Introduction: The transition from a normal fundus to one with early drusen (≥ 20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥ 63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursors lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. Methods: Single-center, 20-year follow-up of 138 twins, including biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) 1) < 20 small hard drusen, 2) ≥ 20 small hard drusen, 3) drusen ≥ 63 µm, or 4) ≥ 20 small hard drusen combined with drusen ≥ 63 µm. Additive and dominant genetic effects as well as shared and non-shared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. Results: Median participant age was 59 (range 41 - 66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥ 20 small hard drusen, and 18 had drusen ≥ 63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥ 20 small hard drusen (p = 0.04) and incident drusen ≥ 63 µm (p = 0.003). Having ≥ 20 small hard drusen at baseline was associated with incident drusen ≥ 63 µm at follow-up (p = 0.02). Development of drusen ≥ 63 µm was attributable to 49% genetic effects and 51% environmental effects. Conclusion: The risk of progressing from 0-19 small hard macular drusen per eye to having ≥ 20 small hard drusen or drusen ≥ 63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥ 20 small hard drusen in the absence of drusen ≥ 63 µm at baseline was associated with incident drusen ≥ 63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

Purpose To study age‐ and sex‐adjusted heritability of small hard drusen and early age‐related macular degeneration (AMD) in a population‐based twin cohort. Methods This was a single‐centre, cross‐sectional, classical twin study with ophthalmic examination including refraction, biometry, best‐corrected visual acuity assessment, colour and autofluorescence fundus photography, and fundus optical coherence tomography. Grading and categorization of drusen was by diameter and location. Results The study enrolled 176 same‐sex pairs of twins of mean (SD) age 58.6 (9.9) years. The prevalence of the four phenotypes ≥20 small hard macular drusen (largest diameter < 63 μm), ≥20 small hard extramacular drusen, intermediate drusen (63–125 μm) anywhere, and large drusen (>125 μm) anywhere was 12.4%, 36.4%, 5.8%, and 8.4%, respectively, and the respective heritabilities, adjusted for age and sex, were 78.2% [73.5–82.9], 69.1% [62.3–75.9], 30.1% [4.1–56.1], and 65.6% [26.4–100]. Age trajectory analysis supported a gradual transition to larger numbers of small hard drusen with increasing age. The heritability of ≥20 small hard drusen was markedly lower than the 99% found in the 40% overlapping twin cohort that was seen 20 years earlier. Conclusion Numerous (≥20) small hard drusen and larger drusen that fit the definition of dry AMD were highly heritable. Small hard drusen counts increased with age. Decreasing heritability with increasing age suggests that the impact of behavioural and environmental factors on the development of small hard drusen increases with age.

Purpose The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 μm in diameter). Methods This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 μm), intermediate soft drusen (63–125 μm), and large soft drusen (> 125 μm), of which the soft drusen are compatible with a diagnosis of AMD. Results Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen. Conclusions Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.