# Spreading Tau Pathology in Non-Amnestic Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $747,239

## Abstract

A hallmark of typical amnestic Alzheimer's disease (aAD) is neurofibrillary tau pathology. Braak first described
staging of tau pathology in AD, classically evident early in the medial temporal lobe (MTL) implicated in
impaired episodic memory, and then spreading to neocortical regions important for language, visuospatial and
executive function and to basal ganglia for motor function. However, AD pathological change can also present
clinically as a focal neocortical syndrome without amnesia, known as non-amnestic Mild Cognitive Impairment
(naMCI). This includes disorders of language (logopenic variant primary progressive aphasia, lvPPA),
visuospatial (posterior cortical atrophy, PCA), executive (frontal variant MCI, fvMCI), and motor (corticobasal
syndrome due to AD, CBS-AD) function. Rare clinical, imaging, and autopsy studies suggest that tau pathology
in naMCI is greater in neocortex than MTL, challenging fundamental assumptions about the MTL origin of
cerebral tau pathology in AD. However, staging tau pathology at autopsy in naMCI has not been investigated,
and longitudinal in vivo imaging to validate spreading disease in naMCI is very rare and involves small groups
of clinical cases using a single imaging modality. These represent major gaps in our knowledge. In Aim 1, we
study stages of spreading tau pathology at autopsy in naMCI and aAD with a novel, validated, digital method.
We hypothesize that stages of accumulating tau pathology are consistent with neocortical origin and spread in
naMCI, and only later spread to MTL, differing from the MTL origin of tau pathology in aAD. Pathologic staging
depends on inferences from cross-sectional studies at autopsy, so Aim 2 proposes to validate stages of
spreading disease in vivo with novel longitudinal MRI and tau-PET imaging in naMCI and aMCI/ aAD using
unique imaging and graph theory approaches. We hypothesize a cortical origin and spread of tau in naMCI,
with later accumulation of tau in MTL, reversing the MTL origin of disease in aMCI/ aAD. These findings would
challenge assumptions about the MTL origin of tau pathology in AD. We test the novel hypothesis that genetic
factors in FTLD-tau bias the anatomic distribution of tau pathology contributing to the atypical spread of tau in
naMCI. In Aim 1, we expect that stages of tau pathology in naMCI resemble that seen in primary tauopathies
due to FTLD-tau, including non-fluent/agrammatic variant PPA, behavioral variant frontotemporal dementia,
and corticobasal degeneration/progressive supranuclear palsy. In Aim 2, we expect that patterns of longitudinal
in vivo imaging in naMCI resemble that seen in FTLD-tau. Finally, Aim 3 proposes a targeted study of FTLD-
tau-related single nucleotide polymorphism (SNP) risk alleles in naMCI. Based on our preliminary findings, we
hypothesize that FTLD-tau-related risk alleles are more common in naMCI than aMCI/ aAD. These findings
would challenge long-held assumptions about the pathophysiologic basis for AD patho...

## Key facts

- **NIH application ID:** 10120602
- **Project number:** 5R01AG054519-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jeffrey S Phillips
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $747,239
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120602

## Citation

> US National Institutes of Health, RePORTER application 10120602, Spreading Tau Pathology in Non-Amnestic Alzheimer's Disease (5R01AG054519-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10120602. Licensed CC0.

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