Heterogeneity in Alzheimer Disease Progression Affects Clinical Trial Results

Neurons with amyloid plaques (right side) compared to healthy neurons (left). Amyloid plaques accumulate outside neurons. Amyloid plaques are characteristic features of Alzheimer’s disease. They lead to a degeneration of the affected neurons, that are destroyed through the activity of microglia cells.
Investigators assessed the variability in effect of treatment over time among patients with mild cognitive impairment or dementia.

Results from a study published in Neurology confirm the heterogeneity of disease progression among patients with early Alzheimer disease (AD). In a cohort study of patients with mild cognitive impairment (MCI) or dementia, 18-month disease trajectories were highly variable and ranged from mild improvement to moderate decline. These results underscore the importance of accounting for differing disease trajectories in clinical trials of AD therapeutics.

Trials assessing AD treatments often use a primary endpoint of slowed or halted cognitive decline. However, natural differences in disease progression may conceal the true effects of AD therapies. To better assess this, investigators extracted data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) research database, a multicenter longitudinal cohort study focused on illustrating clinical progression on 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; baseline Mini-Mental State Examination (MMSE) score ≥24; global Clinical Dementia Rating (CDR) score of 0.5; and at least 1 follow-up cognitive assessment. The investigators simulated a clinical trial; patients were placed in “treatment” or “placebo” groups and followed up for 18 months. Between-group differences were computed for the CDR sum of boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), and the MMSE. The simulated trial was repeated 10,000 times to produce a 95% confidence interval (CI) for estimated treatment effect sizes. The estimated effects of certain AD risk factors were also examined.

The study cohort comprised 302 patients with a mean age of 73 ± 6.7 years, among whom 133 (44%) were women. The majority of patients (n=207; 68.5%) were apolipoprotein E (APOE) ε4 carriers. At enrollment, 274 patients (90.7%) had MCI and 28 (9.3%) had mild dementia. Mean follow-up duration was 3.8 ± 2.3 years; mean number of cognitive assessments was 5 ± 2.1. Over 18 months of follow-up, disease progression trajectories varied significantly between patients. Person-specific slope estimates for the CDR-SB ranged from an annual improvement of -0.31 points to an annual worsening of +3.73 points. Mean annual change on the CDR-SB was +0.76 points (95% CI, 0.65-0.88; P <.001). Highly variable patient-specific slopes were also observed on the ADAS-Cog (mean annual change, +2.44 points; 95% CI, 2.08-2.82; P <.001) and the MMSE (mean annual change, -0.96 points; 95% CI, -1.13 to -0.079; P <.001).  

Trial simulation results confirmed the heterogeneity of disease progression trajectories. In 10,000 repetitions of randomized “placebo” and “treatment” groups, 95% of group differences on the CDR-SB fell between -0.35 and +0.35. On the ADAS-Cog, 95% of differences ranged from -1.00 to +1.00; for the MMSE, the 95% range was -0.42 to +0.42. Group differences in the trial simulations were not associated with group differences in patient age, sex, education level, APOE ε4 carrier status, or baseline tau levels.

Per these results, disease progression in AD is highly variable in the early stages. If unaccounted for, these differences in disease trajectories could affect clinical trial outcomes. Disease progression heterogeneity may be even broader than estimated in this study, as the study cohort was small, had a high average educational attainment, and was primarily White. Further study of prodromal AD progression in a larger cohort is warranted.

“Our findings may have use in determining thresholds for detecting (actual) treatment effects in prodromal AD and may thereby advance the successful evaluation of future clinical trials,” investigators wrote.

Disclosure: Some study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


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