothyroxine and dioctyl sulfosuccinate were found to reduce the LDH activity compared to basal condition in SH-SY5Y cells (Fig. 2B). Such differential effects of same drug components in mouse and human cell line could be due to intercellular/species differences in metabolic activities [36]. 25 µM amlodipine was highly toxic to both mouse and human neuroblastoma cell lines, as demonstrated by 2×increase in LDH activity in the culture medium (Fig. 2A-B). We have validated our cytotoxicity experiment using MTT assay with N2A cells, which showed similar results (Supplemental Fig. 1). Our results demonstrated that high concentrations of these drugs may have detrimental effects on neuronal cells if they penetrate the brain.

Fig. 2
figure 2

Cytotoxicity of 18 highly recommended drugs in the ND, MCI, and AD cohorts was determined by using the LDH assay. N2A (A) and SH-SY5Y (B) cells were incubated with 25 µM for 24 h, and LDH activity in the culture medium was measured. The drug components Lipitor, Colace, Plavix, and Norvasc significantly increased LDH activity in N2A cells. Only two drugs, vitamin D and Norvasc showed toxicity to SHSHy-5Y cells. Levothyroxine and Colace significantly reduce LDH activity compared to DMSO in SHSY-5Y cells. * indicates p ≤ 0.05, *** indicates p ≤ 0.001 (Student’s t test, N = 3)

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Differential effects of highly prevalent geriatric drugs on the fibril formation by monomeric Aβ42 peptide

Genetic, neuroimaging, and biomarker data demonstrate that Aβ deposition in patients’ brains is the earliest event during AD onset [13,14,15]. Aβ undergoes spontaneous aggregation in multiple steps, including primary nucleation, fibril extension, and secondary nucleation [37]. In this multistep aggregation pathway, the Aβ conformation changes from monomer to oligomer, oligomer to protofibril, and then oligomer/protofibril converts into β-sheet fibrils. The ThT assay is commonly used to determine Aβ aggregation by measuring the amount of fAβ in a reaction mixture [28,29,30]. To assess the effects of 18 highly recommended geriatric drugs on Aβ fibril formation, we performed a ThT assay after treating 10 µM Aβ42 with 25 µM each drug. We measured the endpoint ThT reading to determine the amount of fibrils in each reaction mixture after incubating for 6–48 h in PBS (pH 7.2). Several drug components, including Tylenol, Lipitor, vitamin D3, Levothyroxine, Prilosec, Lisinopril, Metformin, Eliquis, Flomax, Plavix, Cozaar, and Norvasc, significantly reduced the amount of fibrils in the reaction mixture after incubation for 6 h (Fig. 3A). Among these drugs, Lipitor, vitamin D3, Levothyroxine, Prilosec, Palvix, Cozaar, and Norvasc consistently inhibited Aβ42 fibrillation when the reaction mixtures were incubated for 48 h (Fig. 3B). Interestingly, we found that the Aspirin, vitamin C, and Lopressor drug components increased the amount of fibrils after incubation for longer durations (Fig. 3B). These results suggest that frequently prescribed geriatric drug component differentially affects Aβ fibrillation process.

Fig. 3
figure 3

Alteration of Aβ aggregation by drugs with a high prevalence. (A) The amount of fibrils in the 25 µM drugs and 10 µM Aβ42 reaction mixtures was measured by ThT assay after 6 h of incubation. (B) Similarly, a ThT assay was performed after 48 h of incubation. Multiple drug components, including vitamin D3, levothyroxine, Prilosec, Flomax, and Norvasc significantly reduced the amount of fibrils when Aβ42 was incubated for longer durations. * indicates p ≤ 0.05, ** indicates p ≤ 0.01 *** indicates p ≤ 0.001 (Student’s t-test, N = 3)

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Effects of frequently prescribed geriatric drugs preformed fAβ

We also investigated the disaggregating efficiency of 18 high-prevalence drug compounds against fAβ. 5 µM fAβ was incubated with 25 µM of the drug for 48 h, and the amount of fibrils in the reaction mixture was estimated using ThT assay. We detected a significant reduction in RFU when fAβ was incubated with vitamin D3, Prilosec, Flomax, Calcium, and Norvasc drug components (Fig. 4). However, the fibrils amount was increased in for Colace (dioctyl sulfosuccinate). Our ThT assay data demonstrate that vitamin D3 (cholecalciferol), Prilosec (omeprazole), Flomax (clopidogrel hydrogensulfate), and Norvasc (amlodipine) may have both inhibitory effects on inhibiting Aβ42 aggregation and disintegrating efficacy on preformed fAβ.

