Using initial cognitive symptoms to predict trajectories of neurodegenerative pathologies

Using a cohort of 2426 participants from the National Alzheimer’s Coordinating Center, a recent retrospective longitudinal study aimed to see whether initial cognitive symptoms caused similar rates of decline in Alzheimer’s disease pathology (ADP), Lewy body-related pathology (LRP ) and mixed ADR-LRP. Data were collected over a mean period of 5.5 (SD 2.8) years from initial visit to autopsy, using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as the primary outcome.

Linear mixed models adjusted for CDR-SB at baseline, age, gender, education, and apolipoprotein (APOE) e4 status were used to assess longitudinal outcomes. Overall, initial nonamnestic symptoms among these neuropathologies had a faster rate of functional decline than other amnestic symptoms affecting executive, verbal, and visuospatial outcomes. A 10% increase in the number of these patients would increase the CDR-SB change by 0.07 points at 2 years.

To learn more about the analysis, NeurologyLive® spoke to lead researcher Jagan A. Pillai, MD, PhD. Pillai, a neurologist at the Cleveland Clinic’s Lou Ruvo Center for Brain Health, provided background on key take-home points, the clinical application of the findings, and how they have significant implications for the results of future clinical trials.

NeurologyLive^®: What was the motivation behind the study?

Jagan Pillai, MD, PhD: The main motivation for the study is that there is great awareness and interest that Alzheimer’s disease often manifests itself beyond memory loss. Patients might have early symptoms related to changes in language, their visuo-spatial skills, or their judgment. The question was, do the initial symptoms they face play a role in terms of their future, prognosis, or rate of change? This study essentially attempted to answer that question. The importance of the study is that the results have good potential impact on the interpretation of clinical trials. Does it make sense to compare people with similar or very different initial symptoms?

Can you discuss the differences in symptoms you’ve observed?

When people have amnestic symptoms, they have changes in their memory scores, while later in life people who have judgment problems tend to perform worse on tasks involving their frontal lobe or aspects of executive functioning. With visual-spatial changes, they might have trouble tracking visual-spatial tests. Language problems relate to inventing names of things or verbal fluency. But there was always the thought that people with some of these non-amnestic symptoms might do worse on cognitive tests but maybe not on functional skills. The primary outcome used was the Clinical Dementia Rating-Sum of Boxes, a measure used in studies tracking functional and cognitive changes. For example, we use the same scale to assess the rate of change in these surrogates in a recent aducanumab study. What is also interesting about this study is that all the diagnoses were confirmed pathologically, so we know exactly what was behind these changes. This is from a retrospective cohort study, and similar cohorts, research cohorts, can also be used in clinical trials.

Are there any symptoms that clinicians typically type in as early indicators of cognitive decline and neuropathologies?

The takeaway point is that there probably isn’t a single clinical symptomatology that will alert you that you’re looking at a progressive degenerative disease. Depending on which part of the brain is initially involved, you may experience some variations and initial symptoms. I think it sheds more light on the heterogeneity of the initial symptoms compared to what people used to think.

How do these results affect clinical trials and drug development?

The main finding of this study was that there was a clear difference between people with non-amnestic symptoms, who showed a faster rate of decline after two years than people with amnestic symptoms. If you compare the slopes of people with non-amnestic and amnestic symptoms and extrapolate that from a drug-placebo study with a 10% difference, you could have a fairly significant amount of cognitive change attributable to the difference in the number of subjects with amnestic symptoms could either hamper the interpretation of results or create a false alarm. In this aducanumab study, the two CDR-SB changes were -0.39 in one study and 0.03 in another study. Based on our models, which estimate a 10% difference in case history between the two arms, you could get a CDR-SB change of about 0.07 over two years. That’s pretty much halfway between the success and failure arm. Being aware of this as a potential confounder and interpretation and study will be very important in light of these minor changes reported by some of the more recent clinical studies to come.

Transcript edited for clarity. Click here to learn more about AAIC 2022.

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1. Pillai JA, Bena J, Leverenz JB. Non-amnestic onset symptoms have a more rapid course of clinical progression than amnestic symptoms in Alzheimer’s, Lewy body, and mixed dementia neuropathologies. Presented at: 2022 Alzheimer’s Association International Conference; July 31 to August 4; San Diego, CA 66804