The research, led by Marina M. Watowich and colleagues, took an unusually direct approach to this question. Rather than comparing separate studies conducted in different countries with different methods, the team worked with two Indigenous groups in which individuals of shared ancestry currently span a continuum of lifestyles, from traditional subsistence practices to urban, industrialized living. The first group was the Turkana of Kenya, pastoralists in East Africa whose communities range from mobile livestock-keeping camps to settled towns. The second was the Orang Asli of Peninsular Malaysia, whose populations likewise include people practicing forest-based subsistence and others living in urban environments. Because both genetic background and lifestyle vary within these groups, the researchers could test whether the same gene behaves differently across environments within a single population, a design that minimizes the confounding that plagues cross-population comparisons.

The team focused on three domains of biology in which APOE is known to play a role: cholesterol metabolism, immune function, and reproduction. APOE encodes a protein that shuttles lipids through the bloodstream and is deeply involved in how the body handles cholesterol. It also modulates inflammatory and immune responses, and previous work has hinted that it may influence fertility. Participants were genotyped for the three major APOE isoforms, ε2, ε3, and ε4, and the researchers measured total cholesterol, LDL cholesterol, HDL cholesterol, a panel of innate immune biomarkers, and reproductive traits including reproductive lifespan and the number of children born. Crucially, they then formally tested for genotype-by-environment interactions, asking whether the effect of carrying ε4 depended on the lifestyle a person was living.

The first finding was reassuring in its consistency: the established effects of APOE on lipid biology held across all lifestyles. Having more ε4 alleles was associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol, regardless of whether a person was a mobile Turkana herder, an Orang Asli villager, or an urban resident of either population. This matters because some researchers have proposed that traditional diets and high physical activity might simply erase the lipid effects of ε4. The new data do not support that strong version of the hypothesis. The allele’s influence on cholesterol appears to be a robust, intrinsic feature of its biology, one that persists even when people eat little saturated fat and walk long distances daily.

Where the environment did matter was in the immune system. The researchers found lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli, meaning that the relationship between carrying ε4 and levels of circulating immune markers changed depending on whether individuals lived non-industrial or industrialized lives. Intriguingly, this interaction was not observed in the Turkana, suggesting that even among non-industrial populations, the environmental modulation of APOE’s immune effects is not universal. The authors interpret this as evidence that local ecological conditions, such as pathogen exposure, diet, or other lifestyle factors that differ between the two groups and between subsistence and urban settings, can reshape how the allele expresses itself in immune biology. This kind of genotype-by-environment interaction provides a concrete mechanism by which the costs and benefits of a genetic variant can differ between the settings in which humans evolved and the settings most people inhabit today.

The reproductive findings were more nuanced and, in some ways, more sobering for advocates of the idea that ε4 is straightforwardly beneficial in traditional contexts. Across the combined samples, having more ε4 alleles was correlated with an extended reproductive lifespan, the span of years during which a person reproduces. Such an effect could, in principle, help explain how the allele persisted through natural selection despite its late-life costs: if ε4 carriers can reproduce over a longer window, the allele might pay an evolutionary dividend early enough in life to outweigh its disadvantages in old age. Previous studies in other populations, including forager-horticulturalist groups, have reported positive associations between ε4 and fertility, fueling this evolutionary argument.

However, the new study tempers that narrative considerably. The association between ε4 and extended reproductive lifespan was relatively weak, and it was not consistent across the two populations studied. Moreover, a longer reproductive lifespan did not translate into a measurable increase in reproductive output: ε4 carriers did not have more children. From an evolutionary standpoint, reproductive output is what selection ultimately acts upon, so a weak, population-inconsistent extension of reproductive lifespan that fails to produce more offspring provides only limited support for the idea that fertility benefits maintain ε4 in the human gene pool. The authors are explicit that ε4 is not universally beneficial in non-industrial contexts, a conclusion that pushes back against overly simple stories about the allele being a blessing in the wild and a curse in the city.

What the study does establish is that industrialized environments can modify the biology of APOE ε4. The immune findings in the Orang Asli demonstrate that lifestyle can change what a genotype does to the body, and the consistent lipid effects show that some consequences of the allele are more environmentally buffered than others. This layered picture fits a broader theme in modern human genetics: the effects of many variants are context-dependent, shaped by diet, activity, pathogen exposure, and other exposures that have changed radically since the advent of agriculture, cities, and industrial food systems. For APOE ε4 specifically, the implication is that the allele’s strong association with neurodegenerative and cardiometabolic disease in industrialized nations may be, in part, a mismatch phenomenon, an ancestral variant pushed into an environment that amplifies its harmful effects while stripping away whatever advantages it once offered.

