Early amyloid PET scan improves aetiological diagnosis among memory clinic patients

17th May 2023

An early amyloid PET scan provides a high certainty diagnosis in memory clinic patients three months after their diagnosis, according to a new study.

Amyloid-β is the predominant pathologic protein in Alzheimer’s disease (AD) and which affects disease progression and prognosis. Moreover, an amyloid-imaging PET tracer, provides quantitative information on the extent of these protein deposits in living subjects. Despite this, other work suggests the current appropriate use criteria for imaging cannot effectively identify patients who will benefit from such imaging.

In the current study, researchers sought to assess the value of amyloid scanning in patients from a memory clinic. They wondered if a PET scan performed soon after the patient’s diagnosis, enabled a more confident aetiological diagnosis. Patients had either subjective cognitive decline with symptoms of preclinical AD, mild cognitive impairment or dementia.

Researchers randomly placed individuals into three arms. Arm one (early scan), arm two (scan after eight months) and arm three (scan at the physician’s discretion). The aetiological diagnoses were grouped into three main categories: AD; non-AD and undetermined. The primary outcome was the proportion of participants receiving a high confidence (>90%) etiological diagnosis in arms one and two after three months.

High confidence diagnosis

The study included 840 patients with a similar proportion in each of the three arms. The prevalence of amyloid positivity was higher in those with a baseline diagnosis of AD versus participants with non-AD (69% vs 36%, p < 0.001) at baseline.

After three months, 40% of arm one patients and 11% in arm two, had high confidence diagnosis (p < 0.001). This effect was consistent across cognitive stages.

The findings led to authors to conclude that an early amyloid PET allowed memory clinic patients to receive an aetiological diagnosis with very high confidence after only three months. The findings supported the implementation of amyloid PET early in the diagnostic workup of memory clinic patients.

Early Alzheimer’s disease cognitive decline slowed by lecanemab

8th December 2022

An RCT has found that the cognitive decline in early Alzheimer’s disease and amyloid burden can be significantly reduced with lecanemab

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.

Citation
van Dyck CH et al. Lecanemab in Early Alzheimer’s Disease. N Eng J Med 2022 DOI: 10.1056/NEJMoa2212948