Deciphering Alzheimer’s Clinical Endpoints

Identifying and measuring progression in Alzheimer’s is a key challenge, learn more about the tools used.

Alzheimer’s disease is a chronic, progressive neurodegenerative disease that leads to severe memory impairment as well as behavior and social challenges, with individuals eventually losing the ability to undertake everyday tasks and function independently.

Across different individuals and across disease stages, the disease progresses at different speeds. For example, people in the early stages of the disease often progress slowly while people in later, more moderate stages may get worse at a faster rate. So identifying and measuring a meaningful treatment outcome can depend on multiple factors. In developing potential new treatments for the early stages of this disease, finding the right tools to measure what matters most to people living with Alzheimer’s and care partners does present challenges, but researchers have developed a combination of sensitive tools to help us do this.

Measuring What Matters to People Impacted by Alzheimer’s Disease: Cognition and Function

For people living with Alzheimer’s and their care partners, what’s often reported as some of the most important treatment outcomes are improving memory, slowing or stopping disease progression and retaining their ability to participate in daily activities, and maintaining their interests.1 Clinicians who treat people living with Alzheimer’s refer to many of these features in two main categories: cognition (related to memory and thinking) and function (related to performing daily activities).

Until recently, only symptomatic treatments for Alzheimer’s disease were available – medicines that temporarily ease the ways in which the disease manifests without addressing the underlying disease process. Now, novel disease-modifying treatments (DMTs) are being evaluated in large clinical trials in people with early symptomatic stages of Alzheimer’s disease. While DMTs are not expected to improve specific symptoms, the hope and goal for current DMTs under investigation is to slow disease progression and thereby the cumulative loss of cognition and function.

Alzheimer’s disease includes unique and compounded challenges for demonstrating treatment benefits compared to some other conditions. It develops and progresses over decades compared to other diseases that progress and present initial symptoms more dramatically, and then progress much more rapidly like infections and cancer. In the earlier stages of Alzheimer’s disease, the rate of disease progression on any given measurement scale can be slow, making it difficult to detect a difference from day to day, week to week, or month to month. In clinical trial settings, researchers have identified a series of sensitive scales and tests in order to develop a more complete picture of how a potential treatment may affect a person’s life across different areas. This includes looking at how people living with Alzheimer’s are able to go about their day-to-day activities such as organizing calendar activities, pursuing hobbies, or getting to where they need to go in the community. These tests and measures reflect multiple experiences and perspectives of people living with the disease, and sometimes include input from their care partners and clinicians.

The biological impact from newer DMTs is promising. Most have demonstrated a reduction of key biomarkers associated with Alzheimer’s – beta-amyloid, tau and neurofilament light, among others. The central question is whether those changes to the underlying biology of Alzheimer’s will translate into meaningful differences in a person’s life. That’s why it’s important to use instruments that may be sensitive enough to detect specific changes in cognition and function relevant to daily life when designing clinical trials in earlier stages of Alzheimer’s disease.

Breaking Down Alzheimer’s Benchmarks

There are a variety of clinical outcome assessments and tools the Alzheimer’s field is using to evaluate and quantify the therapeutic effect of potential new DMTs. The volume, complexity and overlap of these measures can be confusing.

Alzheimer’s Disease Clinical Outcome Assessments

Most clinical outcome assessments are validated questionnaires that include information from patients, care partners and clinicians that collectively assess a therapeutic effect.

Measures of Cognition

These tests measure a person’s ability to do different types of mental tasks like answering questions about time (e.g., What day is it? What month is it?), remembering lists of items, identifying objects, following written instructions and copying drawings. While these tasks seem relatively simple for people with normal cognitive abilities, people living with Alzheimer’s will have increasing difficulty as the disease progresses

