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15th August 2023
With a recent study suggesting that components within espresso coffee extract nullified the adverse effects of the Alzheimer‘s-associated tau protein, is drinking coffee a potential lifestyle preventative measure for reducing the risk of such neurodegenerative conditions? Clinical writer Rod Tucker takes a look at the evidence.
There’s no doubt that coffee is a widely consumed beverage and coffee culture has taken the world by storm from the espresso bars of Italy to the commercial giants on seemingly every street corner. Deemed to be one of the most widely traded commodities in the world, around two billion cups of coffee are consumed worldwide each day, according to the British Coffee Association.
Coffee is prepared and drunk in a number of different ways from dehydrated instant varieties revived by adding boiling water, to the perfect European espresso in which high pressure hot water is passed through 5-7g of finely-ground powder to produce an energising 30 ml serving.
For many years, a large proportion of healthcare professionals advised against drinking coffee, particularly for those with anxiety, arrhythmias, palpitations or tachycardia. This was based on the premise that the stimulant effects of caffeine – of which there’s just over 60mg in a single espresso shot – would most likely exacerbate cardiac arrhythmias. However, there is a lack of evidence to support this view. In fact, it seems that the opposite may be true.
For instance, a meta-analysis of seven observational studies including 115,993 individuals concluded that caffeine exposure is not associated with increased risk of atrial fibrillation, and that it may even be protective.
More recently, a 2022 analysis of data from the UK Biobanks, suggested that two to three daily cups of coffee was associated with a lower incidence of cardiac arrhythmias. But coffee is purported to have a plethora of health benefits, which were extolled in a 2017 umbrella review, which concluded that there were large risk reductions for a range of health outcomes when consuming three to four cups of coffee per day.
One of the intriguing findings identified in the umbrella review was habitual coffee drinking being linked to a 27% lower risk of developing Alzheimer‘s disease. Some of the earliest evidence identifying a possible protective effect against Alzheimer‘s disease, came from a study in 2002.
Using a case-control study, researchers observed a significant and inverse association between caffeine exposure and Alzheimer‘s disease (odds ratio, OR = 0.40, 95% CI 0.25 – 0.67). Moreover, other work appeared to confirm this benefit, with a further study reporting that drinking three to five cups of coffee a day during midlife was associated with a 65% lower risk of developing dementia or Alzheimer‘s disease during later life.
But this observational study evidence can only be used to demonstrate correlation and not causation. That is to say, just because the two factors of coffee and Alzheimer‘s disease are correlated does not mean that one either causes or protects against the other. However, evidence of a plausible biological mechanism, which accounts for this correlation, helps to support the observed relationship.
For instance, it has been found that caffeine prevents the β-amyloid-induced neurotoxicity in cultured cerebellar neurons of rats via blockade of adenosine A2A. In fact, the authors concluded that their study constituted the first in vitro evidence to suggest that blockade of adenosine A2A receptors, may be the molecular target for the observed beneficial effects of consuming caffeine in relation to the development of Alzheimer’s disease.
Despite this biological plausibility, not all observational studies demonstrate a positive relationship between caffeine intake and cognitive disorders. In a 2015 meta-analysis of 19 studies, the authors found that in all 19 studies caffeine intake was not significantly associated with the risk of cognitive disorders including dementia, Alzheimer’s disease, cognitive impairment and cognitive decline (OR = 0.82, 95% CI 0.67 – 1.01).
But if coffee does offer protection against Alzheimer‘s disease, could this arise from components other than caffeine?
With a good deal of research focusing on the possible protective role of coffee, it has also been recognised that coffee is actually a mixture of a number of bioactive compounds. These include polyphenols, especially chlorogenic acids and caffeic acid in roasted coffee beans; alkaloids, such as caffeine and trigonelline; and the diterpenes cafestol and kahweol. So, is it possible that some of these bioactive agents are responsible for the purported protective effect against Alzheimer’s disease?