Fig. 4
figure 4

Disintegration of fAβ by highly prevalent drugs. 10 µM fAβ incubated with 25 µM drugs and the amount of the fibrils was measured by ThT assay after 24 h of incubation. The drug components of vitamin D3, Levothyroxine, Prilosec, Flomax, and Norvasc reduced the amount of fibrils when fAβ was co-incubated. * indicates p ≤ 0.05, ** indicates p ≤ 0.01 *** indicates p ≤ 0.001 (Student’s t test, N = 3)

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Preventive effects of highly prevalent drug components on Aβ42 induced neurotoxicity

To determine whether the drug components that reduced the fibrils amount in our ThT assay show preventive effects against Aβ toxicity, SH-SY5Y cells were incubated with 5µM monomeric Aβ42 in the absence or presence of 25µM drug components. Then, LDH activity was measured to assess the cell death after 24 h of incubation. Treatment of Aβ increases ∼ 30% cell death, which is demonstrated by increased LDH activity in the culture medium (Fig. 5). The Aβ induced LDH activity was significantly reduced by levothyroxine, vitamin C, and Lopressor drug components. This suggests that these drugs have cytoprotective effects against Aβ induced toxicity. However, amlodipine (Norvasc) likely showed high toxicity itself regardless of Aβ treatment (Figs. 2 and 5).

Fig. 5
figure 5

Protective effects of highly prevalent drug components against Aβ induced cytotoxicity. SH-SHY5Y cells were incubated with or without 5µM Aβ42 in the presence or absence of indicated drug components. 50 µl culture medium was used to measure LDH activity. Aβ treatment (DMSO) increased ∼ 30% LDH activity compared to no Aβ group. * indicates p ≤ 0.05, ** indicates p ≤ 0.01 *** indicates p ≤ 0.001 (Student’s t-test, N = 3)

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Discussion

The global elderly population is projected to triple by 2050 [4, 7]. The worldwide dementia incidence is also growing at a similar rate, as it has been estimated that the number of people with dementia may increase from 55 million in 2019 to 139 million in 2050 [3]. The majority of elderly people, including those suffering from dementia, have two or more chronic conditions or comorbid physical diseases [38,39,40]. It has been shown that multimorbidity causes polypharmacy in 30–60% of the elderly (≥ 65 years) population, which is expected to be greater in people with dementia [9, 32,33,34]. However, our results revealed a much higher occurrence of polypharmacy in the elderly population, which includes ∼ 91% in ND, ∼ 82% in MCI, and ∼ 85% in AD cohorts (Fig. 1C). Such higher polypharmacy may lead to adverse outcomes, including an increased incidence of falls, frailty, dementia, and decreased quality of life in the geriatric population [33, 41, 42].

Among 18 drugs (Table 1), the components of Tylenol, Colace, Plavix, and Norvasc showed toxicity to neuronal cells at 25 µM concentration when tested in vitro (Fig. 2A-B). Although, there is no evidence showing that Colace and Plavix cross the blood–brain-barrier (BBB), acetaminophen (Tylenol) has been shown to penetrate the brain and exhibit toxicity to brain tissue at higher concentrations [43,44,45]. Similarly, the high toxicity of amlodipine (Fig. 2A-B), the drug component of Norvasc, could be detrimental to neurons if it can penetrate the brain and concentration reaches a toxic level [46, 47].

