Amyloid‐beta (Aβ) load in the post‐mortem brain correlates with APOE genotype and ante‐mortem cognitive performance in centenarians

Background

The prevalence of amyloid‐beta (Aβ) pathology increases at higher ages in non‐demented individuals¹. With anti‐amyloid‐beta therapies on the horizon and the growing number of elderly in our population, a clear perception of the association between accumulated Aβ pathology, APOE genotype and cognitive performance in the oldest‐old is warranted.

Methods

In 93 post‐mortem brains donated by participants of the Dutch 100‐plus Study, who self‐reported to be cognitively healthy at inclusion, we evaluated: 1) the spatiotemporal Aβ spread using Thal phases²; and 2) Aβ load in frontal, parietal, temporal and occipital cortices using a quantitative image analysis method. Spread and load of Aβ pathology were compared between different APOE groups (ɛ2/2 and ɛ2/3 (n = 20); ɛ3/3 (n = 65); ɛ2/4 and ɛ3/4 (n = 8)). Post‐mortem Aβ measurements were correlated to ante‐mortem test scores on a comprehensive neuropsychological test battery³ and a composite z‐score for global cognitive performance. Median age at death was 103.3 (interquartile range (IQR): 102.3‐104.9) and median time between neuropsychological assessment and brain donation amounted 0.61 years (IQR: 0.28‐0.93).

Results

Notably, only 10% of the centenarians had not accumulated Aβ pathology. APOE ɛ2/2 and ɛ2/3 carriers had lower Aβ load (median frontal AB load = 0.30%, IQR: 0.02‐6.15), but not spread, compared to APOE ɛ2/4 and ɛ3/4 carriers (median frontal AB load = 5.08%, IQR: 2.13‐30.71) (p = 0.041), but not compared to ɛ3/3 carriers (median frontal AB load = 2.19%, IQR:0.23‐7.54) (p = 0.245). Higher Aβ load in all four analyzed regions associated with lower performance on the Digit Span Backward test (r_frontal = ‐0.29, r_parietal = ‐0.29, r_temporal = ‐0.28, r_occipital = ‐0.32, FDR corrected p<0.05) and the Clock Drawing test (r_frontal = ‐0.40, r_parietal = ‐0.29, r_temporal = ‐0.29, r_occipital = ‐0.33, FDR corrected p<0.05), which assess executive‐ and visuospatial‐functioning. Moreover, higher Aβ load in the frontal cortex correlated with lower performance on the Mini Mental State Examination (MMSE) (r = ‐0.24, p = 0.049) and a seperate composite score of global cognitive performance (r = ‐0.28, p = 0.019).

Conclusion

Although Aβ pathology seems nearly inevitable at extreme ages, our results suggest that Aβ load, rather than Aβ spread, affects cognitive performance in the oldest‐old

1 https://doi.org/10.1002/alz.12899

2 https://doi.org/10.1212/wnl.58.12.1791

3 https://doi.org/10.1007/s10654-018-0451-3