The work also carries practical implications for medicine and public health. APOE genotyping is increasingly discussed as a tool for predicting Alzheimer’s risk and tailoring interventions, but this study is a reminder that risk estimates derived from industrialized cohorts may not transfer cleanly to people living different lifestyles, or to populations with different local ecologies. Understanding precisely which environmental factors modulate ε4’s effects on immunity and lipid biology, whether pathogen burden, physical activity, dietary composition, or something else entirely, could point toward interventions that recreate protective aspects of non-industrial conditions. At the same time, the inconsistency between the Turkana and Orang Asli results cautions against assuming that any single traditional lifestyle confers uniform protection.

Ultimately, the study reframes a familiar genetic villain as something more conditional. APOE ε4 is neither an unambiguous liability nor an ancestral gift; it is a variant whose consequences are negotiated between genome and environment, with cholesterol effects that persist across contexts, immune effects that bend with lifestyle in some populations but not others, and reproductive effects too weak and inconsistent to tell a clean evolutionary story. By working with the Turkana and Orang Asli across their own lifestyle transitions, the researchers have provided some of the most direct evidence yet that the biology of a single gene can diverge between industrialized and non-industrial worlds. As more populations undergo subsistence transitions, studies of this kind will be essential for understanding how the genomic legacies of our evolutionary past interact with the environments of the present, and for predicting who bears the greatest burden from variants like ε4 as the world urbanizes.

Subject of Research: Environment-dependent effects of APOE ε4 on cholesterol, immune, and reproductive traits in Turkana and Orang Asli populations

Article Title: Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments

Article References: Watowich, M. M., Petersen, R. M., Brassington, L., Arner, A. M., Rodenberg, G., Tan Boon Huat, T. B. T. A., Tam, K. L., Schellenberg, E., bin Mohd Sayed, I., John, E., Kahumbu, J. C., Muhoya, B., Gurven, M., Trumble, B. C., Njeru, S. N., Martins, D., Ayroles, J. F., Lim, Y. A. L., Venkataraman, V. V., … Lea, A. J. (2026). Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments. PLOS Genetics, 22(9), e1012285. https://doi.org/10.1371/journal.pgen.1012285

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012285

Keywords: APOE ε4, genotype-by-environment interaction, Turkana, Orang Asli, cholesterol, innate immunity, reproductive lifespan, evolutionary medicine, PLOS Genetics, lifestyle transition, Alzheimer's disease risk, human population genetics

The biological rationale behind the study is grounded in a growing appreciation of the midlife female brain as a uniquely dynamic organ. Neuropathological changes associated with Alzheimer’s disease begin to manifest during midlife, and in females this period coincides with perimenopause and early postmenopause, two reproductive stages characterized by dramatic fluctuations in hormones, cognition, and cerebrovascular function. During perimenopause, estradiol levels swing erratically before declining, follicle-stimulating hormone rises, and many women report subjective changes in memory and attention. Early postmenopause then ushers in a sustained low-estrogen state. Because estrogen receptors are abundant in the hippocampus and prefrontal cortex, and because estrogen influences cerebral blood flow and glucose metabolism, researchers have long suspected that the timing of an intervention relative to these hormonal shifts could matter enormously. Yet no randomized controlled trial had previously examined whether resistance training affects cognition differently across these two reproductive stages, or whether reproductive stage moderates the efficacy of exercise for brain health at all.

The SMART brain trial was designed to fill that gap with rigorous methodology. The parent trial, registered at ClinicalTrials.gov as NCT05961371, enrolled 40 perimenopausal and early postmenopausal females aged 45 to 60 years in an assessor-blinded randomized controlled design. Participants were randomized to either a nine-month, twice-weekly, supervised progressive resistance training program or a wait-list control group, with randomization stratified by menopause hormone therapy use and reproductive stage. Stratification by these variables was essential, since hormone therapy could itself influence cognitive and cerebrovascular outcomes, and reproductive stage was the moderator of primary scientific interest. Thirty-five of the participants volunteered for this pilot sub-study, seventeen in the resistance training arm and eighteen in the control group, providing the dataset for the analyses now reported.

The primary outcome was cognitive function, assessed with a battery of validated neuropsychological instruments. These included the Rey Auditory Verbal Learning Test for episodic memory, the Trail Making Test and a set-shifting task derived from the Dimensional Change Card Sort Test for executive function, the Digit Symbol Substitution Test for processing speed, and the List Sorting Working Memory Test for working memory. The secondary outcome was arguably more novel: task-induced cerebral hemodynamics, measured with functional near-infrared spectroscopy, or fNIRS. This optical neuroimaging technique, provided by the Experimental Imaging Lab at Calgary’s Cumming School of Medicine, uses near-infrared light to track changes in oxygenated hemoglobin, deoxygenated hemoglobin, and total hemoglobin concentration in the cortex while participants perform cognitive tasks. Unlike functional magnetic resonance imaging, fNIRS is quiet, tolerable, and inexpensive, making it well suited to repeated testing in an exercise trial, though it samples only superficial cortical regions such as the dorsolateral prefrontal cortex and premotor cortex.

