Heterogeneity in Alzheimer’s disease progression affects clinical trial results

Results from a study published in Neurology confirm the heterogeneity of disease progression in patients with early-stage Alzheimer’s disease (AD). In a cohort study with patients with mild cognitive impairment (MCI) or dementia, the course of the disease over 18 months was very variable and ranged from slight improvement to moderate decline. These results underline the importance of considering different disease courses in clinical studies with AD therapeutics.

Studies evaluating AD treatments often use slowed or stopped cognitive decline as the primary endpoint. However, natural differences in disease progression can hide the true effects of AD therapies. To better assess this, the researchers extracted data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) research database, a multicenter longitudinal cohort study that focused on visualizing clinical progression in the AD spectrum. The current study enrolled ADNI participants with a clinical diagnosis of MCI or dementia who met the following criteria: abnormal amyloid positron emission tomography (PET) imaging results; Mini-Mental-State-Exam (MMSE) baseline ≥24; global Clinical Dementia Rating (CDR) score of 0.5; and at least 1 cognitive follow-up exam. The researchers simulated a clinical study; Patients were divided into “treatment” or “placebo” groups and followed up for 18 months. The differences between the groups were calculated for the CDR sum of the boxes (CDR-SB), the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and the MMSE. The simulated study was repeated 10,000 times to obtain a 95% confidence interval (CI) for the estimated treatment effect sizes. The estimated effects of certain AD risk factors were also examined.

The study cohort comprised 302 patients with an average age of 73 ± 6.7 years, of whom 133 (44%) were women. The majority of patients (n = 207; 68.5%) were carriers of apolipoprotein E (APOE) ε4. At study enrollment, 274 patients (90.7%) had MCI and 28 (9.3%) had mild dementia. The mean follow-up was 3.8 ± 2.3 years; the mean number of cognitive ratings was 5 ± 2.1. Over a period of 18 months after follow-up, the progression of the disease varied significantly between the patients. The person-specific slope estimates for the CDR-SB ranged from an annual improvement of -0.31 points to an annual deterioration of +3.73 points. The mean annual change in CDR-SB was +0.76 points (95% CI, 0.65-0.88; P <0.001). Highly variable patient-specific slopes were also found in the ADAS-Cog (mean annual change +2.44 points; 95% CI 2.08-2.82; P <0.001) and in the MMSE (mean annual change -0.96 points; 95% CI, -1.13 to -0.079; P <0.001).

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The results of the study simulation confirmed the heterogeneity of the disease progression curves. With 10,000 repetitions of the randomized “placebo” and “treatment” groups, 95% of the group differences in the CDR-SB fell between -0.35 and +0.35. With the ADAS-Cog, 95% of the differences were between -1.00 and +1.00; for the MMSE the 95% range was -0.42 to +0.42. Group differences in the study simulations were not associated with group differences with regard to patient age, gender, level of education, APOE ε4 carrier status or baseline tau values.

According to these results, disease progression in AD is very variable in the early stages. If not taken into account, these differences in disease progression could affect the results of clinical trials. The heterogeneity of disease progression may be even broader than estimated in this study because the study cohort was small, had high average educational attainment, and was mostly white. Further investigation of prodromal AD progression in a larger cohort is warranted.

“Our results can be useful in determining thresholds for the detection of (actual) treatment effects in prodromal AD and thus advance the successful evaluation of future clinical trials,” the researchers wrote.

Disclosure: Some study authors stated links with biotech, pharmaceutical, and / or device manufacturers. For a full list of the author’s disclosures, see the original reference.


Jutten RJ, Sikkes SAM, Van der Flier WM, et al. Finding treatment effects in Alzheimer’s studies in view of the heterogeneity of the disease course. Neurology. 2021; 96 (22): e2673-e2684. doi: 10.1212 / WNL.0000000000012022

This article originally appeared on Psychiatry Advisor

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