A recent study set out to address this issue. The researchers used nuclear magnetic resonance to characterise the molecular composition of an espresso coffee extract. Since aggregation of the protein tau is implicated in the pathophysiology of Alzheimer’s disease, the researchers focused on any components that affected this process. In particular, they considered whether any components in the espresso extract could prevent tau aggregation, condensation – which is a purported mechanism initiating aggregation – and the seeding activity of the tau protein whereby further aggregation occurs once tau fibrils have been formed.
The research uncovered several important actions of the espresso coffee extract in relation to tau. First, the extract had an inhibitory effect on tau fibril formation, preventing aggregation and the ability to induce intracellular tau fibrillisation. Second, the extract interfered with early events (condensation), which led to the accumulation of tau. Finally, the tau fibrils that were formed in the presence of the espresso extract not only had a reduced ability to aggregate, but the resulting species displayed either reduced or no cellular toxicity and were unable to ‘seed‘ further aggregation.
Taken together, the findings suggested that the espresso extract was neuro-protective against tau-induced toxicity in cultured cells. In fact, the authors even suggested that ‘based on the bioavailability of coffee components in the brain, and on the results of our study, we expect that moderate coffee consumption may provide a sufficient amount of bioactive molecules to act separately or synergistically as modulators of tau protein aggregation and toxicity‘.
The evidence to date indicates that coffee intake may be a protective factor against Alzheimer‘s disease. Moreover, there is data showing neuro-protective effects for many of the bioactive components within coffee. While much of the evidence is derived from observations studies, one Mendelian randomisation study that avoids the influence of confounders, has shown that genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer’s disease.
With the totality of the evidence appearing to suggest a possible benefit from drinking coffee in relation to the development of Alzheimer‘s disease, the espresso research was cell-based and therefore preliminary in nature.
Nevertheless, whether drinking espresso coffee over a lifetime might reduce the risk of developing Alzheimer‘s disease remains an intriguing thought and certainly provides basis for future studies.
18th July 2023
Donanemab has been found to slow the progression of early symptomatic Alzheimer’s disease after 76 weeks of treatment, according to the findings of a phase 3 randomised trial.
The monoclonal antibody donanemab, which targets the insoluble, modified, N-terminal truncated form of β-amyloid present only in brain amyloid plaques, was given to patients with early symptomatic Alzheimer disease with amyloid and tau pathology. Nearly half of those given the drug showed no signs of disease progression after 12 months.
Commenting on the research, Dr Richard Oakley, associate director of research and innovation at the Alzheimer’s Society, said: ‘This is truly a turning point in the fight against Alzheimer’s and science is proving that it is possible to slow down the disease. Treatments like donanemab are the first steps towards a future where Alzheimer’s disease could be considered a long-term condition alongside diabetes or asthma.‘
Published in the Journal of the American Medical Association, participants of the TRAILBLAZER-ALZ 2 trial were categorised as having either low/medium or high tau pathology and randomised 1:1 ratio to receive donanemab or a placebo intravenously every four weeks for 72 weeks.
The primary outcome of interest was the change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks. There were a number of secondary outcomes, one of which was the change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score.
A total of 1,736 participants (57.4% women) with a mean age of 73.0 years were recruited. Some 68.1% had low/medium tau pathology and 76% completed the trial.
The least-squares mean (LSM) change in iADRS score at 76 weeks was −10.2 with donanemab and −13.1 with placebo (difference = 2.92, p < 0.001) for the combined population. In addition, the LSM change in CDR-SB score at 76 weeks was 1.72 with donanemab and 2.42 with placebo (difference = −0.7 p <0 .001) in the combined population.
Furthermore, an estimated 47% of participants receiving donanemab had no change in the CDR-SB at one year (i.e. no disease progression) compared with 29% of participants receiving the placebo.