In AD patients’ brains, initial pathology onset begins with the formation of β-amyloid (Aβ) aggregated plaques, which stimulate other pathology such as tau-associated tangles formation, and eventually emerge the clinical symptoms [13, 48]. Hence, inhibition of Aβ production and Aβ aggregation are growing interest in AD therapeutic development [13, 25]. In this study, we identified that cholecalciferol (vitamin D), levothyroxine, omeprazole (Prilosec), clopidogrel hydrogensulfate (Flomax), Calcium, and amlodipine (Norvasc) efficiently inhibited Aβ42 aggregation and disaggregates fAβ (Figs. 3B and 4). Interestingly, the chemical structures of these efficient molecules contain polyphenol components (Fig. 6), a characteristic feature of the structures of Congo Red and other polyphenolic inhibitors of Aβ fibrillation. Common polyphenol inhibitors are composed of at least 2 phenolic rings with 2–6 atom linkers and a minimum number of 3 OH groups on the aromatic rings [49]. This structural property makes it feasible for polyphenolic compounds to exhibit 3-dimensional structures, which are essential for non-covalent interactions with Aβ peptides [49]. Hence, the non-covalent interaction between these drug components and the Aβ peptide is likely the mechanism of fibril remodeling by these molecules. This speculation is also supported by the fact that the drug components of Tylenol, Lopressor, and Colace, which have non-phenolic or mono-phenolic structures, were not able to inhibit Aβ fibrillation or to disintegrate fAβ (Figs. 2A-B and 3, and 6).

Fig. 6
figure 6

Chemical structures of Congo red, acetamidophenol, cholecalciferol, omeprazole, clopidogrel hydrogensulfate, amlodipine, levothyroxine, and metoprolol tartrate are shown (structures not drawn to scale). The structures of cholecalciferol, levothyroxine, omeprazole, clopidogrel hydrogensulfate, and amlodipine contain polyphenolic components, which are characteristic features of polyphenolic inhibitors of Aβ aggregation, such as Congo red

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Aβ aggregation proceeds in multiple steps that convert monomers to oligomers, and oligomers to fibrils [37, 50]. Hence, inhibition of these steps or reduction of fibrils leads to various types of Aβ aggregates including toxic and non-toxic oligomers [26,27,28,29,30]. Our cytotoxicity data demonstrated that levothyroxine is the only compound that reduces Aβ fibrils and attenuates Aβ- induced neurotoxicity (Figs. 2A-B and 3, and 5). This suggests that levothyroxine likely converts the Aβ aggregation pathway to an off-pathway that generates non-toxic aggregates [29, 30]. Interestingly, vitamin C (L-ascorbic acid) and Lopressor (metoprolol tartrate) elevated fibrils formation (Fig. 3A-B) and also prevented Aβ induced toxicity to SH-SY5Y cells. Possibly, these drug compounds protect cells from Aβ toxicity by different mechanisms.

A greater intake of vitamin D is pivotal because 90% of elderly people suffer from hypovitaminosis [51]. Our study showed that more than 65% of elderly people were recommended to consume at least one vitamin, among whom 38–42% were adherent to vitamin D (Figs. 2B and 3B). Studies have shown that vitamin D can cross the BBB and that this supplement is beneficial for attenuating neuroinflammation, improving cognition, and reducing amyloid pathology by impairing APP processing and enhancing Aβ degradation in mice [52,53,54,55]. Our results showed that vitamin D efficiently reduced fibril amounts when incubated with monomeric Aβ42 and fAβ, which could contribute to attenuating the plaque load in vitamin D-treated AD mouse brains [54].

