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Short telomeres might lead to increased risk of Alzheimer's disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer's disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer's disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer's Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer's disease was 1.02 (95% CI 1.00–1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0–1 alleles (p = 5 × 10−105). Genetically, odds ratio for Alzheimer's disease was 1.08 (1.01–1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer's disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer's disease. [ABSTRACT FROM AUTHOR]