Martha Clare Morris

Background: The Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet is a hybrid of the Mediterranean and DASH diets, with added foods designed to target brain health. Observational studies demonstrate inverse relations with cognitive decline but clinical trial evidence is lacking.Method: We assigned at random 604 older adults without cognitive impairment, a family history of dementia, BMI>25, and a MIND diet score ≤8 on a 14‐item screener, to the MIND diet or placebo (usual diet) for three years (January 2017 ‐ June 2021); all participants received diet counseling for weight loss, monthly cooking sessions, and other support over 3 years. Cognition was assessed with a 12‐test battery from which a measure of global cognition was derived. The trial was interrupted due to the COVID‐19 global pandemic and analyses were conducted to account for the interruption. Using random effects analyses we assessed rate of cognitive decline from baseline to trial close in each group, both pre‐ and post‐COVID.Result: Overall, 564 participants (93%) completed the trial. In an intent‐to‐treat analysis, those assigned to MIND diet maintained better global cognition compared to placebo control (difference in standard units = 0.015 per year, 95% CI: ‐0.005, 0.034); findings were borderline significant. To help interpret findings, the effect estimate was equivalent to being 4.3 years younger in age for this sample population. Pre‐pandemic, we observed a significant, positive effect of MIND on change in cognition over two years compared to placebo/usual diet (beta = 0.026, 95% CI: 0.001, 0.052).Conclusion: Over three years, the MIND diet was beneficial for cognition compared to usual diet, although results were not formally statistically significant. However, there was evidence of a statistically significant effect of the MIND diet before the start of the COVID‐19 pandemic, which impeded the intervention protocol and outcome ascertainment.

Background: Copper (Cu) is an essential element for brain health. There is increasing recognition that altered Cu homeostasis is related to the development of Alzheimer’s disease (AD). Neuropathologic findings of amyloid plaque and neurofibrillary tangles are the hallmarks of Alzheimer's disease process. Whether brain Cu is associated with AD neuropathology in humans is unknown. This study examines the relationship between brain Cu levels and AD neuropathology in autopsies from a community sample of older adults.Method: The study was conducted in 679 deceased participants from the Rush Memory and Aging Project, a cohort study. Brain Cu levels were measured using ICP‐MS in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellum. Diffuse and neuritic plaques and neurofibrillary tangles were assessed in multiple brain regions and summarized as standard measures of AD pathology, including Braak, CERAD, NIA‐Reagan, global AD pathology. Linear regression analyses were used to evaluate the associations of brain Cu (grouped in tertiles) with the AD pathology in models controlled for age at death, sex, education, and APOE‐ ε 4 status.Result: The mean age at death was 90.2 (±6.2) years, 70% were women, and 25% carriers of the APOE4 allele. Higher brain Cu levels were associated with less AD neuropathology. Participants in the middle and highest tertile of overall brain Cu levels had less global AD pathology (T3 vs. T1:β = ‐0.10; T2 vs. T1 = ‐0.11; p trend = 0.007) and Braak stage (T3 vs. T1: β = ‐0.31; T2 vs. T1 = ‐0.22; p trend = 0.005) when compared to those in the lowest tertile. Similar associations were found between inferior temporal brain Cu levels and AD neuropathology: global AD pathology (T3 vs. T1: β = ‐0.17, p = <0.0001); Braak (T3 vs. T1: β = ‐0.42, p = 0.0001); CERAD (T3 vs. T1: β = ‐0.17, p = 0.008); NIA‐Reagan (T3 vs. T1: β = ‐0.21, p = 0.002)). Brain Cu levels in mid‐frontal and cerebellum had a marginal association, whereas anterior cingulate Cu levels had no association with AD neuropathology.Conclusion: Higher brain copper levels are associated with fewer AD neuropathology, suggesting that brain Cu levels either may reflect the severity of the disease or may indicate its potential beneficial effect on the disease process.

