jfa journal

AND option

OR option



T. Daly


Corresponding Author: Timothy Daly, Sorbonne Université, Science Norms Democracy UMR 8011, Paris, France, timothy.daly@sorbonne-universite.fr


Dear Editor,

Canevelli and colleagues’ insightful Editorial highlights the untapped prognostic and therapeutic value of frailty to dementia (1). Their insight into frailty, understood as cumulative health deficits, offers scope for a broad research programme into how events outside the brain shape dementia outcomes via different mechanisms (Table 1). Such a programme offers the field an alternative to the dominant Alzheimer’s Disease neuropathology research programme and invites greater study of, and action against, health disparities and deprivation.
While the prognostic and therapeutic value of targeting AD neuropathology in patients with dementia is indeed still unknown, it remains the dominant therapeutic approach. However, beyond neuropathology, frailty indices offer long lists of potential targets or proxy targets for improving dementia outcomes. We could make use of the wisdom of the expert and informed patient majority to distribute research capital between putative targets in ways respectful of scientific pluralism and plausibility (6).
Yet there is an epistemological issue for such a research framework. The plural nature of cumulative health deficits appears to lend itself to multi-domain interventions. But I would argue that combining treatments before validating them is a mistake, because such an approach makes it impossible to infer active ingredients in a treatment recipe (7). We ought to use simple tests of treatments for frailty before combining them.
For example, Pérez-Zepeda and colleagues recently showed improved frailty outcomes in the intervention group of an RCT with adults over 75 undertaking physical exercise (8), thus contradicting the therapeutically pessimistic notion that only multi-domain interventions can improve elderly health outcomes.
I would argue that establishing whether single-domain frailty interventions can lead to therapeutic improvements in dementia should be a priority for a frailty framework of dementia, given the problems of targeting AD neuropathology on one side and the interpretative issues associated with multi-domain interventions on the other. Müller and colleagues’ finding that in families with rare and deterministic familial AD, long-term physical exercise meant for up to 15 more dementia-free years (9), should make us optimistic about the impact of interventions, even though associations are not interventions.
To conclude, we should be ambitious about the study of frailty for dementia, but also about action against frailty from a public health point of a view, well beyond individualistic late-life interventions. There are very broad determinants of brain and bodily health across the entire lifetime, and an adequate response to them should include action at a society-wide level against deprivation, inequalities, and structural and social determinants of health (10).

Table 1. A frailty framework for dementia based on Canevelli et al.’s Figure 1 (1) and other recent literature


Conflicts of Interest: The author declares no financial declarations and no conflicts of interest.



1. Canevelli M, et al. Could there Be Frailty in the Discrepancy between Lesions and Symptoms of Alzheimer’s Disease?. J Frailty Aging (2022). https://doi.org/10.14283/jfa.2022.43
2. Frisoni GB, et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. 2022 Jan;23(1):53-66. doi: 10.1038/s41583-021-00533-w. Epub 2021 Nov 23. PMID: 34815562; PMCID: PMC8840505.
3. Vidoni ED et al. Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer’s: A 1-year randomized controlled trial. PLoS One. 2021;16(1):e0244893. Published 2021 Jan 14. doi:10.1371/journal.pone.0244893
4. Wallace LMK, et al. 10-year frailty trajectory is associated with Alzheimer’s dementia after considering neuropathological burden. Aging Med (Milton). 2021 Dec 15;4(4):250-256. doi: 10.1002/agm2.12187.
5. Rosenberg A, et al. Multidomain Interventions to Prevent Cognitive Impairment, Alzheimer’s Disease, and Dementia: From FINGER to World-Wide FINGERS. J Prev Alzheimers Dis. 2020;7(1):29-36. doi: 10.14283/jpad.2019.41.
6. Daly T. The informed majority could help make research into Alzheimer’s disease fairer and more efficient. J Am Geriatr Soc. 2022 Jun;70(6):1882-1883. doi: 10.1111/jgs.17756.
7. Daly T, Mastroleo I, Henry V, Bourdenx M. An Argument for Simple Tests of Treatment of Alzheimer’s Disease. J Alzheimers Dis. 2022;86(1):49-52. doi: 10.3233/JAD-215492.
8. Pérez-Zepeda MU, Martínez-Velilla N, Kehler DS, Izquierdo M, Rockwood K, Theou O. The impact of an exercise intervention on frailty levels in hospitalised older adults: secondary analysis of a randomised controlled trial. Age Ageing. 2022 Feb 2;51(2):afac028. doi: 10.1093/ageing/afac028.
9. Müller S, et al. Dominantly Inherited Alzheimer Network (DIAN) (2018). Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer’s disease. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 14(11), 1427–1437. https://doi.org/10.1016/j.jalz.2018.06.3059
10. Daly T. The vital need for action against the social determinants of frailty. Aging Med (Milton). 2022 Feb 1;5(1):73. doi: 10.1002/agm2.12195.