An underlying issue for GWAS of Alzheimer’s disease is the use of clinical phenotypes, often in the absence of specific biomarkers or neuropathologically defined phenotypes. Although Alzheimer’s disease is mainly characterised by the presence of amyloid plaques and neurofibrillary tangles, concomitant or alternative neuro degenerative pathologies can lead to clinical phenotypes analogous to Alzheimer’s disease.2 For example, in a community–based autopsy cohort, approximately 60% of patients with clinical diagnoses of Alzheimer’s–type disease were in fact affected by a vascular disease pathology, TDP43, or Lewy body pathology rather than plaques and tangles.19 This problem is further exacerbated in the GWAX framework, because parental history of Alzheimer’s disease is often less precise than clinical diagnoses due to a lack of distinction between Alzheimer’s disease and other dementia subtypes. Phenotypic heterogeneity due to misdiagnosis of Alzheimer’s disease results in genetic heterogeneity and reduced statistical power for GWAS discovery.20 Furthermore, Alzheimer’s disease pathology can be found in cognitively normal individuals, who might develop the clinical manifestations of Alzheimer’s disease if they live long enough.2 Inclusion of young–old (60–69 years) or younger participants as controls