Background: Brain iron has been reported elevated in Alzheimer’s disease (AD) in mostly small studies that were without extensive clinicopathological classification. Brain iron may be important for disease progression since it can become pro‐oxidant and induce cell death (by ferroptosis) or inflammation (by promoting an inflammatory phenotype of microglia). Here, we report the largest post‐mortem study of brain iron in AD, examining iron in multiple brain regions in a large (645) group across the clinicopathological staging of the disease with extensive cognitive data collected in the decade prior to death.Methods: Iron was measured in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellar cortices from 645 post‐mortem brains (Memory and Aging Project). AD pathology was defined by CERAD criteria. NINCDS‐ADRDA criteria were used to assign AD clinical diagnosis during life. Cognitive performance (test batteries for multiple cognitive domains) was assessed annually in the decade prior to death. Analysis consisted of mixed‐effects models with quadratic and linear variables: iron, age, sex, APOE ε4, plaque counts, neurofibrillary tangle counts, Lewy bodies, vascular infarcts.Results: This study included 166 pathology‐negative subjects without dementia, 40 pathology‐negative subjects with dementia, 212 subjects with AD pathology but without dementia, and 227 subjects with AD pathology and dementia. In subjects without dementia, iron levels were not associated with pathological status, demonstrating that iron does not elevate in the brain merely with increasing pathology load. Iron was elevated (p = 2 × 10⁻⁴) in the inferior temporal cortex of people with AD pathology and clinical dementia, but not in any other region. Nonetheless, the iron status of each region was strongly associated with accelerated cognitive decline in the years prior to death, regardless of whether iron was increased, with a composite of iron values in each region demonstrating the greatest performance (Figure 1).Conclusions: Iron is regionally elevated in AD brains, but, importantly, iron need not be increased to pathological levels to influence neurodegeneration. Rather, iron burden acts as a risk factor trait in brains with iron levels in the normal range.

Background: While prevention trials are recruiting individuals at high risk of dementia, including those who are genetically predisposed, it has become uncertain whether these interventions, in particular, lifestyle factors can lessen the increased genetic risk. We investigated whether the association between lifestyle factors and cognitive decline differed as a function of APOE4 status in an elderly population.Method: Using data from the Chicago Health and Aging Project, a population‐based cohort study, we defined a healthy lifestyle score based on non‐smoking, >=150 min/week moderate/vigorous physical activity, light‐to‐moderate alcohol consumption, high‐quality MIND diet, and engagement in late‐life cognitive activities, yielding an overall composite score that ranged from 0 to 5. Global cognitive function was assessed using brief tests of episodic memory, executive function, and the MMSE in approximately 3‐year cycles for over 18‐years. We examined the association of adherence to lifestyle factors with cognitive decline separately in those with and without APOE4 using a linear mixed effect model adjusted for age, sex, education, race, cardiovascular disease, time, and their interactions with time.Result: Of 3,886 older adults included in the study, 1,269 (33%) were APOE4 carriers. Compared to non‐carriers, APOE4 carriers were younger (71y vs. 72y; p<0.001), mostly African American (68% vs. 57%; p<0.001), and had a lower global cognitive score at baseline (0.37 vs. 0.43; p=0.01). In the multivariable‐adjusted model, a higher healthy lifestyle (4‐5 healthy lifestyle factors versus 0‐1 factor) was associated with a slower rate of cognitive decline in both carriers (beta=0.029; p<0.001) and non‐carriers (beta=0.011; p=0.013). However, when we created a propensity score‐matching sample where groups with and without APOE4 were not different concerning age, gender, race, education, baseline global cognitive score, and sample size, these associations differed by APOE4 status. In the matched sample, adherence to a healthy lifestyle was not associated with a cognitive decline in non‐APOE4 carriers (beta=0.002; p=0.763) but remained significant in APOE4 carriers (beta=0.046; p<0.001).Conclusion: A healthy lifestyle should be promoted to everyone, especially to individuals with a genetic predisposition for Alzheimer’s dementia.

Background: Strawberries have been identified to have antioxidant and anti-inflammatory properties that improve neuronal function and cognition, mostly in animal studies. It is unknown if the consumption of strawberries or related bioactives may reduce the risk of Alzheimer’s dementia risk. Material and Methods: The study was conducted in 925 participants, aged 58–98 years of the Rush Memory and Aging Project. Participants were dementia-free at baseline, completed a food frequency questionnaire, and had at least two annual neurological evaluations. The diagnosis of Alzheimer’s dementia was based on structured clinical neurological examination and standardized diagnostic criteria. The association of strawberry intake and incident Alzheimer’s dementia was analyzed using proportional hazard models adjusted for age, sex, education, physical activity, participation in cognitive activities, APOE-ɛ4 genotype, dietary intake of other fruits, and total calorie intake. Results: A total of 245 participants developed Alzheimer’s dementia over the mean follow-up of 6.7 (±3.6) years. Higher strawberry intake was associated with reduced risk of Alzheimer’s dementia (HR = 0.76, 95% CI: 0.60–0.96). In separate adjusted models, highest vs. lowest quartile intakes of Vitamin C (HR = 0.64, 95% CI: 0.45, 0.92), Pelargonidin (0.63, 95% CI: 0.43, 0.92), total anthocyanidins (0.69, 95% CI: 0.48, 0.99), and total flavonoids (0.67, 95% CI: 0.46, 0.98) were each associated with lower Alzheimer’s dementia risk. These associations remained after further adjustment for cardiovascular conditions. Conclusion: Consumption of strawberries and foods rich in vitamin C, pelargonidin, anthocyanidins, and total flavonoids may reduce the risk of Alzheimer’s dementia.