The trial also revealed how donanemab treatment significantly reduced brain amyloid plaque at all time points assessed, with 80% (low/medium tau population) and 76% (combined population) of participants achieving amyloid clearance at week 76.
The level of clearance beyond 76 weeks, as well as levels of Alzheimer disease biomarkers, are currently being studied in an ongoing extension phase.
In subgroup analysis, among participants with mild cognitive impairment, donanemab slowed decline by 60% on iADRS and 46% on CDR-SB. Additionally, in an analysis based on participant’s age, in those under 75 years, donanemab slowed decline by 48% on iADRS and 45% on CDR-SB, whereas the drug slowed decline by 25% on iADRS and 29% on CDR-SB in those over 75 years.
Liana Apostolova, distinguished professor in Alzheimer’s Disease research and professor in neurology, radiology, medical and molecular genetics at Indiana University School of Medicine, said: ‘These results demonstrate that diagnosing and treating people earlier in the course of Alzheimer’s disease may lead to greater clinical benefit. The delay of disease progression over the course of the trial is significant and will give people more time to do such things that are meaningful to them.‘
Dr Oakley added: ‘It’s also important to note that side effects did occur, although serious side effects only occurred in 1.6% of people receiving the drug. Regulators will need to balance these side effects against the benefits of the drug.
‘We should also note that the majority of people who took part in this trial were white – it’s crucial that in future trials we see more diversity to prove that new drug treatments have similar effects for everyone living with Alzheimer’s disease.‘
Highlighting the ‘defining moment for dementia research‘, Kate Lee, Alzheimer’s Society CEO, added: ‘New treatments could mean nothing if we don’t fix dementia diagnosis. We estimate around 720,000 people in the UK could potentially benefit from these emerging new Alzheimer’s disease treatments if they’re approved for use here. But the NHS is simply not ready to deliver them.
‘Everyone living with dementia deserves access to a speedy, accurate diagnosis to get the support and treatments they need, now and in the future.‘
This comes shortly after news that diagnosing Alzheimer’s disease through the use of blood biomarkers could transform care for patients after new proposed guidelines were presented at the International Alzheimer’s Congress in Amsterdam.
17th July 2023
Diagnosing Alzheimer’s disease through the use of blood biomarkers could transform care for patients after new proposed guidelines were presented at the International Alzheimer’s Congress in Amsterdam.
Developed by clinicians and researchers from around the world, the proposed guidelines incorporate blood-based biomarkers, which offer a low cost and easily accessible alternative to more traditional routes of diagnosis.
A blood test has been developed for this purpose in recent years, which has shown good results, and this can be used outside of specialist clinics, meaning underserved and rural populations can also benefit.
Charlotte Teunissen, professor of neurochemistry at Amsterdam University Medical Centre, who was involved in drafting the new guidelines, said: ‘A new generation of biomarkers is now available to detect Alzheimer’s disease more and more effectively. We have already gained a lot of experience with this in our Alzheimer’s centre, but in the long term the test can also be successfully implemented after a GP’s referral.‘
Currently, Alzheimer’s is diagnosed through the analysis of cerebrospinal fluid, acquired through an invasive lumbar puncture, or via an expensive PET scan. The proposed diagnostic criteria would prove less stressful to patients as well as speeding up diagnosis, offering a gateway to earlier treatment and allowing patients to make more informed decisions about their treatment and disease management.
Defining neurodegenerative diseases biologically, rather than based on syndromic presentation, has become a unifying concept common to all neurodegenerative diseases, not just Alzheimer’s.
While many biomarkers have shown promise and performance in the ability to detect Alzheimer’s disease, some of the biomarkers described in the proposal have not yet been extensively tested in broadly representative populations, and further analysis in these groups is urgently needed, the Alzheimer’s Association said.
The draft proposal will be open for consultation for 30 days, and the working group invites comments from scientific and clinical audiences.
