Executive Function

Considerations for compiling the ADNI neuropsychological battery included the following: 1. Coverage of the domains of interest (memory, executive functions, language, attention, and visuospatial abilities); 2. Adequate sampling of cognitive domains of interest in subjects who are normal or who have MCI or AD; 3. Can measure change over a 2–3 year period; 4. Avoid ceiling or floor effects; 5. Were efficient and met practical demands; 6. Were utilized in the AD Clinical Study (ADCS) MCI trial and worked well in that setting. Additionally, the tests are widely used in AD Centers (ADCs) that are required to collect a Uniform Data Set, to reduce the amount of testing needed for participants enrolled in ADNI from ADCs.
The RAVLT uses a 15-item list of unrelated words. This list is read to the participant, who is asked to recall aloud as many of the words as they can. The number of successfully recalled words is recorded. The list is then repeated, and the participant again asked to recall as many words as they can. This process is repeated for a total of 5 learning trials, resulting in 5 scores. Then the examiner reads a new list of 15 words to the participant (an interference word list), and the participant is asked to recall as many of these words as possible. The participant is then asked to recall the initial word list, and the number of words recalled is recorded. After thirty minutes of other testing, the participant is again asked to recall as many words from the initial list as they can. The two versions of the RAVLT include different versions of the initial and interference word lists.
The ADAS-Cog includes two different memory tasks. First is a word list learning task similar to but distinct from that of the RAVLT. The ADAS-Cog word list includes 10 unrelated words (rather than 15) that are printed on cards. The participant is asked to read them aloud (while in the RAVLT they are read to the participant) and to remember them. There are three learning trials (rather than five in the RAVLT). After five minutes (rather than 30) of unrelated testing, the participant is asked to recall as many words as possible from the list.
The second memory task included in the ADAS-Cog is a word recognition task. In this task, the participant is given 12 cards with words printed on them, and asked to read them aloud and to remember them. Then the target words along with 12 distractor words are shown to the participant, who is asked to indicate whether the word was one they were supposed to recall. Two scores are recorded: the number of target words correctly identified as being part of the list (i.e., true positives), and the number of distractor words correctly identified as not being part of the list (i.e., true negatives).
The three different versions of the ADAS-Cog include different lists of the 10 words for the list learning trial as well as different lists of the 12 words for the recognition task.
For logical memory, a brief fact-laden passage is read aloud once. The participant is asked to recall as many of the passage’s 25 elements as they can, and the number of elements correctly recalled is recorded. After 30–40 minutes of other cognitive testing, the participant is again asked to recall the passage, and the number of elements correctly recalled in this delay condition is recorded.
In the MMSE, 3 words are read to the participant, who is asked to repeat them. Distractor tasks are then administered, after which the participant is asked to spontaneously recall the three words. Scores of 1 point are recorded for each item correctly recalled, and 0 for each item not correctly recalled.

The primary objective of the A4 study is to test the hypothesis that solanezumab, administered as a 400-mg intravenous infusion every 4 weeks for 168 weeks, will slow cognitive decline compared with placebo in participants with preclinical AD. This objective will be assessed using a mixed model of repeated measures (MMRM) analysis of change in the ADCS-PACC score. The specific hypothesis of the A4 study is that there will be less of a decrease in the ADCS-PACC score at the end of the treatment period for participants treated with solanezumab than for participants treated with placebo.
Based on a review of the literature for cohort studies in “normal controls” who progressed to mild cognitive impairment or Alzheimer dementia, we determined that a composite measure sensitive to change in preclinical AD would likely require assessment of 3 key domains: episodic memory, executive function, and orientation. Previous studies^{19 (link)–21 (link)} have reported evidence that both list learning and paragraph recall (measures of episodic memory) tend to decline 7 to 10 years prior to the diagnosis of MCI or Alzheimer dementia. Recent data from amyloid imaging studies^{25 (link)–29 (link)} have reported a decline in multiple cognitive domains looking retrospectively at cognitive trajectories over 8 to 10 years prior to PET amyloid imaging^{22 (link)–24 (link)} and prospectively over 1- to 3-year longitudinal follow-up.
Based on this review, we propose a composite of 4 measures that are well established as showing sensitivity to decline in prodromal and mild dementia, and with sufficient range to detect early decline in the preclinical stages of the disease. The ADCS-PACC includes:

The Total Recall score from the Free and Cued Selective Reminding Test (FCSRT) (0–48 words),^{20 (link),30 (link)}

The Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale (0–25 story units),³¹

The Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised (0–93 symbols),³² and

The MMSE total score (0–30 points).^{33 (link)}

The composite score is determined from its components using an established normalization method.^{34 (link)} Each of the 4 component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Thus, a change of 1 baseline standard deviation on each component would correspond to a 4-point change on the composite. In the A4 study, the ADCS-PACC will be administered at baseline and at 24, 48, 72, 96, 120, 144, and 168 weeks, alternating between 3 test versions.

All ADNI CN and MCI participants were diagnostically reclassified using Jak/Bondi actuarial neuropsychological test methods [24 (link), 25 (link)] applied to their baseline data. Six neuropsychological measures from ADNI were chosen because of their routine use in assessing early cognitive manifestations of AD and administration across all three ADNI grant periods (ADNI-1, -GO, and -2). The six measures were Category Fluency and Boston Naming Test scores for the language domain, Trail-Making Test Parts A and B scores for the graphomotor speed/executive function domain, and Rey AVLT delayed recall and delayed recognition scores for the episodic memory domain. None of these cognitive measures were used in making the initial ADNI diagnostic classification. Each measure was converted to an age-corrected standard score using published normative data: Mayo Older Americans Normative Study data (n = 530; [36 ]) for the Rey AVLT and National Alzheimer’s Coordinating Center normative data (n = 3,286; [37 (link), 38 (link)]) for the remaining neuropsychological measures. Participants were considered to have MCI if any one of the following three criteria were met: 1) they had an impaired score, defined as >1 SD below the age-corrected normative mean, on both measures within at least one cognitive domain (i.e., memory, language, or speed/executive function); 2) they had one impaired score, defined as >1 SD below the age-corrected normative mean, in each of the three cognitive domains sampled; or 3) they had a score on the FAQ =9 indicating dependence in three or more daily activities. This latter criterion approximated Jak, Bondi et al.’s [25 (link)] incorporation of instrumental ADL assessment to diagnosis and reflects significant study partner-rated difficulties in everyday function. If none of these criteria were met, the participant was diagnosed as CN.