Alzheimer’s disease stands as one of the greatest challenges facing aging societies worldwide. Despite notable progress in biomarkers and disease-modifying therapies, aging itself remains the main risk factor. Promoting healthy longevity represents, therefore, one of the most potentially effective and scalable strategies for preventing the disease.
The biological mechanisms that drive aging and gerontology are redefining Alzheimer’s disease as a largely preventable condition arising from cumulative and modifiable aging processes. Epigenetic alterations, chronic low-grade inflammation, mitochondrial dysfunction, oxidative stress, impairment of autophagy and proteostasis, cellular senescence, and immune dysregulation interact with amyloid-β and tau pathology, contributing to neurodegeneration.
These mechanisms can act synergistically over decades, creating a long preclinical window during which preventive strategies could be particularly effective.
In addition to anti-amyloid agents, therapeutic development increasingly includes compounds that target neuroinflammation, microglial dysfunction, metabolic alterations, mitochondrial damage, and cellular senescence. Combination therapies that address simultaneously Alzheimer’s pathology and aging-related mechanisms represent an area of particular interest, as they reflect the multifactorial nature of disease risk.
Toward a proactive, function-centered model
The concept of intrinsic capacity, defined as the combination of an individual’s physical and mental abilities, provides a clinically actionable framework for promoting healthy aging and sustaining prevention strategies across the lifespan. Declines in intrinsic capacity are strongly linked to frailty, disability, cognitive decline, and an increased burden of biomarkers associated with Alzheimer’s disease. Conversely, individuals who maintain good intrinsic capacity tend to exhibit greater cognitive resilience and signs of healthier brain aging.
The PROactive Solutions for Preserving Resilience (PROSP), developed by the Advanced Research Projects Agency for Health (ARPA-H), aims to tackle the limitations of a health care system largely oriented toward treating established diseases, by placing greater emphasis on preserving resilience and preventing decline.
According to the program in question, functional deterioration (the trajectory of intrinsic capacity) can manifest long before clinical disease becomes evident. The goal is therefore to detect early, subtle changes in physical, cognitive, and physiological domains through continuous monitoring, supported by technology, including wearables and digital biomarkers. This longitudinal approach could enable the early identification of meaningful changes in functional trajectory, creating opportunities for timely interventions aimed at preventing or slowing decline.
By combining early diagnosis with personalized and multidomain interventions (for example, physical activity, nutrition, cognitive engagement, and emerging biological therapies), PROSPR aims not only to delay deterioration but also to preserve and, where possible, restore functional capacity. PROSPR integrates advanced data analytics and artificial intelligence to support scalable population-level implementation. In this way, PROSPR links innovations in aging biology with real-world health systems. PROSPR represents an example of a shift from disease-centric medicine to a proactive, function-centered model with the potential to extend the healthy lifespan and preserve independence on a broad scale.
Healthy longevity and gerontology, then, naturally align with Alzheimer’s prevention. By acting on fundamental aging mechanisms, promoting healthy aging, and developing rational combination therapies, this approach could contribute to delaying the onset of the disease and reducing its incidence and societal impact.
Protective Mutations Associated with the APOE Gene
Over the past thirty years, the apolipoprotein E (APOE) gene has been recognized as one of the key genetic determinants of sporadic Alzheimer’s disease risk. The APOE4 allele is a major genetic risk factor for Alzheimer’s and is known to exacerbate the disease’s pathological processes. The identification of protective variants that can reduce risk or delay onset is of great importance for developing effective treatments.
Current research indicates that certain APOE variants associated with a protective effect may help mitigate the biological consequences of risk-associated genetic variants, offering new insights into mechanisms of neurodegenerative protection.
Cognitive Function and Longevity Go Hand in Hand
In a recent study published in Alzheimer’s & Dementia, researchers used longitudinal data from the National Alzheimer’s Coordinating Center (NACC) to analyze cognitive trajectories prior to death and cognitive resilience in relation to neuropathology among adults with lifespans ranging from 50 years to well over 100 years.
Individuals with longer lifespans, particularly centenarians, demonstrated both higher levels of preserved cognitive function and slower cognitive decline, with shorter periods of cognitive impairment before death, suggesting a compression of cognitive decline in extreme longevity. The relationship between neuropathological burden and dementia risk was attenuated, and cognitive resilience to neuropathology increased substantially with longer life, indicating that cognitive resilience may be more common in those who reach extreme longevity.
It was also observed that the associations between genetic and modifiable factors and cognitive resilience vary with lifespan duration, a condition that could reflect selection among more resilient individuals across the lifespan or a different distribution of risk factors in extreme longevity.
Research findings support the hypothesis of compression of cognitive decline in advanced age and underscore the importance of cognitive resilience for healthy aging. Intervention strategies that enhance cognitive resilience could represent a meaningful research avenue for preserving cognitive function in later years.
Sources
- Bruno Vellas, Healthy longevity, intrinsic capacity, geroscience and Alzheimer’s disease prevention, The Journal of Prevention of Alzheimer’s Disease, Volume 13, Issue 5, 2026, 100570, ISSN 2274-5807, https://doi.org/10.1016/j.tjpad.2026.100570;
- Ma Y., Li Y., Wu G. et al. Protective mutations associated with APOE in Alzheimer’s disease. Mol Psychiatry 31, 3618–3636 (2026). https://doi.org/10.1038/s41380-026-03496-5;
- Zhang W, Cai W, Zhang Y, et al. Compression of cognitive decline and cognitive resilience in extreme longevity. Alzheimer’s Dement. 2025; 21:e70683. https://doi.org/10.1002/alz.70683.
Abbonati a Karla Miller
