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Abstract 


Introduction

Current literature presents conflicting results regarding the impact of neuroinflammation on Alzheimer's disease (AD)-related neurodegeneration. While some studies suggest that neuroinflammation potentiates neurodegeneration, others indicate a protective effect.

Methods

We evaluated 145 individuals with positron emission tomography (PET) for amyloid beta (Aβ), tau, and translocator protein (TSPO), a proxy of neuroinflammation, to test the hypothesis that Aβ and tau are associated with the dual effect of neuroinflammation on neurodegeneration across the AD continuum.

Results

The detrimental effects of neuroinflammation on gray matter density occurred in two waves. The first neuroinflammation-related detrimental wave was associated with brain Aβ deposition, while the second was with widespread tau tangle pathology. Furthermore, the concomitant presence of neuroinflammation, Aβ, and tau was associated with faster cognitive decline over 2 years.

Conclusions

Our results support a model in which Aβ- and tau-associated neuroinflammation are related to two waves of deleterious effects on AD-related neurodegeneration.

Highlights

Two waves of detrimental neuroinflammation effects on brain density associated with Aβ or tau. Aβ associated with deleterious effect of neuroinflammation on brain density in early AD. Tau associated with deleterious effect of neuroinflammation on brain density in late AD. Interactions of Aβ, tau, and neuroinflammation are associated with cognitive decline.

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    Funding 


    Funders who supported this work.

    Alzheimer's Association (7)

    • Grant ID: 24AARFD‐1243899

    • Grant ID: AARFD‐22‐923814

    • Grant ID: AARFD‐22‐974627

    • Grant ID: AARFD‐24‐1307995

    • Grant ID: AARF‐D‐231150249

    • Grant ID: 24AACSF‐1200375

    • Grant ID: AARGD‐21‐850670

    Alzheimer's Society (1)

    • Grant ID: GBHI ALZ UK‐23‐971089

    Alzheimer's Association (7)

    • Grant ID: AARF-D-231150249

    • Grant ID: AARFD-22-974627

    • Grant ID: 24AACSF-1200375

    • Grant ID: AARFD-22-923814

    • Grant ID: 24AARFD-1243899

    • Grant ID: AARFD-24-1307995

    • Grant ID: AARGD-21-850670

    Alzheimer's Society (1)

    • Grant ID: GBHI ALZ UK-23-971089

    CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging (1)

    • Grant ID: 200691/2021-0

    Fonds de Recherche du Québec - Santé (1)

    • Grant ID: 2020-VICO-279314

    Fundação de Amparo a pesquisa do Rio Grande do Sul (1)

    • Grant ID: 21/2551-0000673-0

    Global Brain Health Institute

      Instituto Serrapilheira (2)

      • Grant ID: Serra-1912-31365

      • Grant ID: Serra‐1912‐31365

      NIA NIH HHS (3)

      • Grant ID: R01AG075336

      • Grant ID: R01AG073267

      • Grant ID: AG025204-17

      National Academy of Neuropsychology (2)

      • Grant ID: ALZ-NAN-22-928381

      • Grant ID: ALZ‐NAN‐22‐928381

      National Institute on Aging (3)

      • Grant ID: R01AG073267

      • Grant ID: AG025204‐17

      • Grant ID: R01AG075336

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