Alzheimer’s Risk

Sildenafil (Viagra) may help reduce Alzheimer’s risk, study suggests

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A blister pack of sildenafil (viagra) tablets for erectile dysfunction
New research is looking at Viagra’s potential to treat Alzheimer’s.
  • Sildenafil, a compound in drugs that treat erectile dysfunction and one type of hypertension, could be used to prevent and treat Alzheimer’s disease, the results of a new study suggest.
  • Among people who already take sildenafil, the main ingredient in Viagra, the incidence of Alzheimer’s disease was significantly less than in people who did not.
  • At least one expert warned that an observational study such as this may not be telling the whole story, and should be approached with caution.

The compound sildenafil is a main ingredient in Viagra, and it forms the basis of Revatio, a medication for pulmonary arterial hypertension. Now, a new study suggests sildenafil may also help in treating Alzheimer’s disease.

Researchers, led by the Cleveland Clinic, observed a 30% to 54% reduction in the incidence of Alzheimer’s disease among people who were taking sildenafil for erectile dysfunction or pulmonary arterial hypertension, compared to those who did not.

The study is published in the Journal of Alzheimer’s Disease.

Sildenafil lowers tau levels in the brain

Alzheimer’s disease is the most common type of dementia. The Alzheimer’s Association estimatesTrusted Source that about 6.7 million Americans are living with Alzheimer’s. It is the fifth-leading cause of death in the U.S., and its prevalence is expected to rise as the population ages.

According to the Alzheimer’s Association between 2000 and 2019, deaths from stroke, heart disease, and HIV decreased, whereas reported deaths from Alzheimer’s increased more than 145%.

Alzheimer’s is a progressive disease, getting worse over time, typically beginning with memory loss and ultimately leading to difficulties communicating with others, or responding appropriately to the environment in which one finds themselves.

The authors of the new study utilized computational models to parse the data for millions of patients in two medical databases, MarketScan Medicare Supplemental and Clinformatics. In the MarketScan database, the reduction in Alzheimer’s was 54%. In the Clinformatics database, it was 30%.

After sildenafil was identified as a drug of interest from the analyzed data, further research occurred in the lab. Working with brain cells from Alzheimer’s patients, researchers found that sildenafil lowered levels of neurotoxic tau proteins. Such proteins build up in the brain as Alzheimer’s progresses.

For many years, these tau proteins were coupled with amyloid plaques as likely causes of Alzheimer’s. However, the foundational research on amyloid plaques has been discredited. Even so, neurotoxic tau proteins are still considered to be a crucial aspect of Alzheimer’s.

They also observed that neurons they had exposed to sildenafil promoted improved brain function, cell growth, and also reduced inflammation and metabolic processes associated with the cognitive degeneration that occurs with Alzheimer’s.

PDE 5 inhibitors to treat Alzheimer’s?

Sildenafil, as a treatment for erectile dysfunction, is a phosphodiesterase type 5 inhibitor, or PDE 5 inhibitor.

Dr. Ozama Ismail, Ph.D., Alzheimer’s Association director of scientific programs, who was not involved in the new study, noted that there was a recent and large UK study that suggested PDE 5 inhibitors may be able to reduce the likelihood of developing Alzheimer’s, but “there is no evidence that these drugs are able to treat Alzheimer’s disease.”

As far as the current study goes, said Dr. Ismail, “This observational study is based on electronic healthcare records and cannot determine if the connection is meaningful without further exploration.”

“Further research and specifically designed clinical trials are a necessary step before considering phosphodiesterase type 5 inhibitors for Alzheimer’s treatment.

”Such trials would need to include diverse participants — including women — to conclusively determine if this class of drug can meaningfully treat Alzheimer’s disease,” said Dr. Ismail.

He also cited as an “important limitation” of this study that Alzheimer’s was not diagnosed “using ‘gold standard’ testing that included imaging biomarkers and/or assessment at autopsy.”

If sildenafil is helpful for addressing Alzheimer’s, suggested Dr. Neil Paulvin, it may have to do with “activating [the] pakt pathway and increasing blood flow.”

The phosphatidylinositol 3-kinase (PI3K)/Akt pathwayTrusted Source is key to various cellular processes, and has been implicated in cancer, so understanding its mechanisms better could theoretically provide clues as to what occurs in Alzheimer’s.

Dr. Paulvin was likewise not involved in the study.

Safety concerns about repurposing drugs

The identification of sildenafil is an example of what may be possible with computer searches for valuable molecules. Dr. Paulvin noted such searches have turned up drugs such as “gemfibrozil [for cholesterol control], astaxanthin [an antioxidant], [and] minocycline [for treating bacterial infections].”

