Norman Geschwind Prizewinner Advances Lewy Body Disease Research

Alzheimer’s disease pathology may be the dominant driver of cognitive decline in patients with Lewy body disease, according to a new study led by Houston Methodist neurologist Dr. Jon B. Toledo that could help reshape how clinical trials are designed and how overlapping neurodegenerative conditions are treated.

The research, published in Alzheimer’s Research & Therapy, highlights the complex and often underrecognized interplay between Alzheimer’s disease (AD) and Lewy pathology (LP), two of the most common causes of dementia.

The work underscores Houston Methodist’s growing leadership in behavioral neurology, as Dr. Toledo was selected to receive the Norman Geschwind Prize — one of the field’s highest honors — for his full body of research, which also includes foundational brain bank and autopsy research, leadership in biomarker development and validation, and more. He will present his award-winning work at the 2026 American Academy of Neurology Annual Meeting in Chicago.

Coexisting pathologies

Dementia encompasses a range of conditions characterized by progressive decline in memory, thinking and reasoning. Among them, AD remains the sixth leading cause of death among adults 65 and older, while Lewy body dementia (LBD) — which includes Parkinson’s disease dementia and dementia with Lewy bodies (DLB) — is the second most common neurodegenerative cause of dementia after AD. Yet despite their prevalence, these diseases rarely occur in isolation.

“Neurodegenerative diseases such as Alzheimer’s and Lewy body disease co-occur very frequently,” said Dr. Toledo. “Around one-third of Alzheimer’s disease patients have Lewy pathology, and about half of the patients who have dementia with Lewy bodies have the pathology of Alzheimer’s.”

Using the National Alzheimer Coordinating Center (NACC) database, Dr. Toledo and colleagues performed a long-term clinical and cognitive follow-up of a large autopsy series. The study sample included 597 participants with LP and 491 participants with intermediate or high ADNC without LP.

Participants were categorized as cognitively normal, having mild cognitive impairment, or having dementia. A combination of memory, executive and language domain scores from the NACC Uniform Dataset neuropsychological test battery, the Mini-Mental State Examination, and the Clinical Dementia Rating was used for cognitive assessment.

Dr. Toledo concluded that high AD pathologic burden is the primary driver of global cognitive decline in individuals with Lewy pathology. However, Lewy pathology also contributes independently, particularly to the faster progression of the Clinical Dementia Rating when AD pathologic burden is lower.

In addition, the relative burden of Lewy and AD pathology leads to predominantly executive or memory impairment, respectively.

Tracking impact

The study identified how the rate of decline varies across disease stages, depending on the presence of AD and Lewy pathologies; this information is helpful for designing clinical trials and assessing disease progression.

Studying Lewy pathology and ADNC together is imperative because their combined pathologies lead to a faster rate of cognitive decline and more severe brain alterations than either pathology alone. Co-pathologies can have synergistic effects and affect disease progression differently. Hence, understanding this interplay is crucial for evaluating and developing effective treatments for LBD and AD.

“Various pathologies are seen in cognitively impaired older individuals, and each pathology may contribute to cognitive decline, lower the individual's threshold to become symptomatic, and modify the clinical profile,” said Dr. Toledo. “Differences in the type and frequency of co-pathologies could explain discrepancies between studies that have examined cognitive profiles and decline in individuals with Lewy pathology.”

LBD is a complex, multi-system disease with a wide range of symptoms, which makes treatment difficult. Treating one symptom can worsen another.

Moreover, the search for a targeted therapy for LBD is complicated since the condition often co-exists with other neurodegenerative diseases. 

Treatments and trials

Currently, there are no FDA-approved treatments specifically for LBD. However, there are several LB targeting therapeutic trials investigating drugs and treatments for LBD, including those that aim to clear abnormal α-synuclein protein deposits, improve cognition, and manage other symptoms like sleep disturbances and Parkinsonism.

Notably, treatments targeting only AD pathology may not be as effective if LP is also present. Hence, understanding the co-occurrence of pathologies may be vital for the design of clinical trials. Future therapies targeting both pathologies may improve patient outcomes.

“This study may be especially relevant for those clinical trials that include biomarkers for the targeted pathology but don’t address coincident pathologies not targeted by the studied treatment,” Dr. Toledo said. “Our findings demonstrate that concomitant high AD pathology strongly impacts cognitive performance in individuals with Lewy pathology and type of cognitive deficits.”

The researchers offered an estimate of specific cognitive domains across different disease stages in Lewy body dementia to help with the design therapeutic trials that target AD or Lewy pathologies, as well as combination therapies in the future.

“A more nuanced understanding of how overlapping pathologies drive cognitive decline may help redefine the framework for studying and treating dementia,” said Dr. Toledo. “The goal is to translate complex neuroscience discoveries into clinically actionable insights that can help patients.”

Jon B. Toledo, David P Salmon, Melissa J Armstrong, Douglas Galasko. Cognitive decline profiles associated with Lewy pathology in the context of Alzheimer's disease neuropathologic change. Alzheimer's Res Ther. 2024 Dec 20;16(1):270. doi: 10.1186/s13195-024-01628-z.

J.B.T. is the Ann and Billy Harrison Centennial Chair in Alzheimer’s Research and is supported by the endowment. This research was supported by NIA/NIH grant P30 AG062429. This study used publicly available de-identified data; ethics declaration: not applicable. Dr. Armstrong receives research support from the NIH (R01AG068128, P30AG066506, R01NS121099, R44AG062072), the Florida Department of Health (grants 20A08, 24A14, 24A15), and as the local PI of a Lewy Body Dementia Association Research Center of Excellence.