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Rethinking Dementia: Is It Really Inevitable?

  • Feb 22
  • 5 min read

For decades, dementia was framed as the unfortunate but unavoidable consequence of ageing or, for some, genetics. That story is no longer scientifically defensible.

Two of the most credible recent population estimates tell a different story:


“We estimated that the PAF for all 14 risk factors was 45.3%.” [1]

And in England:

“Overall, we estimate that up to 34.5% of dementia cases may be preventable.” [2]

These figures don’t mean any individual can guarantee they won’t develop dementia. They mean that, at a population level, a substantial proportion of dementia burden flows through biological pathways we can influence.


And that changes everything.



What does “45% preventable” actually mean?


The Lancet Commission’s 45.3% figure is a population attributable fraction (PAF): a modeled estimate of how much dementia could be prevented or delayed if exposure to 14 modifiable risk factors were substantially reduced, assuming those relationships are causal [1].

The 14 factors now include:


  1. 🎓 Limited education

  2. 👂 Hearing loss

  3. 🩺 Hypertension

  4. 🚬 Smoking

  5. ⚖️ Obesity

  6. 😔 Depression

  7. 🏃‍♂️ Physical inactivity

  8. 🩸 Diabetes

  9. 🍺 Excess alcohol

  10. 🧠💥 Traumatic brain injury

  11. 🌫️ Air pollution

  12. 🧍‍♂️🧍‍♀️ Social isolation

  13. 👁️ Untreated vision loss

  14. 🧬🩸 High LDL cholesterol


Notably, vision loss and LDL cholesterol were newly added in 2024, reflecting strengthening vascular and sensory evidence [1]. England-specific modeling produces a lower estimate: 34.5% [2].


In Latin America and China, modeled estimates exceed 50%, largely because risk factor prevalence is higher [3,4].


Estimate preventable

Population

Risk-factor set

Source

45·3%

Global

14

Lancet Commission 2024 [1]

34.5%

England

England model

DeNPRU-QM 2025 [2]

54·0%

Latin America

12

Paradela et al. Lancet Glob Health 2024 [3]

60.3%

China

12

Zhou et al. 2025 [4]


The framing is this: In high-income countries, roughly one-third to nearly one-half of dementia may be preventable or delayable at the population level [1–4].


That is not trivial. That is transformative.



Why the amyloid story is changing


For 30 years, Alzheimer’s research focused heavily on amyloid, the protein that accumulates in plaques. The hypothesis was simple: amyloid accumulation > neuron death > dementia.


That model drove enormous therapeutic effort. Recent anti-amyloid trials have shown that clearing plaques is biologically achievable. But the clinical benefit has been only modest.

In CLARITY-AD, lecanemab reduced amyloid burden and slowed decline slightly over 18 months [6]. In TRAILBLAZER-ALZ 2, donanemab similarly showed modest slowing with substantial amyloid clearance [7].


What has changed is not that amyloid is irrelevant. It’s that Alzheimer’s disease is now understood as multi-mechanistic disorder.


Mixed pathologies are common in older adults: Alzheimer pathology plus vascular injury, Lewy bodies, and inflammatory processes [1,9]. Tau burden, cerebrovascular disease, and neuroinflammation significantly influence symptom progression [10,11].


In this updated model, lifestyle and vascular health are not peripheral, they are central.



Genetics ≠ Destiny


APOE ε4 is the strongest common genetic risk factor for Alzheimer’s disease. Homozygotes carry substantially elevated lifetime risk.


But elevated risk is not inevitability.


In UK Biobank data, individuals at high genetic risk who followed a favorable lifestyle pattern had significantly lower dementia incidence (HR 0.68 comparing favorable vs unfavorable lifestyle within the high-risk group) [10].



Risk of incident dementia according to combined genetic and lifestyle risk. The figure (taken from Lourida et al. - 10) shows that dementia risk rises with increasing genetic risk, but that lifestyle still meaningfully modifies outcomes: individuals with high genetic risk and an unfavourable lifestyle have the highest risk, while a favourable lifestyle is associated with lower risk across all genetic groups. This supports the idea that genetics influences baseline risk, but lifestyle factors can partially offset it."A favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk." [10]


The FINGER randomized trial demonstrated that a multidomain intervention (diet, exercise, cognitive training, vascular risk control) improved cognitive trajectories over two years [11]. Subgroup analyses showed benefit in APOE ε4 carriers, with no evidence that genetic risk eliminated responsiveness [12].


