Understanding Dementia Risk as We Age

As global life expectancy rises, dementia has emerged as a pressing public health challenge, affecting over 50 million people worldwide (World Health Organisation, 2020). Dementia, a syndrome characterised by cognitive decline severe enough to impair daily functioning, is most commonly caused by Alzheimer’s disease (AD), followed by vascular dementia (VaD). Ageing remains the primary risk factor, but recent evidence highlights the interplay of genetic predispositions, such as the apolipoprotein E (APOE) gene, and modifiable metabolic risk factors. At FROM WITHIN, we explore the latest evidence on dementia risk, the role of the APOE gene, metabolic contributors, and evidence-based strategies to mitigate risk.

Dementia and Aging: The Scope of the Problem

Dementia prevalence increases exponentially with age, doubling every five years after age 65 (Livingston et al., 2020). By 2050, the number of people with dementia is projected to reach 152 million, driven by population aging (World Health Organization, 2020). However, age-specific incidence is declining in high-income countries, suggesting that lifestyle and environmental factors play a significant role in modulating risk (Livingston et al., 2020). This decline underscores the potential for prevention, with up to 40% of dementia cases potentially preventable through modifiable risk factors (Livingston et al., 2020).

The Role of the APOE Gene

The APOE gene, with its three variants, ε2, ε3, and ε4, is a critical genetic risk factor for late-onset AD, which accounts for most dementia cases. Approximately 25% of individuals carry one APOE ε4 allele, and 2–3% carry two, conferring a significantly higher risk of AD (Narayan et al., 2021). The ε4 allele is associated with earlier and more abundant amyloid-β plaque formation, a hallmark of AD, and disrupts lipid metabolism in brain cells, impairing neuronal function (Narayan et al., 2021). Conversely, the ε2 allele is protective, while ε3 is neutral (Narayan et al., 2021).

Dr. Peter Attia emphasises that while APOE ε4 increases risk, it is not deterministic (Attia, 2023). He notes that lifestyle interventions can modulate its impact, particularly through managing metabolic health. Similarly, Dr. Matthew Phillips, a metabolic neurologist, highlights the role of metabolic dysfunction in exacerbating genetic predispositions, advocating for interventions such as the ketogenic diet to support brain energy metabolism (Phillips, 2024).

Metabolic Risk Factors and Dementia

Metabolic syndrome (MetS), characterised by obesity, hypertension, hyperglycaemia, dyslipidaemia, and insulin resistance, is strongly linked to dementia risk. A 2024 study in The Lancet found that MetS in late midlife (ages 60–69) increases dementia risk by 21%, with elevated blood pressure and glycated haemoglobin (HbA1c) being key contributors (Qureshi et al., 2024). Attia underscores the link between early-onset type 2 diabetes and a threefold increase in dementia risk, emphasising the role of insulin resistance in brain health (Attia, 2023).

Insulin resistance, a hallmark of MetS, impairs glucose uptake in neurons, leading to energy deficits that exacerbate neurodegeneration (Yue et al., 2025). Phillips argues that AD can be viewed as a “type 3 diabetes” of the brain, where insulin signalling deficits parallel those in peripheral tissues (Phillips, 2024). A 2025 study in Neurology further confirmed that MetS in midlife (ages 40–60) is associated with a 24% higher risk of young-onset dementia, particularly vascular dementia, highlighting the importance of early intervention (Lee et al., 2025).

Other metabolic factors, such as variability in blood pressure, glucose, cholesterol, and body mass index, also increase dementia risk. A 2018 study found that high variability in these parameters over time was associated with a 1.12% higher dementia incidence, independent of mean values (Kim et al., 2018). This suggests that stabilising metabolic parameters is a critical prevention target.

Latest Evidence on Dementia Risk

Recent research has advanced our understanding of dementia risk through large-scale cohort studies and biomarker analyses. A 2024 UK Biobank study involving 274,160 participants identified 249 metabolites associated with dementia risk, developing a metabolic risk score (MetRS) that predicts all-cause dementia, AD, and VaD (Yu et al., 2024). The study found that MetRS, combined with demographic factors and APOE ε4 status, significantly improves risk stratification, emphasising the predictive power of blood-based biomarkers (Yu et al., 2024).

Another 2024 study in Alzheimer’s & Dementia highlighted the role of accelerated biological aging, measured by phenotypic age acceleration (PhenoAgeAccel), in increasing dementia risk. Individuals in the highest PhenoAgeAccel quartile had a 14.5% higher dementia risk, with interactions between biological aging and APOE ε4 amplifying genetic susceptibility (Li et al., 2024). These findings underscore the interplay of genetic and metabolic factors in driving dementia pathology.

Mitigation Strategies

The 2020 Lancet Commission identified 12 modifiable risk factors accounting for 40% of dementia cases: low education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, traumatic brain injury, and air pollution (Livingston et al., 2020). Below, we explore evidence-based strategies to address these and other risk factors.

1. Optimise Metabolic Health

Managing MetS components is critical for dementia prevention. A Mediterranean diet, rich in whole foods, fibre, and healthy fats, improves insulin sensitivity and reduces inflammation (Taub, 2025). Phillips advocates for strict ketogenic diets, which enhance brain ketone metabolism, potentially bypassing glucose deficits in AD (Phillips, 2024). A 2023 pilot study by Phillips found that a 12-week ketogenic diet improved cognitive function in early AD patients, though larger trials are needed (Phillips et al., 2023).

Regular exercise, particularly aerobic and resistance training, reduces MetS components and enhances cognitive reserve. A 2019 meta-analysis showed that physical activity lowers dementia risk by 20%, with benefits independent of APOE status (Hamer & Chida, 2019). Attia recommends at least 150 minutes of moderate aerobic exercise weekly, combined with strength training to improve insulin sensitivity (Attia, 2023).

