Sensitive Cognitive Outcomes Preclinical Alzheimer’s Disease Trials

3D rendering of Beta-amyloid found in Alzheimer's disease.

It’s now known that Alzheimer’s disease pathogenesis can begin 20 years or more before symptoms become apparent. Clinical trials are moving toward secondary or even primary prevention—starting therapy in cognitively normal older adults who show elevated β-amyloid (Aβ) and tau pathology, or just emerging Aβ, respectively.

The key to these trials will be outcome measures that can detect the earliest subtle cognitive changes associated with emerging Aβ and tau pathology.

Kathryn V. Papp, PhD, and Reisa A. Sperling, MD, of the Department of Neurology at Brigham and Women’s Hospital, Michelle E. Farrell, PhD, a postdoc at Massachusetts General Hospital, and colleagues recently determined that very early Alzheimer’s disease is associated with a decline in measures of processing speed and memory retrieval. They report the details in Neurology.


Through the Harvard Aging Brain Study, the research team had access to data on 112 older adults who:

  • Were cognitively healthy at baseline (Clinical Dementia Rating score of 0 and Mini-Mental State Exam score ≥27 after adjustment for education)
  • Participated in annual cognitive testing for up to eight years
  • Underwent serial positron emission tomography (PET) for measurement of Aβ (baseline and years 1.5, 3, 5, and 8) and tau levels (years 3, 5, and 8)
  • Initially had low to intermediate Aβ levels, defined as a rating <40 on the Centiloid (CL) scale, a standardized method for quantifying Aβ on PET; importantly, 102 participants were rated <CL20 (had no detectable Aβ at baseline)

Cognitive testing included:

  • Episodic memory tasks—The Free and Cued Selective Reminding Test (FCSRT), the Wechsler Memory Scale–Revised Logical Memory test (LM), and the 6-trial Selective Reminding Test (SRT)
  • Measures of processing speed/executive function—the Wechsler Adult Intelligence Scale–Revised Digit Symbol Substitution Test (DSST), and Trail Making Tests A and B
  • Measures of language—Categorical verbal fluency (CAT, total from animals/vegetables/fruit) and phonemic verbal fluency (FAS, ability to name words in one minute for each of the letters F, A, and S)

Cognitive Change With Aβ Accumulation

The primary analyses were to assess whether each cognitive measure was associated with early detectable Aβ accumulation on PET imaging:

  • Participants initially <CL20—Greater Aβ accumulation was significantly associated with a decline on the DSST and Trails A
  • All participants initially <CL40—Aβ accumulation remained associated with the DSST and Trails A, and was newly associated with all measures of retrieval

Which Test at What Time?

To explore the idea of selecting the right test at the right time, all individuals (including those >CL40 at baseline) were grouped according to their final CL category:

  • A decline in processing speed (dubbed PS, calculated as DSST plus Trails A) predominated as individuals crossed the CL20 threshold
  • A decline in memory retrieval (dubbed MEM, calculated as FCSRT–free recall plus SRT–total recall plus LM–immediate recall) was more consistent as individuals crossed the CL40 threshold
  • The combination of PS and MEM was a significantly stronger marker of decline than the Preclinical Alzheimer’s Cognitive Composite, a standard measure of high Aβ, in individuals with initially low-to-intermediate Aβ who crossed CL40 by their final follow-up

Influence of Tau

Once tau spread into the neocortex, its debilitating impact on cognitive decline far outweighed the subtle changes in memory associated with Aβ. Tau became a strong driver of decline across a broad range of cognitive tasks, particularly episodic memory.


These findings imply that prevention trials will be able to assess the cognitive consequences of emerging Alzheimer’s disease pathology. A composite of measures of processing speed and memory retrieval may be the optimal method for the earliest stages of preclinical AD.

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