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NIH grant 1K99AG097974-01A1: Brain degeneration and cognitive decline in patients with atypical Alzheimer's disease or suspected copathologies treated with amyloid-reducing therapies
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Nick Corriveau-Lecavalier. Award: $132057.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a neurodegenerative condition that affects millions of Americans, either directly or
through caregiver responsibilities, imposing a substantial burden on healthcare, financial, and societal
systems. Advances in clinical and biomarker research have shown that AD encompasses not only the “typical”
amnestic syndrome, but also several atypical presentations affecting non-memory domains, including
dysexecutive, language, and visual variants. Additionally, late-onset Alzheimer’s-type dementia frequently
involves mixed pathologies alongside AD neuropathologic change (ADNC), with limbic-predominant age-
associated TDP-43 encephalopathy neuropathologic change (LATE-NC) often co-occurring and independently
contributing to cognitive impairment. Despite these advances, the natural progression of brain degeneration
and cognitive decline across AD variants remains limited, complicating diagnosis, prognosis, and disease
staging. The recent FDA approval of amyloid-reducing monoclonal antibodies (mAbs), which slow progression
in early symptomatic AD, underscores the urgent need to address these gaps. A chief question is whether
efficacy findings from clinical trials—largely conducted in amyloid-positive individuals with the “typical”
amnestic AD—can be extrapolated to patients with atypical AD variants or common copathologies such as
LATE-NC. Addressing this question is essential to inform therapeutic decision making, optimize clinical trial
design, and develop sensitive phenotyping tools across the AD spectrum. The overarching goal of this
K99/R00 proposal is to identify the disease- and patient-specific factors that are associated with variability in
mAbs treatment response across atypical AD variants and suspected copathologies. Aim 1 focuses on defining
the longitudinal trajectories of brain network degeneration and cognitive decline across the typical and atypical
AD variants, and amyloid-positive individuals with suspected LATE-NC. Aim 2 extends this understanding to
evaluate brain degeneration and cognitive decline in “real-world” patients with atypical forms of AD and
suspected LATE-NC treated with mAbs. The Exploratory Aim will investigate performance on a self-
administered digital cognitive battery in early symptomatic AD patients treated with mAbs relative to historical
untreated cases. This project will leverage large-scale research cohorts at Mayo Clinic, clinical data from the
multi-center Mayo Alzheimer’s Disease Therapy Clinics (ADTC), and mentorship from a multidisciplinary
committee with expertise in AD and related disorders. This study builds upon my prior research on atypical AD
and LATE-NC, while providing an opportunity to accrue additional expertise in disease-modifying treatment
effect modeling and advanced data-driven analytics. The proposed work and training plan will position me as a
multi-faceted clinician-scientist that is uniquely qualified to advance the understanding of treatment variability
and inform personalized approaches to AD care.document fetched 2026-09-20 02:42