Population aging is redefining the clinical reality of Alzheimer's disease and increasing the need for outcome measures that reflect the complexity of older adults. Although recent trials on putative disease-modifying drugs have moved beyond cognition-only endpoints and now include integrated cognitive-functional measures, frailty remains underrepresented in trial design. We discuss the demographic context of aging societies, the relevance of frailty to dementia expression, and the implications of recent amyloid-β-targeting antibody trials, which include substantial numbers of older adults. We propose that frailty can improve external validity, refine biomarker interpretation, and strengthen precision medicine approaches linking biological measures with functional outcomes
United Nations Department of Economic and Social Affairs, Population Division. World Population Prospects 2024: Summary of Results. New York ((UN DESA/POP/2024/TR/NO. 9). New York. Available at: World Population Prospects 2024: Summary of Results (Accessed: 04.23.2026). 2024.
CleggAYoungJIliffeS, et al.Frailty in elderly people. Lancet2013; 381: 752–762.
4.
FriedLPTangenCMWalstonJ, et al.Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci2001; 56: M146–M156.
5.
RockwoodKMitnitskiA. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci2007; 62: 722–727.
6.
RockwoodKSongXMacKnightC, et al.A global clinical measure of fitness and frailty in elderly people. CMAJ2005; 173: 489–495.
7.
WardDDRobinsonMBimmerleE, et al.Frailty and risk of dementia in mild cognitive impairment subtypes. Ann Neurol2021; 89: 1221–1225.
8.
WardDDRansonJMWallaceLMK, et al.Frailty, lifestyle, genetics and dementia risk. J Neurol Neurosurg Psychiatry2022; 93: 343–350.
9.
WallaceLMKTheouOGodinJ, et al.Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer’s disease: a cross-sectional analysis of data from the Rush Memory and Aging Project. Lancet Neurol2019; 18: 177–184.
10.
CanevelliMArisiIBacigalupoI, et al.Biomarkers and phenotypic expression in Alzheimer’s disease: exploring the contribution of frailty in the Alzheimer’s Disease Neuroimaging Initiative. Geroscience2021; 43: 1039–1051.
11.
JackCRJr.BennettDABlennowK, et al.NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement2018; 14: 535–562.
12.
van DyckCHSwansonCJAisenP, et al.Lecanemab in early Alzheimer’s disease. N Engl J Med2023; 388: 9–21.
13.
SimsJRZimmerJAEvansCD, et al.Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA2023; 330: 512–527.
14.
BeardJROfficerAde CarvalhoIA, et al.The World report on ageing and health: a policy framework for healthy ageing. Lancet2016; 387: 2145–2154.
15.
CohenSvan DyckCHGeeM, et al.Lecanemab Clarity AD: quality-of-life results from a randomized, double-blind phase 3 trial in early Alzheimer’s disease. J Prev Alzheimers Dis2023; 10: 771–777.
16.
KleinEGSchroederKWesselsAM, et al.How donanemab data address the coverage with evidence development questions. Alzheimers Dement2024; 20: 3127–3140.
17.
OttavianiSBozzoGDe CesariF, et al.Frailty in early Alzheimer’s disease: complementary clinical value and prognostic significance in biomarker-defined mild cognitive impairment due to Alzheimer’s disease. J Alzheimers Dis2026; 111: 1505–1509.
18.
HampelHO’BryantSEMolinuevoJL, et al.Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol2018; 14: 639–652.
19.
FigueroaJFJoynt MaddoxKEBeaulieuN, et al.Concentration of potentially preventable spending among high-cost Medicare subpopulations: an observational study. Ann Intern Med2017; 167: 706–713.
20.
LivingstonGHuntleyJLiuKY, et al.Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet2024; 404: 572–628.