Maria C. Carrillo, chief science officer, Alzheimer’s Association, said: ‘Care has to evolve with the science. Our understanding of Alzheimer’s disease has advanced, in particular our understanding of biomarkers, and this needs to be reflected in how we describe and diagnose the disease.
‘We look forward to input from the scientific and clinical community on these proposed revisions. The Alzheimer’s Association is proud to lead this important effort, which will ultimately enable people to get a more accurate diagnosis earlier, as well as help those diagnosed enrol in research trials and, if appropriate, get access to approved treatments.‘
13th January 2023
A brain-derived tau biomarker which can be easily measured in blood samples, represents an important step in the specific identification of Alzheimer’s disease-type neuro-degeneration according to a study by an international research group.
Biomarkers for the identification of Alzheimer’s disease (AD) are based on the A/T/N” system where ‘A’ refers to the value of a β-amyloid biomarker, ‘T’ the value of a tau biomarker and ‘N’, biomarkers of neuro-degeneration or neuronal injury. To date, at least two of these markers are satisfactory. For example, plasma β-amyloid marker measurement (A), accurately determines amyloid positron emission tomography status in cognitively normal research participants.
In addition, blood-based tau markers (T) could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer’s disease. Nevertheless, neuro-degeneration (N) markers such as plasma neurofilament light chain (NfL), which measures axonal injury, showed no discriminatory power for AD compared to other neurological diseases.
Rather than focusing on developing a more specific ‘N’, researchers recognised that since tau measurements can be contaminated by peripherally generated (i.e., from liver, kidney or heart), it might be better to focus to identifying a specific brain-derived tau. In the present study, researchers created an anti-tau antibody which was designed to selectively bind with only brain-derived tau and which would hopefully be specific for patients with Alzheimer’s disease. The team then set out to validate the biomarker in five independent cohorts, including autopsy samples.
Brain-derived tau and Alzheimer’s disease
Using paired cerebrospinal fluid (CSF) and serum samples from AD patients and controls, there was a strong correlation (Spearman’s rho = 0.85, p < 0.0001) between the brain-derived (BD) tau levels in serum and CSF samples. In contrast, serum and total tau measurements were no significantly correlated (Spearman’s rho = 0.23, p = 0.3364). In addition, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases, with an area under the curve (AUC) value of 86.4%.
Furthermore, using samples from patients in two memory clinic cohorts, serum brain-derived tau differentiated Alzheimer’s disease from a range of other neurodegenerative disorders (AUC = 99.6%). In another cohort, BD-tau levels were significantly increased in AD patient serum and CSF samples compared to controls (p < 0.0001). Finally, BD-tau levels were inversely correlated with clinical dementia rating global scores (Spearman’s rho = -0.30, p = 0.0352).
Taken together, the authors wrote ‘across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer’s disease-type neuro-degeneration.’
They concluded that the brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.
Citation
Gonzalez-Ortis F et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain 2022.
19th December 2022
According to a press release by drug manufacturer Lilly, donanemab provides a greater level of brain amyloid clearance compared to aducanumab at 6 months.
Brain amyloid-β deposition is a hallmark used to define Alzheimer’s disease. Moreover, in March 2022, the Food and Drug administration (FDA) in the US, approved the first in vitro diagnostic test for early detection of amyloid plaques associated with Alzheimer’s disease. The FDA added that a positive test was consistent with the presence of amyloid plaques, similar to what would be seen in a PET scan and that a negative result is consistent with a negative amyloid PET scan result, reducing the likelihood that a patient’s cognitive impairment was due to Alzheimer’s disease, enabling physicians to pursue other causes of cognitive decline and dementia.
The current data announced by Lilly, comes from the TRAILBLAZER-ALZ 4 trial, which was a randomised, open-label phase 3 study designed to compare donanemab (DM) with aducanumab (AM) on amyloid plaque clearance in participants with early, symptomatic Alzheimer’s Disease. In the trial, donanemab and aducanumab were administered via intravenous infusions every four weeks for up to 18 months.