“This study highlights a potential new avenue for drug repurposing. Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects. This can sometimes reduce the length and cost of studies needed for the new indication,” Dr. Ismail said.

He noted, however, that Alzheimer’s disease is especially “complex and multifaceted.” As a result,” he noted, “it is likely that combination therapies targeting different mechanisms are needed.”

“When considering repurposing an existing drug as an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismail explained.

He cited the Alzheimer’s Association Part The Cloud initiative that has already invested more than $68 million supporting 65 clinical trials. These trials are aimed at “targeting various known and potential new aspects of the disease, including new and repurposed treatments for Alzheimer’s and other dementia.”

He noted that the endeavor is focusing on different pathways to treatment, such as how immune responses affect Alzheimer’s-related brain changes, the manner in which brain cells utilize energy and fuel, how they remove debris, and how the brain’s blood supply is maintained.

As regards to sildenafil, Dr. Ismail stressed that people should not use such prescription medications or over-the-counter [supplements and products similar to] phosphodiesterase type 5 inhibitors in hopes of preventing Alzheimer’s or other types of dementia based on these preliminary findings.

“Always consult your physician before starting or changing your medications,” he added.

H pylori Infection Linked to Increased Alzheimer’s Risk

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TOPLINE:

Patients aged 50 years or older with clinically apparent Helicobacter pylori infection (CAHPI) have an 11% increased risk for Alzheimer’s disease (AD), results of a large and lengthy population-based study suggest.

METHODOLOGY: 

  • Researchers identified all cases with a first-time diagnosis of AD and matched each AD case to up to 40 AD-free control cases on the basis of age, sex, cohort entry date, and duration of follow-up.
  • The exposure of interest was CAHPI, defined based on an algorithm using clinical guidelines and recommendations on the management of HP infection, with researchers focusing on infected individuals presenting with symptoms or developing serious complications from the infection.
  • Researchers performed several sensitivity analyses, which included repeating the primary analysis using alternate lag periods, restricting the cohort to participants with AD (not vascular, alcoholic, and unspecified dementia), and using salmonellosis, an infection not previously associated with AD, as a negative control exposure.

TAKEAWAY: 

  • Compared with no exposure to CAHPI, exposure to CAHPI was associated with a moderately increased risk for AD (odds ratio [OR], 1.11; 95% CI, 1.01-1.21), with no major effect modification by demographics or socioeconomic status.
  • The increased risk peaked 7.3-10.8 years after CAHPI onset (OR, 1.24; 95% CI, 1.05-1.47) before decreasing.
  • Sensitivity analyses yielded findings that were overall consistent with those of the primary analysis.
  • The analysis with salmonellosis as a negative control exposure showed no association with the risk for AD (OR, 1.03; 95% CI, 0.82-1.29).

IN PRACTICE:

“These results support the notion of HP infection as a potential modifiable risk factor of AD” and “pave the way for future randomized controlled trials that would assess the impact and cost-effectiveness of population-based targeted interventions such as individualized HP eradication programs, on the development of AD,” the authors write.

SOURCE:

The study was conducted by Antonios Douros ,Department of Medicine, and Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada, and colleagues. It was published online December 13, 2023 in Alzheimer’s & Dementia.

LIMITATIONS:

Given the observational nature of the study, residual confounding is possible. Because the exposure definition was on the basis of CAHPI recorded by general practitioners, exposure misclassification due to symptomatic patients not seeking primary care is possible, as is outcome misclassification. The authors can’t rule out the possibility of an association between asymptomatic H pylori infection and AD risk.

H pylori Infection Linked With Increased Alzheimer’s Risk

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Adults with a recent history of clinically apparent Helicobacter pylori (HP) infection (CAHPI) have an increased risk for Alzheimer’s disease (AD), compared with patients without CAHPI exposure, data suggested.

In a population-based cohort of 4,262,092 patients aged 50 years or older without dementia, CAHPI in the previous 2 years or more was associated with an 11% increased risk for AD compared with no exposure to CAHPI. A secondary analysis found a similarly increased risk for non-AD dementia with CAPHI exposure.

“Our result confirms the assumption that H pylori infection could be a modifiable risk factor for AD,” senior author Paul Brassard, MD, a professor of medicine at McGill University in Montreal, told Medscape Medical News. “Whether and to what extent the consistent and comprehensive control of this stomach bacterium through so-called eradication programs actually influences the development of AD, however, must first be tested in large-scale, randomized trials.”

photo of Paul Brassard
Paul Brassard, MD

The data were published on December 13 in Alzheimer’s & Dementia.