The statistical approach was deliberately conservative. The researchers used analysis of covariance to test both main effects and interaction effects of experimental group and reproductive stage, adjusting for baseline performance and relevant covariates. Critically, they analyzed the data with both multiple imputation and complete-case approaches, a dual strategy that guards against conclusions being driven by assumptions about missing data. The headline result was a set of significant experimental group-by-reproductive stage interactions for episodic memory and for the executive function task assessing set-shifting, with all interaction p-values below 0.05. In plain terms, the effect of resistance training on cognition was not uniform; it flipped direction of benefit depending on the reproductive stage of the participant.

Planned contrasts unpacked those interactions in a way that the investigators found striking. Resistance training improved episodic memory in perimenopausal women, whereas it improved set-shifting, the executive capacity to flexibly switch between mental rules or tasks, in early postmenopausal women. This dissociation suggests that the cognitive domains most responsive to strength training shift across the menopause transition, perhaps tracking which neural systems are under the greatest hormonal or vascular stress at each stage. Episodic memory, heavily dependent on hippocampal and temporal lobe circuits that are rich in estrogen receptors, may be most malleable during the hormonal turbulence of perimenopause, while set-shifting, which depends heavily on prefrontal networks, may become the dominant beneficiary once the postmenopausal state is established.

The neuroimaging data added a mechanistic layer to this story. A significant group-by-stage interaction was also found for the hemodynamic response function, again with p-values below 0.05. Resistance training increased task-induced total hemoglobin concentration in the left dorsolateral prefrontal cortex, but only in early postmenopausal women; no significant hemodynamic effects were observed in perimenopause. Total hemoglobin concentration is commonly interpreted as a proxy for regional cerebral blood volume and vascular engagement during cognitive effort, so the finding implies that nine months of progressive strength training enhanced the cerebrovascular response of the prefrontal cortex in early postmenopause. This aligns neatly with the behavioral result that set-shifting, a prefrontally mediated function, improved in that same group, and it hints that exercise-induced improvements in neurovascular coupling may be one pathway linking resistance training to cognitive benefit.

The authors are careful to frame these results as preliminary. This was a pilot sub-study, and thirty-five participants is a small sample by the standards of exercise neuroscience, where effect sizes are typically modest and individual variability is high. The wait-list control design, while ethically common, means control participants knew they were waiting for training, and the trial could not blind participants to their assignment, only the assessors. The researchers themselves emphasize that the findings support the need for future studies with larger sample sizes to examine resistance training for protecting brain health in midlife. Still, the consistency of the interaction pattern across behavioral and hemodynamic outcomes, and across both imputation and complete-case analyses, lends credibility to the central claim that reproductive stage moderates exercise responsiveness.

The broader implications reach into two of the most consequential conversations in women’s health and dementia prevention. First, the study suggests that perimenopause and early postmenopause may represent distinct windows of exercise responsiveness for brain health, a concept that echoes the broader timing-of-intervention literature in aging research. If confirmed, this would mean that exercise prescriptions for midlife women could one day be tailored not just to dose and modality but to reproductive stage, with memory-focused benefits expected during perimenopause and executive and cerebrovascular benefits during early postmenopause. Second, the trial highlights the importance of considering reproductive stage of females in exercise trials generally, since pooling perimenopausal and postmenopausal women into a single midlife category could obscure real, stage-specific effects and even make an effective intervention appear ineffective on average.

For now, the practical message for the millions of women navigating the menopause transition is cautiously encouraging rather than prescriptive. Resistance training, twice weekly for nine months under supervision, was feasible and produced measurable, stage-specific cognitive and cerebral hemodynamic changes in this pilot. Given that Alzheimer’s disease begins its silent pathological course in midlife, and given that women bear roughly two-thirds of the global dementia burden, an accessible, low-cost intervention like progressive strength training is an attractive candidate for brain-health protection. The SMART brain trial does not settle the question, but it opens a genuinely new one: not simply whether exercise protects the female brain, but when, across the arc of the menopause transition, it protects it best. Larger trials will now be needed to determine whether these distinct windows of responsiveness hold up, and whether the prefrontal blood-flow changes seen with fNIRS translate into durable protection against cognitive decline in the decades that follow.

Subject of Research: Effects of resistance training on cognition and cerebral hemodynamics across perimenopause and early postmenopause

Article Title: Study of Menopause and Resistance Training for Brain Health (SMART brain): a randomized controlled trial

Article References: Faridi, W., Burma, S. J., Nel, H. J., Whitman, W. P., Dunn, F. J., Gabel, L., & Barha, K. C. (2026). Study of Menopause and Resistance Training for Brain Health (SMART brain): a randomized controlled trial. BMC Medicine. https://doi.org/10.1186/s12916-026-05258-0

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05258-0

Keywords: resistance training, menopause, perimenopause, early postmenopause, cognition, episodic memory, executive function, fNIRS, cerebral hemodynamics, Alzheimer's disease, brain health, randomized controlled trial