Category Archives: Alzheimer’s Disease

Common Class of Medications Linked to AD, MCI Risk 

Several types of medications have been linked to mild cognitive impairment and Alzheimer’s disease (AD) risk in older patients over the years. A growing body of evidence points to drugs with anticholinergic effects as particularly dangerous for certain patient demographics. Emerging results from a recent study indicate that there may be a significant association between anticholinergic medications, AD biomarkers, and the incidence of mild cognitive impairment among cognitively normal older adults.

Anticholinergic Medications

Anticholinergic drugs have been widely used for a variety of medical conditions, ranging from allergies and the common cold to the treatment of hypertension. While certain anticholinergic medications require a prescription, others can be easily purchased over the counter.

This class of medications works by blocking acetylcholine, a neurotransmitter critical for memory function, from binding to receptors on certain nerve cells thereby inhibiting parasympathetic nerve impulses, which underlie involuntary muscle movements and bodily functions.

Examining the Relationship 

A team of researchers aimed to determine whether there were any cognitive consequences of anticholinergic medications (aCH) among a group of cognitively normal older patients and whether the interactive effects of genetic and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) risk factors had any influence.

Led by Alexandra Weigand at the UC San Diego School of Medicine, the team of researchers assessed 688 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative with a mean age of 73.5 years. None of the participants presented with any cognitive or memory problems at the time of study inception. Approximately one-third of patients was taking anticholinergic medications with an average of 4.7 aCH drugs per person. The study’s authors administered comprehensive cognitive tests annually for all participants.

Cox regression models were used to examine the risk of progression to mild cognitive impairment (MCI) over a 10-year period, while linear mixed effects models were utilized to evaluate 3-year rates of memory, executive, and language function as related to anticholinergic medication administration.

Association of Anticholinergic Drugs with AD and MCI

According to the study’s findings published in Neurology, participants with AD biomarkers who were taking anticholinergic medications were up to four times more likely to develop mild cognitive impairment than those lacking biomarkers and not taking aCH drugs. Similarly, participants who were at a genetic risk for Alzheimer’s disease who took anticholinergic medications were up to 2.5 times more likely to develop MCI than those without genetic risk factors who were not taking the medications.

Further, linear mixed effects models found that anticholinergic medications predicted a steeper slope of decline in memory and language functions. This was especially true for participants with AD risk factors, in which the effects were exacerbated.

Researchers believe that the association acts in a “double hit manner” :”In the first hit, Alzheimer’s biomarkers indicate that pathology has started to accumulate in and degenerate a small region called the basal forebrain that produces the chemical acetylcholine, which promotes thinking and memory. In the second hit, anticholinergic drugs further deplete the brain’s store of acetylcholine.” Overall, the combined effect can have a severe impact on a patient’s thinking and memory.

Clinical Implications 

The latest findings implicate an increased risk of incident MCI and cognitive decline as related to anticholinergic medications with effects significantly exacerbated in patients with existing genetic risk factors and CSF-based biomarkers. These results “underscore the adverse impact of these drugs on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD,” the study’s authors wrote, emphasizing the importance of further evaluation to determine whether reductions in drug usage can lead to reductions in MCI progression.

However, the researchers also noted that anticholinergic medications were being taken at levels much higher than the lowest effective dose recommended for older patients; 57% of participants were taking twice the recommended dosage while 18% were taking at least four times the recommended dose.

As the findings suggest, reducing anticholinergic drug consumption may help delay age-related cognitive decline. According to senior author and associate professor at the UC San Diego School of Medicine Lisa Delano-Wood, PhD, the latest study “suggests that reducing anticholinergic drug use before cognitive problems appear may be important for preventing future negative effects on memory and thinking skills, especially for people at greater risk for Alzheimer’s disease.”

While the current evidence indicates a clear association between anticholinergic medications and cognitive effects, further research efforts are needed to determine whether these agents are able to accelerate cognitive changes or lead to the development of Alzheimer’s disease and other neurodegenerative disorders.

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Novel Blood Test Shows Promise for Early Diagnosis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a debilitating and incurable condition affecting approximately 6 million Americans aged 65 and older. As the number of AD cases in the United States is projected to reach an estimated 14 million by the year 2050, there is a pressing need for effective prevention therapies. Currently, there are limitations in diagnostic testing methods for Alzheimer’s disease; to date, the diagnosis of AD has been largely based on amyloid plaques and tau tangles identified in the brain postmortem.

Emerging evidence from Lund University evaluated the potential profound impact on Alzheimer’s research and care an inexpensive and accessible diagnostic test for the presence of plaques and tangles would have. In the recent study, researchers demonstrate the great promise of a novel blood test in discriminating between persons with and without AD as well as identifying the disease in individuals at known genetic risk as early as 20 years before onset.

The large international study was recently published in the Journal of the American Medical Association (JAMA) and reveals that measurements of phospho-tau217 (p-tau217) could help medical professionals accurately identify symptoms of Alzheimer’s in living patients.