Donanemab efficacy
In the co-primary outcomes, brain amyloid plaque clearance, defined as achieving brain amyloid plaque levels of <24.1 Centiloids, was achieved in 37.9% of DM-treated participants compared with 1.6% of AM-treated patients at 6 months. In the intermediate tau subpopulation, 38.5% of DM-treated participants reached brain amyloid clearance compared with 3.8% of AM-treated participants by 6 months. In a key secondary outcome, DM reduced brain amyloid levels vs. baseline by 65.2% compared with 17.0% for AM at 6 months. In an exploratory outcome, donanemab, but not aducanumab treatment significantly reduced plasma P-tau217 at 6 months compared to baseline.
In terms of safety, amyloid-related imaging abnormalities were the most common treatment emergent adverse event in both groups and occurred with a similar frequency (25.4% vs 26.1%, DM vs AM).
Although only 6-month data is currently, available, the press release describes how TRAILBLAZER-ALZ 4 is an on-going study and results from 12 or 18 months will be presented once available.
23rd November 2022
Gantenerumab which is a fully human monoclonal IgG1 antibody failed to meet the primary endpoint of slowing clinical decline in people with early Alzheimer’s disease (AD) in two randomised, double-blind, placebo-controlled trials according to a release by the manufacturer Roche.
It has been estimated that currently, an estimated 6.2 million Americans aged 65 and older are living with Alzheimer’s dementia. Moreover, the World Health Organisation has estimated that there are more than 55 million people with dementia worldwide and nearly 10 million new cases every year, with Alzheimer’s disease accounting for between 60 – 70% dementia cases. The amyloid cascade hypothesis of AD proposes that deposition of the amyloid-β peptide in the brain is a central event in disease pathology and several drugs have been developed, including gantenerumab which binds with high affinity to aggregated amyloid-β species and removes amyloid-β plaques.
The potential value of gantenerumab came from a small trial in 2012, which revealed that it resulted in a dose-dependent reduction in brain amyloid levels. However, these early findings were called into question after a 2017 randomised trial with the drug in patients with prodromal AD, i.e., mild cognitive impairment, over a 2-year period, was halted early for futility. Despite this, the manufacturer Roche embarked to two global phase III trials, GRADUATE I and II designed to evaluate the safety and efficacy of gantenerumab in people with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia over 27 months. The primary endpoint of both trials was the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 116 weeks, a tool that measures cognitive and functional change across six areas including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
Gantenerumab and Alzheimer’s disease outcomes
According to the press release, 1,965 participants across 30 countries were randomised 1:1 to receive gantenerumab or placebo by subcutaneous injection and titrated to reach a target dose of 510 mg which was administered every two weeks. The results showed that while there was a slowing of clinical decline in GRADUATE I of -0.31 (p = 0.095) and -0.19 (p = 0.29) in GRADUATE II of -0.31 (p=0.0954) from baseline on CDR-SB, neither decrease was statistically significant. Additionally, the level of beta-amyloid removal was also lower than expected.
Commenting on the findings, Levi Garraway, Roche’s Chief Medical Officer and Head of Global Product Development said, ‘While the GRADUATE results are not what we hoped, we are proud to have delivered a high quality, clear and comprehensive Alzheimer’s dataset to the field, and we look forward to sharing our learnings with the community as we continue to search for new treatments for this complex disease.’
Nevertheless, the press release reports that Roche remains committed to Alzheimer’s disease and is continuing to develop and deliver tests to enable early and accurate Alzheimer’s diagnosis and has a pipeline of investigational medicines for different targets, types and stages of the disease.
6th October 2022
Lecanemab use in patients with mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) demonstrated an improvement in cognitive function compared to placebo after 18 months of treatment according the joint manufacturers Eisai and Biogen.
