# Clinicopathologic and Neuroimaging Differences in Alzheimer's Disease Variants

> **NIH NIH R01** · MAYO CLINIC  JACKSONVILLE · 2020 · $781,978

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a fundamental gap in the understanding of why Alzheimer's disease (AD), which is defined by amyloid
plaques and tau tangles, exhibits such a diverse topographic distribution of neuropathology and range of
clinical variability. To operationally classify the heterogeneity of AD, the PI designed a mathematical algorithm
using differences in hippocampal and cortical tangle patterns. From these studies, three AD variants were
identified – hippocampal sparing (HpSp), typical, and limbic. Striking clinical differences were revealed, as
exemplified by an aggressive clinical course identified in HpSp AD cases compared to typical AD; and in direct
contrast to limbic AD. As such, we propose an extension to the theoretical concept of heterogeneity in AD by
drawing attention to and investigating limbic AD as an insidious form of the disease. Additionally, HpSp and
limbic variants of AD are relatively under-appreciated in current dementia care, thus a better understanding of
these entities is a genuine public health imperative. The overall objectives are to leverage one of the largest
autopsy-confirmed AD series to decipher neuropathologic features, investigate clinical heterogeneity, and
utilize longitudinal neuroimaging to differentiate these AD variants. Our central hypothesis is that hippocampal-
involving and hippocampal-sparing AD share disease traits, but demographics, phenotypic presentation, and
longitudinal neuroimaging can be used to assess rate of disease progression because they significantly differ
between HpSp and limbic AD variants. In Aim 1, novel neurobiologic insights into AD will be revealed by
investigating differential neuropathologic changes of altered proteins, neuronal loss, and key subcortical nuclei
AD. This will be performed using innovative digital pathology to quantify neuroanatomic distribution of
pathologic severity. In Aim 2, contributors to variability in rate of disease progression across AD variants will be
identified by examining heterogeneity of demographics and phenotypic presentations. To accomplish this aim,
an in-depth investigation of each case's clinical history and functional decline will be performed. Finally in Aim
3, incorporation of longitudinally-collected antemortem neuroimaging characteristics of autopsied AD cases will
enable dynamic interpretation of selective hippocampal and cortical vulnerability. To accomplish this aim,
magnetic resonance imaging will be investigated using sophisticated software to assess atrophy measures.
The contribution of this proposal will be significant because it will establish an objective antemortem approach
to classifying heterogeneity in AD by integrating clinical variability and neuroimaging patterns using a well-
established prospectively followed cohort who have been autopsied. The proposed research is innovative
because it will evaluate one of the largest cohorts of autopsy-confirmed AD cases, objectively classify AD
variants using neuropa...

## Key facts

- **NIH application ID:** 9925198
- **Project number:** 5R01AG054449-04
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Melissa Erin Murray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $781,978
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925198

## Citation

> US National Institutes of Health, RePORTER application 9925198, Clinicopathologic and Neuroimaging Differences in Alzheimer's Disease Variants (5R01AG054449-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9925198. Licensed CC0.

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