  • Mini-Mental State Examination (MMSE)2
    • Set of 11 questions that doctors and other healthcare professionals commonly use to check for cognitive impairment and quantify how severe it is (problems with thinking, visual perception, communication, understanding and memory) with a maximum score, indicating normal performance of 30
    • The MMSE is quick and simple to administer, and provides a snapshot into overall cognitive ability, but may miss more subtle underlying problems that some individuals have which are not measured by the test
    • Example questions include asking the time and date, recall of a short list of objects, copying a geometric figure, and attention questions e.g. “Can you spell ‘world’ backward?”
    • Additional limitations to this test; certain physical or psychiatric disabilities, language differences, speech issues, education level or cultural differences can affect the score. Also, the scale is not sensitive to early impairment, so most patients early in their disease will have a normal score
  • 13-Item Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog 13)3
    • Consists of 13 parts (including word recall, following commands, comprehension, figure copying, concentration and spoken language) and takes approximately 30 minutes to administer
    • It measures errors, so higher scores are worse with a maximum score of 85, but this may not be reached even after a decade of observation
    • Originally developed as a two-part scale: one that measured cognitive functions and one that measured non-cognitive functions such as mood and behavior, but the non-cognitive portion is seldom used
    • Example questions can include recall of 10 words from written cards, following a command to “point to the ceiling and then to the floor”, asking participants to copy a complex drawing and asking participants to name items

Measures of Function

These tests measure a person’s ability to carry out everyday tasks like finding personal belongings, dressing oneself, handling finances, using a phone, traveling outside their home and making meals. As Alzheimer’s progresses it can impact a person’s performance of these daily tasks, which ultimately affect their independence.

  • Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale (ADCS-ADL)4
    • ADCS-ADL was designed to evaluate performance of daily activities, including bathing, dressing, finding belongings and keeping appointments
    • The ADCS-ADL is a 23-item scale that includes a care partner component which rates the degree to which their family member or loved one can perform a variety of tasks
    • The maximum score is 78 and higher scores are better
    • Versions exist to measure impairment from mild cognitive impairment through to severe AD
    • Example questions for care partners include “In the past four weeks, did the person usually manage to find his or her personal belongings at home?” and “In the past four weeks, did the person ever write things down?”
  • Functional Activities Questionnaire (FAQ)5
    • FAQ measures instrumental activities of daily living, such as preparing balanced meals and managing personal finances.
    • The care partner is asked to rate ability to complete 10 key tasks, including shopping alone, playing a game of skill and keeping track of current events on a scale of 1 to 3, with 3 being dependent on support and 0 being normal ability

Global and Composite Measures of Function and Cognition

  • Global and composite tests measure and evaluate both a person’s cognitive and functional ability and may provide a more complete view of a person’s mental state.
  • Examples include:
    • Clinical Dementia Rating scale – Sum of Boxes (CDR-SB)6
      • Measures six domains (three cognitive and three functional), including memory, orientation to time and location, judgement and problem solving, community functioning, hobbies and personal care, and each box is scored as 0.0, 0.5, 1, 2 or 3, and the boxes are then added up. A score of 0 represents no impairment and the maximum score is 18 which represents severe impairment due to dementia, but it can take decades to go from 0 to 18
      • The FDA has noted the CDR‐SB adequately and meaningfully assesses both daily function and cognitive effects in an integrated manner and is consistent with FDA guidance on clinical endpoints appropriate for the early Alzheimer’s disease population
    • Integrated Alzheimer's Disease Rating Scale (iADRS)7
      • Composite tool that combines items from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL)
      • It can be effective in capturing both disease progression and separation of placebo and active drug effect, but as it was recently developed, there is limited evidence for this tool to date

Neurodegeneration – Applying What We’ve Learned to Alzheimer’s

We have a long-standing commitment to follow the science of Alzheimer’s, wherever it leads and no matter how long it takes. Each data set and clinical trial provides important information and builds our understanding of the disease. We have persisted in studying Alzheimer’s for more than two decades and there has been much progress across the field in the development, understanding and application of potential DMTs in Alzheimer’s treatment. We have hope that these new treatments will not only convincingly slow the underlying biology of Alzheimer’s, but will help preserve what matters most to those living with Alzheimer’s disease and their caregivers.