Alzheimer’s disease is a progressive neurodegenerative disease that slowly impairs cognition and function and is the most common form of dementia. The discoveries of amyloid β (Aβ) and tau, the main components of plaques and tangles respectively, has provided detailed information about the molecular pathogenetic events of the disease.
Given the build-up of soluble Aβ aggregates, it is possible that a reduction of such aggregates could represent an effective treatment approach in the early stages of AD. Lecanemab is a humanised IgG1 monoclonal antibody that binds to soluble Aβ aggregates and in a phase 1 dose ranging study in patients with mild to moderate AD, the drug (known as BAN 2401) was well-tolerated across all doses.
Based on these findings, a randomised, double-blind, placebo-controlled, phase 2 trial was undertaken in 854 subjects with early Alzheimer’s disease and observed a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Clarity AD was a phase 3 trial to evaluate the efficacy of lecanemab in patients with early Alzheimer’s disease. Participants were administered lecanemab at a dosage of 10 mg/kg bi-weekly and randomised 1:1 to either placebo or lecanemab.
The primary endpoint was the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) after 18 months of treatment. The CDR-SB is a numeric scale used to quantify the various severity of symptoms of dementia and is an appropriate item for evaluating the effectiveness of therapeutic drugs targeting the early stages of AD.
Based on interviews of people living with AD and family/caregivers, qualified healthcare professionals assess cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
The total score of the six areas is the score of CDR-SB. Key secondary endpoints for the trial were the change from baseline at 18 months compared with placebo of treatment in amyloid levels in the brain measured by amyloid positron emission tomography (PET), the AD Assessment Scale-cognitive sub-scale14 (ADAS-cog14), AD Composite Score (ADCOMS) and the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).
Lecanemab and treatment outcome
Clarity AD included 1,795 people with early AD and lecanemab met the primary endpoint and reduced clinical decline on the CDR-SB, compared with placebo at 18 months by 27%, which represents a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of Intent-to-treat (ITT) population.
Starting as early as six months, across all time points, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all p-values are less than 0.01). All key secondary endpoints were also met with highly statistically significant results compared with placebo (p<0.01).
The incidence of amyloid-related imaging abnormalities-oedema/effusion (ARIA-E), an adverse event associated with anti-amyloid antibodies, was 12.5% in the lecanemab group and 1.7% in the placebo group. The ARIA-H (ARIA cerebral micro-haemorrhages, cerebral macro-haemorrhages, and superficial siderosis) rate was 17.0% in the lecanemab group and 8.7% in the placebo group. The total incidence of ARIA (ARIA-E and/or ARIA-H) was 21.3% in the lecanemab group and 9.3% in the placebo group. Overall, lecanemab’s ARIA incidence profile was within expectations.
Commenting on these early findings, Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “This is a historic moment for dementia research, as this is the first phase 3 trial of an Alzheimer’s drug in a generation to successfully slow cognitive decline. These results show that lecanemab slows the progression of memory and thinking problems in people with early Alzheimer’s, demonstrating a major breakthrough in dementia research. This is the first drug that’s been shown to not only remove the build-up of a protein called amyloid in the brain, but to have a small but statistically significant impact on cognitive decline in people with early-stage disease.’
27th September 2022
A new diagnosis of Alzheimer’s disease appears to be significantly associated with a COVID-19 infection suggesting that the virus might play a causative role in the development of the dementia according to the findings of a retrospective study by a team of US researchers.
