Publications by MELODEM Participants

Congratulations to Erin Ferguson and colleagues on their 2024 publication “Visual Impairment, Eye Conditions, and Diagnoses of Neurodegeneration and Dementia”. This paper aimed to determine whether visual acuity, cataracts, and myopia affect neurodegeneration and dementia risk. Evaluating causality here is difficult because dementia and vision in later life can share risk factors or in some cases influence each other. To disentangle these relationships, the authors used forward and reverse Mendelian Randomization (MR).

Led by Erin Ferguson (PhD candidate at the University of California San Francisco with senior author Dr. Willa Brenowitz at Kaiser Permanente Center for Health Research in Portland, Oregon), the research team conducted observational and Mendelian Randomization (MR) analyses in UK Biobank participants. Observational studies examined the association between visual acuity, eye disorders with dementia diagnoses and brain volumes. 2 sample Mendelian Randomization (MR) analysis was conducted using genetic variants that predict risk for cataracts, myopia, and Alzheimer’s Disease (AD). Variants were selected from prior GWAS of these conditions independent of UK Biobank (this entailed a limitation in that analyses were limited to individuals of European ancestry because the variants were identified in European ancestry populations and may differ for other genetic ancestries). The researchers conducted forward MR (vision conditions as affecting dementia) and reverse MR (AD as affecting vision outcomes) analyses.

Researchers found that observed cataracts were linked to a 25% higher risk of developing Alzheimer's disease (AD) and a 25% higher risk of developing vascular dementia. Genetic risk of cataracts was associated with a reduction of 597.43 mm³ of overall brain volume. In MR studies, genetically predicted cataracts were linked to 92% higher odds of developing vascular dementia. This estimates the causal effect of having cataracts on vascular dementia, assuming valid MR assumptions. Genetically predicted AD was not associated with cataracts or poor vision. Although poor visual acuity (worse than 20/40 vision) was associated with 35% higher dementia risk in observational studies, myopia and genetically predicted myopia was not associated with dementia. These results suggest a causal effect of cataracts—or their underlying pathological processes—on the risk of developing vascular dementia (VaD). This could plausibly occur through vascular pathways such as white matter damage.  Additionally, the lack of association between genetic risk for Alzheimer’s disease (AD) and eye conditions indicates that reverse causation is unlikely to explain the observed links between cataracts, poor vision, and AD. Despite uncertainty in clinical diagnoses of VaD versus AD, the potential role of vascular pathways is consistent with the finding that genetically predicted cataract was associated with VaD and but not AD.

Congratulations Willa and Erin and good luck Erin on your dissertation defense (scheduled for February 2025!)

For more of Erin Ferguson’s work, check out her MELODEM presentation on multiverse analyses in March, 2024.

For more on Mendelian Randomization based approaches to evaluating risk factors for dementia, check out Drs. Roopal Desai & Verena Zuber MELODEM presentation in September, 2024.

The 2024 PNAS publication “Effect of a Cash Transfer Intervention on Memory Decline and Dementia Probability in Older Adults in Rural South Africa” evaluated the impact of a randomized cash transfer on long-term cognitive outcomes in a low-income, aging population.

The study was possible because a randomized study of cash transfers ($36 US per month at time of study, equivalent to about 67% of the average household monthly consumption) happened to include the households of 862 participants in the HAALSI study (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community, 2014–2022). Because HAALSI was already tracking cognitive changes longitudinally, they could compare whether changes were slower for older adults in households randomized to receive a cash transfer. The cash transfer study was launched 2011-2012, and cash payouts continued for 1-5 years based on the age of the teenage girl in the household (who were the original intended beneficiaries of the intervention). HAALSI baseline was in 2014/15 and follow-up continued for 7 years.

Older adults (average age 61 years, SD=12 years) in households who received a short-term cash transfer experienced slower memory decline after 7 years of follow-up in the HAALSI cohort study, with stabilized or slower declines in memory scores compared to those who did not receive the transfer. At the end of follow-up, older adults in households that received the cash transfer had a 3-percentage point lower probability of dementia compared to households that did not receive the transfer. This study showed that modest cash transfers to older adults in low-income settings can slow memory decline and reduce dementia risk, emphasizing financial support as a tool for improving brain health in resource-limited areas.

This manuscript was led by Dr. Molly Rosenberg at the Indiana University School of Public Health and senior authored by long-term MELODEM participant Dr. Lindsay Kobayashi of University of Michigan.  Congratulations to the authors on such an impressive and creative study.

The 2024 Neurology publication “Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort,” explores the relationship between blood-based Alzheimer’s Disease biomarkers and cognitive and functional trajectories over five years in older adults from the French MEMENTO cohort. With senior author Dr. Carole Dufouil and first-author Dr. Leslie Grasset, the team assessed the links between baseline biomarkers from blood samples and cognitive tests, including the Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), Semantic Fluency Test, and Trail Making Tests A and B (TMT-A and TMT-B).

Elevated blood biomarkers p-tau181 (linked to Alzheimer’s) and neurofilament light chain (NfL, indicating nerve cell damage), were associated with faster decline in both multiple cognitive measures (e.g., assessing memory and language), as well as measures of physical functioning and autonomy (e.g., a battery of physical performance tasks such as gait speed, balance, and strength and a brief assessment of limitations in instrumental activities of daily living) physical tasks. Together, p-tau181 and NfL were associated with greater cognitive and functional decline than either alone. A lower Aβ42/40 ratio was only associated with a slightly faster cognitive decline in FCSRT and semantic fluency, as well as a slightly faster progression of disability. The clinical significance of this study lies in its potential to better understand the biomarkers that link with the biological progression of Alzheimer’s and pathologies that cause dementia.