Genetically identical twins show comparable tau PET load and spatial distribution

Abstract

Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer's disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (-0.41 < β < -0.42) and social activity (-0.32 < β < -0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.

Keywords: Alzheimer’s disease; PET; genetics; tau; twins.

Figure 1

Identical twin pair correlations for global and regional ¹⁸F-flortaucipir BP_ND. (A) For each region of interest, we performed age- and sex-adjusted one-way single-measure intra-class correlations across twin pairs (i.e. a correlation between Twin 1 and Twin 2 across the group) to examine within-pair similarities in ¹⁸F-flortaucipir BP_ND (tau load). (B) Scatterplots illustrating twin-pair correlations in ¹⁸F-flortaucipir BP_ND for each region of interest. Each dot represents a twin-pair. The values presented in the plots are the residuals of ¹⁸F-flortaucipir BP_ND in Twin 1 (y-axis) and Twin 2 (x-axis) after regressing out the effects of age and sex. (C) The correlation coefficient observed for twin pairs (see B) is plotted against the distribution of correlation coefficients observed for random pairs. *P < 0.05; **P < 0.01.

Figure 2

Spatial correlations for ¹⁸F-flortaucipir PET between each participant and every other participant. (A) We correlated each participant’s voxel-by-voxel ¹⁸F-flortaucipir spatial distribution to that of every other participant using Spearman correlation models. (B) The distribution of spatial correlations (spearman’s rho coefficient, corrected for age and sex) observed for twin pairs is compared against the distribution of spatial correlations observed for non-twin pairs.

Figure 3

Group average image of ¹⁸F-flortaucipir BP_ND.

Figure 4

Examples of ¹⁸F-flortaucipir PET scans from six genetically identical twin pairs. Shown are the ¹⁸F-flortaucipir PET scans from six genetically identical twin pairs. For illustration purposes, we selected pairs that show within-pair similarities in ¹⁸F-flortaucipir BP_ND and distribution (top and middle row), as well as within-pair dissimilarities (bottom row).

Figure 5

Identical twin pair correlations for hemispheric lateralization in global and regional ¹⁸ F-flortaucipir BP _ND . Shown are the scatterplots illustrating the twin-pair associations in regional laterality quotients for ¹⁸F-flortaucipir BP_ND. Each dot represents a twin-pair. The values presented in the plots are the residuals of the laterality quotient in regional and global ¹⁸F-flortaucipir BP_ND for Twin 1 (y-axis) and Twin 2 (x-axis) after regressing out the effects of age and sex. *P < 0.05; **P < 0.01.

Figure 6

Within twin-pair differences regression models between within-pair differences in ¹⁸F-flortaucipir BP_ND and within-pair differences in Geriatric Depression Scale total score, social activity and Physical Activity Scale for the Elderly total score. Each dot represents a twin-pair. Values presented in the plots represent the raw difference in temporal ¹⁸F-flortaucipir BP_ND between Twin 1 and Twin 2 for each pair (y-axis), and the raw differences in GDS total score, social activity and PASE total score between Twin 1 and Twin 2 for each pair (x-axis). Reported β and P-values are from age and sex-corrected regression models. *P < 0.05.