# Detection of early cognitive change: Linking to clinically meaningful outcomes (Project 4)

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $285,829

## Abstract

SUMMARY—PROJECT 4: COGNITION. Given the series of disappointing clinical trial results at symptomatic
stages of Alzheimer’s disease (AD), it has become even more urgent to elucidate the temporal relationships
between accumulation of the molecular pathology of AD and the emergence of the earliest clinical
manifestations. Over the second cycle of Project 4, we found consistent evidence that elevated amyloid-beta
(aβ) is associated with future cognitive decline; however, there is considerable heterogeneity in rates of
decline. It is increasingly clear that aβ in isolation is not sufficient for imminent decline, and it is possible that aβ
becomes much less relevant once tau pathology and neurodegeneration are widespread. Thus, we now seek
to better understand the patterns of cognitive change associated with the earliest phases of accumulation of
both aβ and tau, even below current thresholds for abnormality, and to characterize the “pre-preclinical” phase
of AD, as well as the factors that promote successful aging and resilience to cognitive decline. At the other end
of the preclinical AD spectrum, we will investigate whether early cognitive change is predictive of progression
to clinical impairment, as we will have up to 15 years of follow-up. In Aim 1, we strive to further elucidate the
temporal association between longitudinal aβ and tau accumulation and cognitive trajectories. In addition to
our work with the Preclinical Alzheimer Cognitive Composite (PACC), we will go deeper and focus on the
specific cognitive processes associated with the earliest accumulation of aβ and tau, in the context of the
multiple factors that may interact with these pathologies. In Aim 2, we will utilize digital technology to advance
our work to go faster by detecting cognitive change more rapidly and with greater specificity and accuracy.
Our initial work using home iPAD testing revealed a marked lack of “practice effect” despite repeated exposure
to face-name pair stimuli every month on the iPad, associated with elevated aβ. We now propose to test
whether we can detect a similar pattern of diminished practice effect over a period of days. We have also
begun working with an Artificial Intelligence (AI) software platform using a digital pen to capture subtle
cognitive inefficiencies in non-memory processes. In Aim 3, we will go broader, beyond cognitive testing, to
examine clinically relevant measures that include self- and study-partner report of cognitive function, every day
activities, and neurobehavioral alterations to elucidate potential bi-directional relationships and temporal
sequence of these changes along the trajectory of preclinical AD. We will use these measures to assess the
“clinical meaningfulness” of early cognitive change, and to improve our predictions of progression to clinical
impairment, in combination with imaging AD markers. Project 4 will leverage the rich longitudinal
neuropsychological, behavioral, and multi-modality imaging data available on...

## Key facts

- **NIH application ID:** 10144911
- **Project number:** 5P01AG036694-12
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** REISA A. SPERLING
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $285,829
- **Award type:** 5
- **Project period:** 2010-07-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144911

## Citation

> US National Institutes of Health, RePORTER application 10144911, Detection of early cognitive change: Linking to clinically meaningful outcomes (Project 4) (5P01AG036694-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144911. Licensed CC0.

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