Low serum total 25-hydroxyvitamin D₃ [25(OH)D₃] concentrations have been associated with cognitive impairment. However, it is unclear if serum 25(OH)D₃ concentrations are a valid indicator of the concentrations of vitamin D and its metabolites in human brain. The aim of this study was to develop and validate a method to quantify vitamin D₃, 25(OH)D₃, and 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] in human brain. The assay developments were performed using porcine brains. Liquid extraction was used in homogenized samples (∼0.1 g each) prior to analysis by LC-MS/MS with electrospray ionization following derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione. This method was then applied to the determination of vitamin D and its metabolites in a whole human brain obtained from the National Development and Research Institutes. The method showed good linearity of vitamin D₃, 25(OH)D₃, and 1,25(OH)₂D₃ over the physiological range (R² = 0.9995, 0.9968, and 0.9970, respectively). The lowest detection limit for vitamin D₃, 25(OH)D₃, and 1,25(OH)₂D₃ in porcine brain was 25, 50 and 25 pg/g, respectively. The method was successfully applied to the determination of vitamin D₃ and its metabolites in the prefrontal cortex, middle frontal cortex, middle temporal cortex, cerebellum, corpus callosum, medulla, and pons of a human brain. All analyzed human brain regions contained 25(OH)D₃, with corpus callosum containing 334 pg/g compared with 158 pg/g in cerebellum. 1,25(OH)₂D₃ was only detected in prefrontal and middle frontal cortices at a very low level. No vitamin D₃ was detected in any examined areas of this single human brain. To the best of our knowledge, this study is the first report of the measurement of concentrations of vitamin D metabolites in human brain. This validated method can be applied to postmortem studies to obtain accurate information about the presence and role of vitamin D and its metabolites in human brain and neurodegenerative diseases.

Objective To increase understanding of the biological mechanisms underlying the association, we investigated the individual relations to cognitive decline of the primary nutrients and bioactives in green leafy vegetables, including vitamin K (phylloquinone), lutein, β-carotene, nitrate, folate, kaempferol, and α-tocopherol. Methods This was a prospective study of 960 participants of the Memory and Aging Project, ages 58–99 years, who completed a food frequency questionnaire and had ≥2 cognitive assessments over a mean 4.7 years. Results In a linear mixed model adjusted for age, sex, education, participation in cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green leafy vegetables was associated with slower cognitive decline; the decline rate for those in the highest quintile of intake (median 1.3 servings/d) was slower by β = 0.05 standardized units (p = 0.0001) or the equivalent of being 11 years younger in age. Higher intakes of each of the nutrients and bioactives except β-carotene were individually associated with slower cognitive decline. In the adjusted models, the rates for the highest vs the lowest quintiles of intake were β = 0.02, p = 0.002 for phylloquinone; β = 0.04, p = 0.002 for lutein; β = 0.05, p < 0.001 for folate; β = 0.03, p = 0.02 for α-tocopherol; β = 0.04, p = 0.002 for nitrate; β = 0.04, p = 0.003 for kaempferol; and β = 0.02, p = 0.08 for β-carotene. Conclusions Consumption of approximately 1 serving per day of green leafy vegetables and foods rich in phylloquinone, lutein, nitrate, folate, α-tocopherol, and kaempferol may help to slow cognitive decline with aging.

After two decades of research on nutrition and dementia there is strong evidence for preventive effects of vitamin E, B vitamins, and n‐3 fatty acids and deleterious effects of saturated fat on dementia. Among specific foods with evidence of neuroprotection are green leafy vegetables, other vegetables, berries, and seafood. A number of studies have examined dietary patterns, particularly the Mediterranean diet and DASH (Dietary Approaches to Stop Hypertension), neither of which is tailored to the specific foods and nutrients that have been identified as neuroprotective. A new diet called MIND (Mediterranean–DASH Intervention for Neurodegenerative Delay) incorporates many elements of the Mediterranean diet and DASH but with modifications that reflect current evidence for brain neuroprotection. The evidence in support of the relation of various nutrients and the Mediterranean diet to dementia has been inconsistent. The inconsistencies may be explained by inattention to nutrient/food intake levels in the interpretation of study findings and trial design, including a shifting metric among studies for scoring adherence to the Mediterranean diet. Future studies should pay particular attention to levels of intake in the design and analyses of nutritional studies.