2. Enhance Cognitive Reserve

Lifelong learning and cognitive engagement build cognitive reserve, buffering against AD pathology. A 2018 study found that intellectual enrichment reduces cognitive decline, particularly in APOE ε4 carriers (Vemuri et al., 2018). Activities such as reading, learning a new language, or playing a musical instrument are protective (Livingston et al., 2020). Attia emphasises the importance of “brain games” and intellectual challenges to maintain synaptic plasticity (Attia, 2023).

3. Address Sleep and Stress

Poor sleep is linked to a 24–37% higher dementia risk, independent of APOE status (Sabia et al., 2021). Attia highlights sleep’s role in clearing amyloid-β from the brain, recommending 7–8 hours nightly (Attia, 2023). Stress management through mindfulness or yoga also reduces inflammation and supports brain health (Basu et al., 2023).

4. Supplements and Emerging Therapies

Choline supplementation may mitigate lipid metabolism deficits in APOE ε4 carriers, with preliminary studies showing reduced lipid accumulation in brain cells (Narayan et al., 2021). Omega-3 supplements (EPA/DHA) may preserve brain structure in APOE ε4 carriers, though evidence is mixed (Cardiotabs, 2025). Phillips is exploring mitochondrial-targeted therapies, including coenzyme Q10, to enhance neuronal energy production, but robust clinical data are currently lacking (Phillips, 2024).

5. Social Engagement and Hearing Health

Social isolation increases dementia risk by 60%, while hearing loss is a major modifiable risk factor (Livingston et al., 2020). Hearing aids reduce cognitive decline in at-risk individuals (Lin et al., 2023). Attia advocates for maintaining strong social networks to enhance emotional and cognitive resilience (Attia, 2023).

Dementia risk is shaped by a complex interplay of aging, genetics, and metabolic factors, with the APOE ε4 allele and MetS playing central roles. While genetic predispositions such as APOE ε4 increase susceptibility, up to 40% of dementia cases are preventable through diet and lifestyle interventions. The latest evidence demonstrates the importance of early intervention, targeting metabolic health, cognitive engagement, sleep, and social connectivity. Taking a personalised approach through diet, exercise, and emerging therapies to optimise brain health, can significantly reduce your dementia risk and enhance cognitive vitality as you age. If you are wanting to preserve your brain health, then book an appointment here today.

References

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Basu, A., Banerjee, P., & Sen, S. (2023). Lifestyle interventions to reduce oxidative stress and inflammation. Journal of Alzheimer’s Disease, 91(2), 567–578.

Cardiotabs. (2025, June 21). Omega-3 supplements and brain structure in APOE ε4 carriers [Post]. X. https://t.co/7CFUEvGVNL

Hamer, M., & Chida, Y. (2019). Physical activity and risk of neurodegenerative disease: A systematic review of prospective evidence. Psychological Medicine, 39(1), 3–11.

Kim, J., Lee, J., & Park, M. (2018). Variability in metabolic parameters and risk of dementia: A nationwide population-based study. Alzheimer’s Research & Therapy, 10(1), 110.

Lee, J., Han, K., Kim, J., Lim, J., Cheon, D., & Lee, M. (2025). Association between metabolic syndrome and young-onset dementia. Neurology, 104(10), e213599.

Li, Y., Tian, Y., & Xu, L. (2024). Associations of combined accelerated biological aging and genetic susceptibility with incident dementia. BMC Medicine, 22(1), 345.

Lin, F. R., Pike, J. R., & Reed, N. S. (2023). Hearing intervention and cognitive decline. The Lancet, 401(10378), 1598–1606.

Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., ... Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413–446.

Narayan, P., Tsai, L., & Lindquist, S. (2021). APOE4 and lipid metabolism in Alzheimer’s disease. Science Translational Medicine, 13(583), eabc9018.

Phillips, M. C. L. (2024). Metabolic strategies for neurodegenerative diseases. Metabolic Neurologist. https://www.metabolicneurologist.com/

Phillips, M. C. L., Deprez, L. M., & Mortimer, G. M. (2023). Ketogenic diet in Alzheimer’s disease: A pilot study. Journal of Alzheimer’s Disease, 92(3), 789–798.

Qureshi, D., Collister, J., Allen, N. E., Kuźma, E., & Littlejohns, T. (2024). Role of age and exposure duration in the association between metabolic syndrome and risk of incident dementia. The Lancet, 404(10458), 1234–1243.

Sabia, S., Fayosse, A., Dumurgier, J., & Singh-Manoux, A. (2021). Association of sleep duration in middle and old age with incidence of dementia. Nature Communications, 12(1), 2289.

Taub, P. (2025). Lifestyle interventions for metabolic syndrome. CNN. https://www.cnn.com/

Vemuri, P., Lesnick, T. G., & Przybelski, S. A. (2018). Association of lifetime intellectual enrichment with cognitive decline in the older population. JAMA Neurology, 71(8), 1017–1024.

World Health Organization. (2020). Dementia fact sheet. https://www.who.int/news-room/fact-sheets/detail/dementia

Yu, J., Wang, J., & Zhang, J. (2024). Plasma metabolic profiles predict future dementia and dementia subtypes: A prospective analysis of 274,160 participants. Alzheimer’s Research & Therapy, 16(1), 22.

Yue, C., Fu, Y., Zhao, Y., Ou, Y., Sun, Y., & Tan, L. (2025). Association between Alzheimer’s disease and metabolic syndrome: Unveiling the role of dyslipidemia mechanisms. Brain Network Disorders, 1(1), 21.