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8th December 2022
The cognitive decline present in patients with early Alzheimer’s disease (AD) as well as the amyloid burden are significantly reduced compared to placebo, in those treated with lecanemab according to the results of a randomised, double-blind, phase 3 trial by US researchers.
There are an estimated 55 million across the world living with dementia of whom, approximately 60 to 70% have the most common form, Alzheimer’s disease. Currently available treatments such as cholinesterase inhibitors and memantine, do not alter disease progression but can help with some symptoms. Current thinking the pathophysiology of Alzheimer’s disease is based on the amyloid β-protein (Aβ peptides) theory which purports that in the early stages, there is an imbalance between production and clearance of Aβ peptides and which is a very early, often initiating factor in Alzheimer’s disease (AD). This leads to a build-up of Aβ peptides, and one therapeutic approach gaining interest is the use of monoclonal antibodies directed against amyloid-β (Aβ). In a 2021 systematic review of such antibodies directed against Aβ, there were clinical improvements but with small effect sizes.
In the current study, researchers examined the value of one such monoclonal antibody, lecanemab. Although in a phase 2b proof of concept trial in patients with early Alzheimer’s disease, the drug did not change clinical progression of the disease, it did demonstrate a reduction in brain amyloid accompanied by a consistent reduction of clinical decline in several endpoints. The current study was designed to evaluate the efficacy of lecanemab in patients with early Alzheimer’s disease, i.e., either mild cognitive impairment or mild dementia due to AD and with evidence of amyloid protein as assessed by either PET scan or CSF fluid measurement. Participants were randomised 1:1 to either intravenous lecanemab (10 mg/kg every two weeks) or placebo. The primary endpoint was the change from baseline after 18 months in the Clinical Dementia Rating Sum of Boxes (CDR-SB) which ranges from 0 to 18 and for which higher scores indicate greater cognitive impairment. There were several secondary endpoints, one of which was the change in amyloid burden on PET scanning whereas others assessed changes in cognition.
Early Alzheimer’s disease and change in cognition
A total of 1734 participants with a mean age of 71.2 years (52.3% women) were included and randomised to lecanemab (859) or placebo. The mean baseline CDR-SB score was approximately 3.2 in both groups.
The adjusted mean change from baseline in CDR-SB score was less with lecanemab (1.21) compared to placebo (1.66), i.e., there was less decline in cognition and the mean difference of -0.45 (95% CI -0.67 to -0.23) was statistically significant (p < 0.001).
In a subgroup of 698 participants, the mean amyloid level reduced by -55.48 centiloids in the lecanemab group and by 3.64 in the placebo group (mean difference = -59.12, 95% CI -62.64 to -55.60, p < 0.001).
There were also significant and positive changes favouring lecanemab in the cognition-related outcomes.
The overall incidence of adverse effects was similar between the two groups although lecanemab use resulted in a higher incidence of infusion-related reactions compared to placebo (26.4% vs 7.4%).
The authors concluded that the use of lecanemab reduced markers of amyloid in early Alzheimer’s disease and gave rise to moderately less decline on measures of cognition compared to placebo. They called for longer trials to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.
van Dyck CH et al. Lecanemab in Early Alzheimer’s Disease. N Eng J Med 2022 DOI: 10.1056/NEJMoa2212948
28th March 2022
Increased physical activity levels in older adults with high serum levels of neurofilament light chain (NFL) leads to a reduction in the rate of cognitive decline. This was the conclusion of a study by researchers from the Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, US.
Neurofilament light chain is a neuronal cytoplasmic protein expressed in large calibre myelinated axons. Furthermore, in both central nervous system and peripheral nervous system diseases associated with axonal injury or degeneration, the concentration of NFL has been found to increase in both cerebrospinal fluid (CSF) and blood. In addition, levels of CSF NFL are associated with cognitive impairments in patients with Alzheimer disease and fronto-temporal dementia. As a result, it has been suggested that NFL could be used to predict the development of sporadic Alzheimer’s disease and cognitive decline. One factor which appears to be associated with a reduced cognitive decline is physical activity and in a 2011 meta-analysis, the authors concluded that there was a significant and consistent protection for all levels of physical activity against the occurrence of cognitive decline.
For the present study, the US team wanted to examine whether among individuals with high NFL concentrations, increased physical activity was associated with a slowed rate of cognitive decline over time. They turned to the Chicago Health and Aging Project (CHAP), which is a longitudinal population study of common chronic health problems of older persons and in particular, risk factors for incident Alzheimer’s disease. Blood samples were taken and the concentration of NFL measured at baseline and during each follow-up appointment and dichotomised as low (< 25.5 pg./ml) or high (> 25 pg./ml). Levels of physical activity were self-reported divided into three groups: little activity, medium and high, in which the latter group reported physical activity levels > 150 minutes/week. A number of cognitive tests were used to assess global cognitive function. The main outcome measure was the association of baseline activity and NFL concentrations with changes in global cognitive function over time.