Identifying Alzheimer’s Disease 

Researchers in Arizona, Sweden, and Colombia investigated the discriminative accuracy of plasma phospho-tau217 at differentiating Alzheimer’s disease from other neurodegenerative disorders. To do so, the study’s authors evaluated a new p-tau217 blood test administered in 1,402 cognitively impaired and unimpaired participants. Subjects included 81 participants from Arizona’s Banner Sun Health Research Institute Brain Donation program, 699 patients from the Swedish BioFINDER Study, and 522 Colombian autosomal dominant AD-causing mutation carriers and non-carriers.

P-tau217 Accurately Distinguishes Risk

The cross-sectional study found that plasma p-tau217 discriminated Alzheimer’s disease from other neurodegenerative diseases with significantly more accuracy than established AD plasma- and MRI-based biomarkers.

In the Arizona cohort, the novel blood test successfully discriminated between brain donors with and without the subsequent diagnosis of “intermediate or high likelihood of Alzheimer’s” with 89% accuracy. Meanwhile, in participants with and without a diagnosis of “high likelihood” the assay was 98% accurate. Higher p-tau217 measures were associated with increased brain tangle counts only in participants with present amyloid plaques.

Within the Swedish cohort, the assay discriminated between persons with clinically diagnosed Alzheimer’s and other neurodegenerative diseases with 96% accuracy, similar to tau PET scans and CSF biomarkers and better than several other blood tests and MRI measurements. Further, it distinguished between patients with and without an abnormal tau PET scan with up to 93% accuracy.

Finally, in the Colombian cohort, the blood test was able to distinguish between mutation carriers and non-carriers 20 years before their estimated age of onset of mild cognitive impairment. For all of the analyses performed, p-tau217 was found to outperform p-tau181 – a similar component of tau tangles and blood test – as well as several other studied assays; its performance did not differ significantly from that of key CSF- or PET-based measures.

In recent years, much progress has been made in the development of blood tests for Alzheimer’s disease. Although the plasma p-tau217 was found to discriminate AD from other neurodegenerative disease, additional research is needed to validate these findings in larger and more diverse cohorts in order to both optimize the blood test and determine its potential role in the clinical setting.

”The p-tau217 blood test has great promise in the diagnosis, early detection, and study of Alzheimer’s,” lead author Oskar Hansson, MD, PhD, told Science Daily.“While more work is needed to optimize the assay and test it in other people before it becomes available in the clinic, the blood test might become especially useful to improve the recognition, diagnosis, and care of people in the primary care setting.”

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Ketone-Rich Diets May Reduce Alzheimer’s Disease Risk

In the early stages of development, Alzheimer’s disease (AD) causes overactive brain functioning, potentially as a result of the loss of inhibitory – GABAergic – interneurons that control the signaling of other neurons in the circuit. Interneurons require more energy compared with other neurons, which makes them more susceptible to degeneration upon encountering the Alzheimer’s disease protein – amyloid beta. Research has shown the negative impact of amyloid beta interaction , revealing its ability to damage mitochondria by interfering with SIRT3 – a protective protein.

Impaired mitochondrial function and abnormal neuronal network activity are thought to be some of the early signs of the development of Alzheimer’s disease, however, how mitochondrial alterations contribute to the abnormal activity in neural circuits and their connection to AD remains unknown.

SIRT3 in Mice with Alzheimer’s Disease 

In a recent study published in the Journal of Neuroscience, Aiwu Chang, PhD, and her colleagues investigated the function of the mitochondrial protein by genetically reducing the levels of SIRT3 in mouse models of Alzheimer’s disease. Per their findings, mice with low levels of SIRT3 experienced a significantly higher mortality rate, more violent seizures, and increased interneuron death compared with mice from the standard Alzheimer’s disease model as well as the control group. Both male and female mice were observed to die prematurely before 5 months of age.

On the other hand, mice with reduced levels of SIRT3 who consumed a ketone-rich diet experienced fewer seizures and were less likely to die. Consuming the fatty acid also increased levels of SIRT3 in these mice.  “When comparing male mice among different genotypes, SIRT3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability,” researchers wrote.

In short, SIRT3 proteins work to preserve GABAergic interneurons and protect cerebral circuits against hyperexcitability; this neuroprotective mechanism can potentially be reinforced by dietary ketone intake.

Ketone Consumption for Risk Reduction

The latest findings implicate that the consumption of ketones may be a way of protecting interneurons and delaying the progression of Alzheimer’s disease. By preserving mitochondrial function, SIRT3 protects interneurons against amyloid beta-induced dysfunction ad degeneration in mice with Alzheimer’s disease. According to Dr. Chang and her team, “the neuronal network dysfunction that occurs in Alzheimer’s disease can be partially reversed by physiological, dietary, and pharmacological interventions to increase SIRT3 expression and enhance the functionality of GABAergic interneurons.”

Due to the growing popularity of the ketogenic diet – which can support weight loss, diabetes management, and several other health conditions – there is an increased awareness and availability of ketone-rich foods. Limiting carbohydrate consumptions and incorporating ketone-rich foods such as seafood, low carb vegetables, high-quality meat and poultry, and eggs into the diet may prove to have neuroprotective effects.

The study’s findings implicate the potential benefit of ketone consumption; however, the results need to be verified in human studies before any recommendations can be made. Further research is necessary to determine whether a ketogenic diet in humans may reduce Alzheimer’s disease risk and to what degree.

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