While, the ability of clopidogrel hydrogen sulfate and amlodipine to penetrate the brain remains unclear, the ability of omeprazole to penetrate the brain is well documented [45,46,47, 56, 57]. However, the effects of omeprazole on dementia remain controversial. Studies focused on European and Asian populations have shown a positive correlation between the use of proton pump inhibitors (such as omeprazole, esomeprazole, lansoprazole, and pantoprazole) and dementia [58, 59]. In contrast, a large population-based study and a recent report showed a negative correlation between the use of proton pump inhibitors and dementia [60, 61]. In our study, omeprazole was the most effective compound that significantly reduced fibrils amount when incubated with monomeric Aβ42 and preformed fAβ (Figs. 3A-B and 4). However, our cytotoxicity results showed that omeprazole does not prevent Aβ toxicity to SH-SY5Y cells (Fig. 5). One possibility is that incubation of Aβ with omeprazole hinders β-sheet fibrils formation but enriches soluble oligomer species. In other words, the drug compound of omeprazole is likely ineffective in converting the Aβ aggregation pathway to an off-pathway that generates non-toxic oligomers [29, 30]. A further study using an animal model is necessary to determine the effectiveness of this molecule against amyloid pathology and cognitive deficit in the AD brain.

Conclusion

We found that the polypharmacy prevalence in the elderly population was greater in the ND population than in the MCI and ND populations. We identified several high-prevalence drug components, namely, cholecalciferol, levothyroxine, omeprazole, clopidogrel hydrogensulfate, and amlodipine, which significantly reduce the amount of fibrils when incubated with Aβ42 monomers and fAβ. Structurally, all these molecules contain polyphenols, which have been identified as effective components for preventing Aβ aggregation. However, only levothyroxine was able to prevent Aβ42 neurotoxicity. While, these polyphenolic molecules are potential inhibitors against Aβ pathology, further studies are needed to determine the inhibitory mechanism, in vivo efficacy, and clinical benefit of these molecules against AD.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Aβ:

β-Amyloid

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

BBB:

Blood–brain barrier

CDR:

Clinical Dementia Rating Scale

DMSO:

Dimethyl sulfoxide

LDH:

Lactose dehydrogenase

MCI:

Mild cognitive impairment

MMSE:

Mini-Mental Status Examination

ND:

Non-demented

Th-T:

Thioflavin T

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Funding

This work is supported by the Alzheimer’s disease Research Program startup fund to Dr. Sharoar from the Corewell Health East (formally Beaumont Health).

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Authors and Affiliations

  1. Corewell Health Research Institute, Corewell Health East, 3811 W 13 mile Road, Royal Oak, MI, 48073, USA

    Zakia Zaman, Radia Islam, Bhavya Koganti, Vaibhavkumar Falki, Tammy Osentoski, Stewart Graham & Md. Golam Sharoar

  2. Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Corewell Health East, 3811 W 13 mile Road, Royal Oak, MI, 48073, USA

    Md. Golam Sharoar

  3. Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Corewell Health East, 3811 W 13 mile Road, Royal Oak, MI, 48073, USA

    Stewart Graham

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  1. Zakia Zaman
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Contributions

Z.Z., B.K., and V.F. sorted and analyzed the medication data. Z.Z. and R.I. cultured the cells and performed ThT and LDH assays. R.I searched the literature and partially wrote the manuscript draft. T.O. collected the data. S.G. interpreted the data and edited the manuscript. M.G.S. designed the study, analyzed and interpreted the data, and wrote the manuscript draft. All author reviewed the manuscript.

Corresponding author

Correspondence to Md. Golam Sharoar.

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Human Ethics and Consent to Participate

The study was approved by the Human Investigation Committee of Corewell Health East (CHE) (formally William Beaumont Hospital), Royal Oak, MI, USA under an approved protocol by the Institutional Review Board (IRB#2017 − 214). The CHE Institutional Review Board is accredited by the Association for the Accreditation of Human Research Protection Programs and complies with Good Clinical Practice Guidelines as defined by the U.S. Food and Drug Administration under the Code of Federal Regulations (21 CFR Parts 50 and 56; 45 CFR Part 46) and International Conference on Harmonization (ICH) Guidelines (Section E6). Written consent was obtained from study participants or their legal representatives prior to obtaining the data.

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The authors declare no competing interests.

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Zaman, Z., Islam, R., Koganti, B. et al. Highly prevalent geriatric medications and their effect on β-amyloid fibril formation. BMC Neurol 24, 445 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12883-024-03930-7

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BMC Neurology

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