It has been speculated for many years that infectious agents in the brain have a role in the pathogenesis of Alzheimer disease (AD) and while discarded in the past, several recent discoveries have reignited interest in the infectious theory. For instance, in a retrospective study of the electronic health records of 61.9 million adult and senior patients, it was found that those with dementia were at an increased risk for COVID-19 compared to those without it and that the risk was also significantly elevated among those with Alzheimer’s disease. Moreover, genome-wide association studies indicate that a large percentage of AD risk genes are associated with innate immunity and inflammation, suggesting that the immune system plays a critical, and previously unappreciated, role in AD pathology. In addition, follow-up studies of patients infected with COVID-19 have demonstrated the presence of neuropsychiatric symptoms which would suggest that the virus is able to enter the brain. Taken together, these findings imply that inflammatory changes, particularly if these occur within the brain, could increase Alzheimer’s disease risk but this topic has not been studied in any detail. For the present study, the US researchers retrospectively examined the de-identified electronic health records of older adults ( > 65 years of age) without a prior diagnosis of AD. The cohort were then divided into two groups: those with and without a documented infection of COVID-19. The team then examined the subsequent development of AD between the two groups and propensity-matched individuals for demographics, occupational exposure, physical and social and psychosocial environments and known risk factors for AD.
Alzheimer’s disease risk and COVID-19
After propensity matching, the COVID-19 cohort contained 410,478 individuals with a mean age of 73.7 years (53.6% female), the majority of whom (75.3%) were of White ethnicity. Co-morbidities included hypertension (59.4%), overweight and obesity (23%) and type 2 diabetes (30.4%).
After matching, the COVID-19 cohort had a significantly higher Alzheimer’s disease risk (hazard ratio, HR = 1.69, 95% CI 1.53 – 1.72). This risk was elevated in all groups when stratified by age although the highest risk occurred in those aged 85 years and older (HR = 1.89, 95% CI 1.73 – 2.07). Individuals of Black and White ethnicity had a similar level of increased risk (HR = 1.62 and 1.61, for Black and White ethnicities respectively).
The authors concluded that older adults with COVID-19 had an increased Alzheimer’s disease risk although they accepted the limitation of using a retrospective analysis and called for research to better understand the underlying mechanisms and for continuous surveillance of the long-term impact of COVID-19 on Alzheimer’s disease.
Citation
Wang L et al. Association of COVID-19 with New-Onset Alzheimer’s Disease J Alzheimers Dis 2022
23rd August 2022
Increased amounts of all types of leisure activities e.g., cognitive, physical and social reduce the risk of developing all-cause dementia (ACD) including Alzheimer’s disease (AD) and vascular dementia (VD) according to a systematic review and meta-analysis by a team of Chinese researchers.
Although there are several types of dementia, the most common is Alzheimer’s disease, followed by vascular dementia. There is currently no cure for dementia and recommendations to reduce risk factors include switching to a healthy diet and staying mentally and socially active.
Indeed, there is some evidence that cognitively stimulating leisure activities may delay the onset of dementia in community-dwelling elders although the value of such activities are uncertain. For example, one study found that neither intellectual or physical activity lifestyle factors were associated with AD biomarkers with another concluding that physical inactivity was not associated with all-cause dementia or Alzheimer’s disease.
With some uncertainty over whether any of these leisure activities impact on ACD, for the present study, the Chinese team undertook a systematic review and meta-analysis. They set out to assess the effect of three different forms of leisure activities: physical (PA), cognitive (CA) and social (SA).
For the purposes of the study, PA was defined to include walking, playing sports etc, CA, reading books, writing for pleasure or solving crossword puzzles and SA anything that involved communication with others, e.g. attendance at social centres, volunteer work etc.
The researchers used regression analysis to determine the relationship between the different leisure activities and ACD and both subtypes, adjusting their results for covariates such as age, gender, education and apolipoprotein E.
Leisure activities and all-cause dementia
The literature review identified a total of 38 eligible studies with 215, 818 participants and a mean age of 45 years at baseline.
Overall, 36 studies were used to investigate the relationship between the different activities and all-cause dementia. The analysis revealed that participation in leisure activities, compared to no participation, was associated with a 17% lower risk of developing ACD (relative risk, RR = 0.83, 95% CI 0.80 – 0.87, p < 0.001). In subgroup analysis, there was also a significant reduction for each of the different forms of activity, e.g., the relative risk for CA was 0.77 (95% CI 0.68 – 0.87).
