Cleveland ADRC Renewal Boosts Research Into Alzheimer’s Progression

The Cleveland Alzheimer’s Disease Research Center (CADRC) has received new funding to help illuminate factors influencing the rate of progression in Alzheimer’s disease (AD) and AD-related dementias.

The support, which comes in the form of a five-year grant renewal from the National Institute on Aging of the National Institutes of Health (NIH), is expected to total $21.1 million from 2026 to 2031. It will continue funding of the CADRC, which was established in 2019 to accelerate research of AD and AD-related dementias. The multi-institutional collaborative — the only ADRC in Ohio — brings together physicians and scientists from Cleveland Clinic, Case Western Reserve University, Veterans Affairs Northeast Ohio Health Care System, the MetroHealth System and University Hospitals.

“By following our cohort participants over time, we gain invaluable insight into the earliest changes well before the onset of dementia,” says CADRC Director Jagan Pillai, MD, PhD, who also directs Cleveland Clinic’s Center for Brain Health in Cleveland. “Our vision for the CADRC over the next five years is to build a clinical cohort and research ecosystem that will allow us to assess and begin tackling the medical, biological, cognitive and functional predictors of the rate of progression of AD and related dementias.”

CADRC: Current and future states

The CADRC focuses on understanding why Alzheimer’s disease and related neurodegenerative disorders progress at different rates among individuals, with the goal of slowing progression and developing new treatments and cures. The center supports a wide range of studies while also educating scientists, healthcare professionals and the public on the causes and treatment of dementias. It has an education component designed to enhance research efforts of the Northeast Ohio Alzheimer’s medical community and add unique value to the National Alzheimer’s Coordinating Center (NACC) program and other national and international research partners.

The NIH grant renewal will support the CADRC in pursuing a number of specific aims over the next five years, as outlined below.

Growing a robust clinical cohort

A central objective is to expand the CADRC’s longitudinal cohort with populations that will help provide insights for rate-of-progression research. By 2031, after accounting for attrition, the center expects to study progression in a cohort of close to 700 participants.

Recruitment priorities include the following:

• Individuals with dementia with Lewy bodies (DLB). The CADRC cohort to date is notable for extensive phenotyping, including cerebrospinal fluid (CSF) sampling and access to CSF seed amplification assays for α-synuclein-related pathology. This facilitates examination of pure DLB versus mixed DLB+AD and, when assessed along with vascular brain changes, promises insights into how coexisting pathologies impact progression rates. Dr. Pillai expects nearly 20% of new cohort participants over the next five years to have DLB.
• Individuals with atypical AD. Atypical AD, including nonamnestic phenotypes such as language, visuospatial and dysexecutive presentations, are often associated with faster decline. CADRC has access to biospecimens from rapidly progressive AD (rpAD) cases, including autopsy-confirmed cases with survival under three years. CADRC aims to validate whether rpAD has a distinct CSF proteomic signature and collaborate with other centers to improve biomarker development for atypical and rapidly progressive disease.
• Well-phenotyped cognitively normal adults at high risk. At present, about 18% of the CADRC cohort are cognitively normal older adults who are amyloid-positive and/or APOE ε4 carriers and have both CSF and plasma samples available. This group is intended to support research on early disease biology, predictors of progression and resilience. The center projects that 35% of new participants over the next five years will have preclinical AD.

The center also aims to address barriers to enrolling patients receiving anti-amyloid therapies, an increasingly important subgroup for understanding treatment response and real-world progression.

Advancing deep phenotyping

Another key objective is to strengthen biologic characterization of participants through a range of biomarkers, including:

• Biofluid biomarkers. The CADRC has prioritized collection of matched CSF and plasma, with paired samples already available for 51% of its current cohort. In the next five years, the center projects that at least 100 participants will undergo full characterization of ATNSVI factors (amyloid, tau, neurodegeneration, α-synuclein, vascular, inflammation) every two years. Additional novel biomarkers will be measured in a subgroup to assess for additional markers of progression. The center also plans to validate candidate biomarkers associated with rapid progression.
• Neuroimaging. Participants undergo longitudinal structural, functional and advanced MRI, as well as amyloid and tau PET. Imaging is integrated with clinical and biofluid data and also is used for vascular characterization. Novel imaging methods include chi-separation imaging, which may improve interpretation of susceptibility-related tissue changes, and neuromelanin imaging, which may help detect locus coeruleus and substantia nigra involvement earlier and track disease longitudinally. Postmortem 7T MRI is also used to correlate imaging findings with pathology.
• Neuropathology. The center’s neuropathology program links antemortem clinical features, biomarkers and genetics with autopsy findings. Areas of emphasis include tau and α -synuclein seeding activity, mixed pathologies, and tissue banking of fixed and frozen brain and related tissues. This work is designed to improve clinicopathologic correlation, refine biologic subtyping and support biomarker-based stratification for future therapeutic trials.

Data-sharing and educational objectives as well

In addition to the above objectives, the CADRC has developed infrastructure and support for data collection and sharing along with advanced computational approaches to model disease progression and identify therapeutic opportunities.

The center also plans to mentor clinicians and scientists entering AD-related research and provide education and training for health professionals and the public. Institutional support will fund new Research Education and Career (REC) scholars, developmental grants, clinician-scientist startup support, cross-ADRC travel and research retreats.

“This center is more than a research hub,” Dr. Pillai observes. “It is an ongoing partnership with our community that brings together researchers, clinicians and community members across Northeast Ohio to drive innovation and improve brain health for future generations.”

The center is funded by NIH grant P30AG072959.

This article is solely the responsibility of Cleveland Clinic and does not necessarily represent the official views of the NIH.