👤 Maria Eriksdotter

Neurotrophins are a class of proteins that maintain the health and phenotype of neuronal cells under normal physiological conditions. Nerve growth factor was the first neurotrophin to be discovered, supporting the survival and cholinergic phenotype of basal forebrain cholinergic neurons, which are crucial in maintaining cognitive function in healthy individuals. Nerve growth factor metabolism is altered in Alzheimer's disease and, along with the degeneration of basal forebrain cholinergic neurons and loss of cholinergic pathways in the affected brain, contributes to cognitive problems. These findings initiated the application of nerve growth factor supplementation as a regenerative strategy against Alzheimer's disease in the late 20 th century. Later decades witnessed the development of drugs that support cholinergic activity, namely, cholinesterase inhibitors offering small but persisting cognitive benefits in Alzheimer's disease patients. Further developments in the Alzheimer's disease field have witnessed the rise of anti-amyloid immunotherapies that target the amyloid plaques in Alzheimer's disease brains in an attempt to reduce disease pathology. Over the years, several reports have appeared in support of or undermining the therapeutic claims of each strategy, while many other therapeutic approaches are being presently tested. In this narrative review, we present broader perspectives regarding cholinergic therapeutic strategies against Alzheimer's disease, highlighting aspects in the Alzheimer's disease field that need to be addressed, and propose future perspectives. We provide a special focus on neurotrophic molecules, especially on nerve growth factor, due to its close association with cognitive pathways and its relationship with cholinergic pathways, since cholinesterase inhibitors remain a widely used medication for Alzheimer's disease patients even after 30 years of research. Show less

The apolipoprotein E (APOE) ε4 allele increases Alzheimer disease risk. Understanding genotype-specific dietary needs could inform more personalized prevention strategies. To test the hypothesis that higher meat consumption may be associated with cognitive health benefits in individuals with APOE genotypes ε3/ε4 and ε4/ε4 (APOE34/44) and to examine whether this association differs from that in other genotypes. This population-based cohort study used panel data analyses conducted in January 2025 to January 2026 over 15 years of follow-up in the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), using strategies aligned with causal inference principles. Recruitment was done in 2001 to 2004 among adults without dementia aged 60 years or older. The primary exposure was total meat consumption in grams per total kilocalories assessed via validated food frequency questionnaires. The secondary exposure was the ratio of processed to total meat. Global cognitive trajectory, measured as change in z score per 10 years, was analyzed by linear regression. Incident dementia was analyzed using Fine and Gray subdistribution hazard ratios (sHRs), treating nondementia death as a competing risk. Among 2157 older adults without dementia (mean [SD] age 71.2 [9.2] years; 1337 female [62.0%]), 1680 participants had longitudinal cognition data and 569 participants (26.4%) had APOE34/44 genotypes. During follow-up, 296 participants developed dementia and 690 died without dementia. Among participants with APOE34/44 genotypes, higher total meat consumption (top vs bottom quintile) was associated with better cognitive trajectories (β = 0.32; 95% CI, 0.07 to 0.56; P = .01) and reduced dementia risk (sHR, 0.45; 95% CI, 0.21 to 0.95; P = .04). No associations were found in participants with APOE22/23/24/33 genotypes (cognitive trajectory: β = -0.11; 95% CI, -0.27 to 0.06; P = .20; dementia: sHR, 0.95; 95% CI, 0.57 to 1.61; P = .86). P values for APOE interaction were .004 for cognition and .10 for dementia. In the top quintile of meat consumption, dementia risk and cognitive decline were similar between APOE strata. A higher ratio of processed to total meat was unfavorably associated with dementia (sHR, 1.14; 95% CI, 1.01 to 1.29; P = .04), showing no APOE interaction and no substantial difference between unprocessed red meat and poultry. Post hoc analyses suggested concordant APOE interaction for all-cause mortality (unprocessed meat exposure, APOE34/44: HR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04; P for interaction = .03). In this study, higher meat consumption was associated with better cognitive trajectories and lower dementia risk among individuals with APOE34/44 genotypes. The expected cognitive disadvantage among individuals with APOE34/44 genotypes was not observed at high meat consumption, suggesting clinical and public health relevance. Show less