For AD, there was an 18% lower risk for participation in leisure activities (RR = 0.82, 95% CI 0.74 – 0.90, p < 0.001) and again, while the lower risk was similar for PA and CA, it was non-significant for SA (RR = 0.89, 95% CI 0.63 – 1.26) although the latter activity assessment was based on only a single study.
For vascular dementia, the reduction was even greater at 32% (RR = 0.68, 95% CI 0.54 – 0.86, p = 0.007). However, this association was only significant for PA and not for CA although there were no studies which examined the relationship with SA.
The authors concluded that leisure activities including physical, cognitive and social, were all significantly associated with a reduced risk of incident dementia and that both PA and CA were linked to a lower risk of AD.
Citation
Su S et al. Leisure Activities and the Risk of Dementia: A Systematic Review and Meta-Analysis Neurology 2022
19th July 2022
Noradrenergic drugs produce a small but significant improvement in global cognition and apathy in patients with Alzheimer’s disease(AD) with no important effects on any other measures according to the findings of a meta-analysis by UK researchers.
The World Health Organization (WHO) defines dementia as a syndrome in which there is deterioration in cognitive function beyond what might be expected from the usual consequences of biological ageing. WHO also estimates that worldwide in 2021, there were approximately 55 million people living with dementia and that AD, which is the most common form of dementia, may contribute to 60-70% of all cases.
The neurotransmitter noradrenaline is released by the locus coeruleus and has become recognised as a contributor to various aspects of cognition, including attention, behavioural flexibility, working memory, and long-term mnemonic processes. Furthermore, the locus coeruleus is one of the first sites of tau deposition in AD and with noradrenergic dysfunction being an early sign in patients with AD, it would seem logical to use noradrenergic drugs as a treatment for the disease.
Nevertheless, trials examining the value of noradrenergic drugs in AD have generally proved to be unsuccessful. Despite this, there has been no attempt to assess the overall impact of this drug class in AD which was the purpose of the present study.
The UK team performed a systemic review and meta-analysis to assess the degree to which drugs, whose principle action is as a noradrenergic agent, could improve the cognition and behavioural aspects of AD.
They searched for trials that included patients with AD in which noradrenergic drugs, that increased levels of noradrenaline, were compared against placebo and where the studies reported on cognitive and neuropsychiatric (e.g., agitation, apathy) changes. The outcomes of interest were changes in measure of both global cognition and neuropsychiatric symptoms.
Noradrenergic drugs and Alzheimer’s disease outcomes
The search identified a total of 19 trials with 1811 patients and all of the studies were prospective, randomised trials and with a treatment duration of between 2 and 52 weeks. The most commonly used noradrenergic drugs were noradrenaline re-uptake inhibitors, alpha1 adrenergic receptor antagonists, alpha2 receptor agonists, alpha2 receptor antagonists and beta adrenergic receptor blockers.
For global cognition, the overall pooled effect size was small but statistically significant in comparison to placebo (standardised mean difference, SMD = 0.14, 95% CI 0.03 – 0.25, p = 0.01). To provide some perspective for this effect, the authors included the SMD for cholinesterase inhibitors from studies in AD which was 0.38. Although noradrenergic drugs had a positive effect on semantic memory (SMD = 0.20), the drugs had no significant effect on any of the other cognitive measures.
For neuropsychiatric measures the only measure for which there was a significant effect was apathy with a pooled SMD of 0.45 (95% CI 0.16 – 0.73, p = 0.002).
The authors concluded that pharmacotherapies targeting the noradrenergic system appeared to improve both cognition and apathy. In addition, they suggested these data provided a strong case for further trials to examine the value of these drugs in AD and other neurodegenerative diseases.
Citation
David MCB et al. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis J Neurol Neurosurg Psychiatry 2022
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