A 2024 Nature Medicine study suggests APOE ε4 homozygotes represent a biologically distinct high-risk subtype with earlier biomarker changes, implying prevention should begin earlier and more consistently in this group [13].


High genetic risk clarifies urgency.


It does not remove agency.



Predicting Alzheimer’s Before Symptoms Start


A 2026 Nature Medicine study showed that a single blood biomarker: plasma %p-tau217 (the ratio of phosphorylated to non-phosphorylated tau at position 217) can be used to estimate when Alzheimer’s symptoms are likely to begin. In two longitudinal cohorts, the estimated age at %p-tau217 positivity predicted age at symptom onset with a median absolute error of about 3–4 years [14].



Probability of remaining cognitively unimpaired according to age at plasma %p-tau217 positivity (TIRA model). Individuals who become biomarker-positive at older ages progress to symptomatic Alzheimer’s disease more quickly [16].


Notably, people who became biomarker-positive at older ages progressed to symptoms more quickly. While not yet precise enough for individual forecasting, this approach highlights a measurable preclinical window where earlier and more aggressive vascular and metabolic risk management could meaningfully shift outcomes [14].




A new biological narrative


Modern dementia biology integrates:


  • Amyloid accumulation

  • Tau propagation

  • Vascular injury

  • Neuroinflammation

  • Metabolic dysfunction

  • Mixed pathology


This multi-pathway framework aligns with the Lancet’s prevention model [1].


When you control blood pressure, reduce LDL, treat hearing loss, prevent diabetes, or reduce inflammation, you are influencing the same biological systems that shape dementia risk.



The Big Picture


If roughly up to a half of dementia is preventable or delayable in high-income settings and possibly more in some regions, then dementia is not simply an inevitable feature of ageing.


The next question is obvious. What should we actually do? That’s where Part 2 begins.



References


  1. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet Standing Commission. The Lancet. 2024;404:572–628. https://doi.org/10.1016/S0140-6736(24)01296-0

  2. Mukadam N, et al. Dementia Population Attributable Fractions for England. NIHR DeNPRU-QM; 2025.(Policy report – institutional publication) https://qmro.qmul.ac.uk/xmlui/handle/123456789/107134

  3. Paradela RS, et al. Population attributable fractions of modifiable dementia risk factors in Latin America. Lancet Global Health. 2024. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(24)00275-4/fulltext

  4. Chen X, et al. Population attributable fractions of modifiable risk factors for dementia in China: a national modelling study using CHARLS 2018. Journal of Prevention of Alzheimer’s Disease. 2025;12. https://pmc.ncbi.nlm.nih.gov/articles/PMC12329568/

  5. Giannoni-Luza S, Urso D, Logroscino G. Global, regional and national population attributable fraction of potentially modifiable risk factors for dementia in the adult population: an analysis using global health databases. BMJ Public Health. 2025;3(2):e003409. https://bmjpublichealth.bmj.com/content/3/2/e003409

  6. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. New England Journal of Medicine. 2023;388:9–21. https://doi.org/10.1056/NEJMoa2212948

  7. Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio PA, Sparks J, et al. Donanemab in Early Symptomatic Alzheimer Diseas: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512–527. https://pubmed.ncbi.nlm.nih.gov/37459141/

  8. Aljuhani M, et al. Clinical meaningfulness and safety considerations of anti-amyloid therapies in Alzheimer’s disease. 2024 https://academic.oup.com/braincomms/article/6/6/fcae435/7915707

  9. Alzheimer’s Association. 2023 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia. 2023;19(4):1598–1695.https://doi.org/10.1002/alz.13016

  10. Lourida I, Hannon E, Littlejohns TJ, et al. Association of lifestyle and genetic risk with incidence of dementia. JAMA. 2019;322(5):430–437. https://doi.org/10.1001/jama.2019.9879

  11. Ngandu T, Lehtisalo J, Solomon A, et al. A 2-year multidomain intervention (FINGER trial). The Lancet. 2015;385:2255–2263. https://doi.org/10.1016/S0140-6736(15)60461-5

  12. Solomon A, et al. Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle Intervention. JAMA. 2018;75(4):462–469. https://doi.org/10.1016/j.jalz.2017.09.003

  13. Fortea J, et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease. Nature Medicine. 2024; 30:1284-1291 https://www.nature.com/articles/s41591-024-02931-w

  14. Petersen, K.K., Milà-Alomà, M., Li, Y. et al. Predicting onset of symptomatic Alzheimerʼs disease with plasma p-tau217 clocks. Nature Medicine (2026). https://doi.org/10.1038/s41591-026-04206-y

 
 
 

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