Small Effect Size

The study cohort was taken from the UK Clinical Practice Research Datalink (CPRD) GOLD, a large primary care database covering more than 11 million patients at 674 UK general practices. Participants were enrolled between January 1988 and December 2017 and were followed until December 2019: Diagnosis of AD, end of registration with the CPRD’s general practice, or death from any cause.

AD was defined as one or more of these criteria: AD diagnosis and one or more prescriptions for AD medications in any sequence, unspecified dementia diagnosis followed by two or more prescriptions for AD medications, two or more records of an AD diagnosis, AD diagnosis after a dementia test, and AD diagnosis and any dementia symptom (such as memory impairment, aphasia, apraxia, or agnosia). The investigators matched each AD case to as many as 40 AD-free controls selected from the same cohort with risk-set sampling.

They focused on patients with CAHPI who presented with symptoms or developed serious complications from the infection because “the majority of HP-infected individuals remain asymptomatic over time and may never develop any medical condition,” the researchers wrote.

The definition of CAHPI was based on one or more of the following criteria: Positive urea breath test or monoclonal stool antigen test and eradication therapy within 30 days of the test, diagnosis of HP-related disease or related complication (such as uninvestigated or functional dyspepsia, unspecified gastric or duodenal ulcer, unspecified gastritis, or confirmed HP-gastritis) and eradication therapy within 30 days of the diagnosis, or diagnosis of gastric mucosa-associated lymphoid tissue lymphoma or noncardia gastric cancer.

The mean age of participants at cohort entry was 60.4 years, and 52.1% of the population were women. In all, 40,455 patients were diagnosed with AD. Compared with no exposure to CAHPI, exposure was associated with a “moderate but statistically significant” increase in the risk for AD (odds ratio [OR], 1.11), wrote the researchers. The increase in risk peaked at 7.3-10.8 years after CAHPI onset (OR, 1.24).

“Indeed, the effect size is small but significant and at the population level would not have a major impact taken alone,” said Brassard. “We think it supports the infectious hypothesis in general as a potential contributor, through various mechanisms, to a neurodegenerative process.” 

A Chance Observation?

Commenting on the study for Medscape Medical News, David S. Knopman, MD, a clinical neurologist specializing in AD at the Mayo Clinic and professor of neurology at the Mayo Clinic College of Medicine, both in Rochester, Minnesota, said that he has concerns that such reports are “either of no use or actually misleading.” Knopman did not participate in the research.

“First, the claim that they are looking at AD is simply a gross overstatement of diagnostic specificity. You can be certain that these administratively defined cases had dementia of diverse etiology,” he told Medscape Medical News. “To make claims about risk for AD, where AD in this context actually meant all-cause dementia, is misleading.”

Another concern “is that the likelihood that this is a chance observation that has no biological significance is very high, especially given the tiny effect size. Alternatively, it’s possible that the association is real but entirely nonspecific. It is well known that there is a link between general health and risk of dementia, but in the end, a report like this just adds noise and confusion, not substance.”

Adults at Alzheimer’s Risk May Reverse Memory Loss with Music, Meditation

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Meditation, Music May Help Reverse Early Memory Loss in Adults with Alzheimer’s Risk

A West Virginia University research team, led by Kim Innes, PhD, conducted a randomized, controlled clinical trial in 60 adults with subjective cognitive decline (SCD), a condition that might be associated with preclinical-stage AD. They found that beginner meditation (Kirtan Kriya, or KK) or listening to music for 12 minutes a day for three months had significant benefits.

The team detailed its findings in the study, “Meditation and Music Improve Memory and Cognitive Function in Adults with Subjective Cognitive Decline: A Pilot Randomized Controlled Trial.” It was published in the Journal of Alzheimer’s Disease.

Participants were assigned to KK or a music listening (ML) program, and asked to practice 12 minutes per day for three months, then at their discretion for three months. Their memory and cognitive function were measured at baseline, three months and six months using the memory functioning questionnaire (MFQ), trail making test (TMT-A/B), and digit-symbol substitution test (DSST).

53 people (88%) completed the study.

Participants performed an average of 93% of sessions (91% in the KK group and 94% in ML) in the first three months, and 71% of sessions (68% in KK and 74% in ML) during the three-month follow-up period.

Both groups showed significant improvements at three months in memory and cognitive performance. At six months, overall gains were maintained or improved. The benefits did not differ by age, gender, baseline cognition scores, or any other factor.

The improvements were in cognitive functioning areas most likely to be affected in preclinical and early stages of dementia, such as attention, executive function, and subjective memory function. There were substantial gains in memory and cognition, and they were sustained or enhanced at the six-month mark.

In another paper, the team said both study groups showed improvements in sleep, mood, stress, well-being, and quality of life, particularly those in the mediation group. All the benefits were sustained or enhanced post-intervention, the researchers said.

