Hippocampal sclerosis (HS) is an age-related degenerative condition characterized by neuronal loss and astrogliosis in the subiculum and the Cornu Ammonis 1 (CA1) region. It affects around 20% cognitively impaired individuals. It causes dementia over Alzheimer’s disease (AD), frequently coexisting with AD-pathology and limbic-predominant TDP-43 encephalopathy (LATE-NC). Since modifiable risk factors influence the risk of HS-related dementia. Mediterranean principles and Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean DASH Intervention for Neurodegenerative Delay (MIND) diet have been linked to decreased AD risk, better brain health, and slower cognitive decline. This study investigated whether adherence to the MIND diet is associated with neural loss, LATE-NC, HS, and dementia proximate to death.
The Rush University IRB approved this cohort study, which utilized data from the Rush Memory and Aging Project (MAP). It is a continuous, longitudinal clinical-pathological study of older adults who enrolled without dementia and were followed every year until death. By April 2024, 2312 participants had enrolled. The present analysis included 809 decedents with both autopsy and dietary data. Participants completed validated food frequency questionnaires (FFQs) annually and updated in 2017 to reflect contemporary dietary patterns. These FFQs captured typical intake and were used to calculate MIND diet scores (range 0-15) based on the consumption of 10 brain-healthy food groups and the avoidance of 5 unhealthy groups. Average MIND scores were calculated from repeated measures taken across the follow-up period.
Postmortem brain examinations assessed HS by hematoxylin and eosin staining of the CA1 and subiculum, grading the severity of neuronal loss on a standardized scale. LATE-NC was measured by immunohistochemistry, with stages 2 to 3 considered positive. Logistic regression models evaluated the links between MIND diet scores and neuropathologic outcomes (HS, HS with LATE-NC, LATE-NC alone, and hippocampal neuronal loss), adjusting for age at death, sex, education, total calories, APOE-ε4 status, AD pathology, vascular changes, body mass index (BMI), and lifestyle factors. Mediation analyses tested whether HS mediated the relationship between the MIND diet and dementia diagnosis at death. Sensitivity analyses excluded participants with severe cognitive impairment and those with FFQs completed within 3 years of death. Analyses were performed in SAS 9.4, with two-sided P < 0.05 considered significant.
Among 809 autopsied participants (mean standard deviation [SD] age at death 91.2 [6.1] years, 72% female, mean follow-up 7.2 [4.4] years). Around 71 (8.8%) had HS with LATE-NC, and 82 (10.1%) had HS. 529 (65%) had AD neuropathologic changes (ADNC), 299 (37%) had LATE-NC, 209 (26%) had cerebral atherosclerosis, 252 (31%) had arteriolosclerosis, and 301 (37%) were diagnosed with Alzheimer’s dementia proximate to death. A higher MIND diet score was associated with a lower risk of dementia (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.68-0.87).
For HS, each additional point in the MIND diet score was linked to 22% lower odds (OR: 0.79, 95% CI: 0.66 to 0.95). Associations remained after adjustment for APOE-ε4 and ADNC (model A), vascular pathologies (model B), β-amyloid load (OR: 0.75, 95% CI: 0.62 to 0.92), and β-amyloid plus tau (OR: 0.76, 95% CI: 0.63 to 0.93). HS with LATE-NC showed the same findings (OR: 0.80, 95% CI: 0.66-0.98). There is no association found between the MIND diet and LATE-NC alone (OR: 1.00, 95% CI: 0.91 to 1.11).
In 300 participants with neuronal loss data, those in the highest MIND diet tertile had 48% lower odds of severe neuronal loss (OR: 0.52, 95% CI: 0.27-0.98). Continuous MIND scores also predicted reduced neuronal loss (OR: 0.75, 95% CI: 0.59 to 0.95). Mediation analysis revealed that HS explained 20.7% of the association between the MIND diet and dementia (indirect β = −0.05, 95% CI: −0.10 to −0.01, P = 0.02). Only the Mediterranean diet was associated with HS.
This study found that sticking to the MIND diet was associated with lower odds of HS, hippocampal neuronal loss, and HS with LATE-NC. The unique components of the MIND diet, particularly leafy greens and berries, may contribute to the protection of the hippocampus. It supports animal studies demonstrating that a high-fat, unhealthy diet impairs hippocampal function through inflammation, glial activation, and oxidative stress. Further research is needed to explore mechanisms and evaluate dietary interventions across diverse populations.
References: Agarwal P, Agrawal S, Wagner M, et al. MIND Diet and Hippocampal Sclerosis Among Community-Based Older Adults. JAMA Netw Open. 2025;8(8):e2526089. doi:10.1001/jamanetworkopen.2025.26089