Increased physical activity and NFL in relation to cognitive decline
A total of 1158 participants with a mean age of 77.4 years (63% female) were included in the study. The mean level of physical activity per week was 170.78 minutes and the geometric mean NFL concentration was 26.1 pg/ml.
Among those with a high NFL levels, indicating more axonal injury, individuals engaging in medium physical activity (< 150 minutes/week), had a 12% slower rate of global cognitive decline compared to those in the low physical activity group. Similarly, those with increased physical activity (i.e., the high group), had a 36% slower rate of decline in comparison to the low physical activity group.
Interestingly, the the rates of cognitive decline were also higher among those with lower levels of NFL, i.e., with less neural damage. For example, in comparison to the group who undertook little or no physical activity, those who undertook medium physical activity had a 43% slower decline and the high activity group, at 30% slower decline.
The authors concluded that among older adults with high levels of serum NFL, increased physical activity levels were associated with a slower rate of cognitive decline. They added that future studies should examine the relationship between cognitive decline and different forms of exercise such as aerobics and strength training.
Desai P et al. Examination of Neurofilament Light Chain Serum Concentrations, Physical Activity, and Cognitive Decline in Older Adults JAMA Netw Open 2022
11th February 2022
Elevated generalised and visceral body fat levels seen on a magnetic resonance imaging scan have been found to be associated with reduced cognitive scores even after adjustment for cardiovascular risk factors. This was according to a study by researchers from the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada.
Increased levels of body fat and in particular central adiposity, measured by the waist-to-hip ratio, has been found to have a highly significant association with myocardial infarction risk. The use of magnetic resonance imaging (MRI) enables the detection of visceral fat volume and accumulated evidence shows that visceral adipose tissue is an independent risk marker of cardiovascular and metabolic morbidity and mortality. However, whether elevated levels of both generalised and visceral fat are linked with an impairment of cognitive functioning remain unclear. One prospective study of older adults concluded that abdominal fat in late life appears to confer an increased risk for dementia and cognitive impairment and where body fat levels have been assessed through electrical impedance, visceral fat accumulation was also associated with mild cognitive impairment. In contrast, however, a study in 1047 individuals aged 60 years and older concluded that abdominal obesity might be a protective factor for cognitive function.
With some uncertainty over the relationship between generalised and visceral fat and cognitive function, the Canadian team set out to examine this relationship based on MRI scan results. They turned to data from the Canadian Alliance of Healthy Hearts and Healthy Minds and the Prospective Urban Rural Epidemiological–Mind (PURE-MIND) studies. These studies recruited adults between the ages of 30 and 75 years of age and who had their body fat levels measured by bioelectrical impedance and MRI of the abdomen to measure visceral adipose tissue levels. In addition, all participants underwent MRI of the brain to measure vascular brain injury and cardiovascular risk factors were assessed using lifestyle questionnaires and physical measures. Cognitive assessment was measured using the Digital Symbol Substitution Test (DSST) and the Montreal Cognitive Assessment (MoCA). The DSST scores range from 0 to 133 with lower scores indicative of worse performance. In contrast, the MoCA score ranges from 0 to 30, with higher scores denoting normal cognitive function.
Generalised and visceral body fat levels and cognitive impairment
A total of 9189 adults with a mean age of 57.8 years (56.4% women) were included in the analysis. The women had a higher percentage of body fat compared to men (35.6% vs 25.1%) although men had a higher mean visceral adipose tissue volume (83.6 vs 64.1 ml). The mean DSST score was 72.6 and the MoCA score was 27 and both were slightly higher in women compared to men.
Overall, both a higher total percentage of body fat and visceral adipose score were associated with the lowest DSST score although this was not the case for visceral adipose scores and the MoCA. In regression models fully adjusted for age, sex, educational level and cardiovascular risk factors, the total percentage of body fat remained independently associated with reduced cognitive scores. The authors calculated that for each standard deviation increase in adiposity (9.2% for generalised fat and 36ml of visceral fat), there was a reduction of 0.8 in the DSST score, which was equivalent to 1 year of cognitive ageing. For example, comparing individuals in the highest versus the lowest percentage of body fat, was equivalent to 2.8 years of cognitive ageing. A similar amount of cognitive ageing was also seen between the highest and lowest levels of visceral adipose tissue. However, there were no significant associations between either total body or visceral fat with MoCA scores.
The authors concluded that based on these finding, excess adiposity was a risk factor for reduced cognitive scores and called for strategies to reduce or prevent adiposity as a means of preserving cognitive function in adults.
Anand SS et al. Evaluation of Adiposity and Cognitive Function in Adults JAMA Netw Open 2022