“The findings of this trial suggest that two simple mind-body practices, Kirtan Kriya meditation and music listening, may not only improve mood, sleep, and quality of life, but also boost cognition and help reverse perceived memory loss in older adults with SCD,” the team wrote.

Source:alzheimersnewstoday.com

Estrogen Patch in Newly Postmenopausal Women May Reduce Alzheimer’s Risk

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Summary: According to a new study, amyloid deposition is reduced in newly postmenopausal women who received a estrogen replacement therapy.

Source: Mayo Clinic.

Can estrogen preserve brain function and decrease the risk of Alzheimer’s disease when given early in menopause? Newly postmenopausal women who received estrogen via a skin patch had reduced beta-amyloid deposits, the sticky plaques found in the brains of people with Alzheimer’s disease, a Mayo Clinic study published this month in the Journal of Alzheimer’s Disease found. Ultimately, these deposits harm neurons, leading to cognitive problems.

In the study, women with APOE e4 — one form of the most common gene associated with late-onset Alzheimer’s disease — had lower levels of amyloid deposits.

“This study showed, for the first time, that the brain amyloid deposition — a hallmark of Alzheimer’s disease — is reduced in newly postmenopausal women who received 17beta-Estradiol patch form of hormone therapy,” says lead author Kejal Kantarci, M.D., a Mayo Clinic radiologist. “Women with APOE e4, who have a greater genetic risk for Alzheimer’s disease, particularly benefited from this therapy.”

Menopause is defined as occurring 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. In the U.S., the average age of menopause is 51. A rapid decline in estrogen with menopause may be associated with an increased risk of Alzheimer’s disease risk in women.

The Women’s Health Initiative study by the National Institutes of Health (NIH) reported that menopausal hormone therapy started in women 65 or older increased the risk of dementia. In contrast, the multicenter Kronos Early Estrogen Prevention Study tested the hypothesis that healthy and younger women would respond to menopausal hormone therapy more favorably.

The Mayo Clinic study used data from the Kronos study to determine the effects of menopausal hormone therapy shortly after menopause, during the critical window of rapid estrogen depletion — five to 36 months past menopause. Researchers investigated the brain amyloid deposition in 68 women ages 42 to 59 who participated in the Kronos trial during this critical window. The researchers used positron emission tomography, also known as a PET scan, to look for the brain amyloid deposits three years after the trial ended.

An alzheimer's brain slice.

Menopause is defined as occurring 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. In the U.S., the average age of menopause is 51. A rapid decline in estrogen with menopause may be associated with an increased risk of Alzheimer’s disease risk in women. NeuroscienceNews.com image is for illustrative purposes only.

Of the 68 women, 21 received estrogen via a skin patch, 17 received estrogen orally and 30 received a placebo. Amyloid deposition was lower in women who received the patch, compared to the placebo, and the effect was most apparent in women with the APOE e4 genotype. The oral treatment was not associated with lower amyloid deposition.

The authors are seeking funding to perform amyloid PET imaging at eight more Kronos Early Estrogen Prevention study sites around the U.S.

“If our results are confirmed in the larger group of women, this finding has the potential to change the concepts for preventive interventions that drive the Alzheimer’s disease field today,” Dr. Kantarci says. “It also may have a significant impact on women making the decision to use hormone therapy in the early postmenopausal years.”

Stress Tied to Alzheimer’s Risk

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Worrying about things you can’t control may put you at greater risk of developing Alzheimer’s disease later in life, according to a study published in Alzheimer Disease and Associated Disorders.

Researchers at the Albert Einstein College of Medicine and Montefiore Health System in New York looked at data from more than 500 adults 70 and older to examine the connection between chronic stress and what’s known as amnestic mild cognitive impairment (aMCI), which is often a precursor of Alzheimer’s.

The study authors gave questionnaires to just over 500 adults, aged 70 and older, asking about how much stress they experience. None of the adults had signs of dementia at the study’s start. The researchers then followed the study participants for more than three years. Each year, they underwent a series of tests related to their daily living, their memory and their ability to think clearly.

Stress Tied to Alzheimer's Risk

Adults who perceived themselves to be under the most stress had a considerably greater risk of early cognitive impairment, according to the study. This risk remained after accounting for the participants’ depression symptoms, age, sex, race, education level and genetic risk of Alzheimer’s disease.

The researchers acknowledged that the study showed only an association between stress and aMCI, but not clear evidence that it causes that type of cognitive impairment.

About 5 million people in the U.S. 65 and older had Alzheimer’s disease in 2013, according to the Centers for Disease Control and Prevention. That number is expected to triple by 2050.’