KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease

Abstract

Klotho-VS heterozygosity (KL-VS^het) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VS^het is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VS^het and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VS^het showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VS^het on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VS^het was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VS^het carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VS^het against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

Fig. 1. Association between KL-VS heterozygosity, amyloid-, and tau-PET.

Scatterplots display the relationship between global amyloid-PET levels and a, b cross-sectionally assessed tau-PET levels or c, d longitudinally assessed tau-PET annual change rates measured in inferior temporal gyri (left panel) and globally in neocortical areas (right panel) as a function of KL-VS^het variant. Blue and gray colors indicate individuals with heterozygous or non-heterozygous KL-VS alleles. Statistics of the KL-VS^het × amyloid-PET interaction effect on tau-PET uptake were derived from multiple linear regression analyses, controlled for the main effects of KL-VS^het and amyloid-PET levels as well as age, sex, diagnosis, education, and ApoE ε4 carrier status. Linear model fits are indicated together with 95% confidence intervals.

Fig. 2. Spatial patterns of KL-VS^het-related attenuation of tau-PET and Klotho mRNA expression.

a Surface mapping of the interaction effect between KL-VS^het and amyloid-PET levels on tau-PET accumulation within 34 left-hemispheric regions of the Desikan–Killiany atlas. Yellow colors indicate higher t-values reflective of a stronger interaction effect (all t-values inverted for illustration purpose; see Supplementary Table 2 for details statistical results). b Thresholded spatial map color-code only regions with a significant (p < 0.01, unadjusted for multiple comparisons) KL-VS^het × amyloid-PET interaction effect. c Surface mapping of median KL mRNA expression (i.e., log2 derived from the Allen Brain Atlas) within the identical 34 atlas regions. Yellow colors indicate higher KL mRNA expression. d Thresholded spatial maps restricted to regions falling above the 75th percentile of KL mRNA expression. e Scatterplot depicting the association between ROI-based KL mRNA expression and KL-VS^het × amyloid-PET interaction effect on regional tau-PET uptake. Statistical results are derived from the Pearson correlation (two-sided). Linear model fits are indicated together with 95% confidence intervals. Source data are provided as a Source Data file.

Fig. 3. Association between KL-VS heterozygosity and memory in amyloid-positive individuals.

Boxplot shows memory performance as a function of KL-VS^het variant in individuals with a positive amyloid-PET (SUVR_FBP ≥ 1.11 or SUVR_FBB ≥ 1.08). Blue and gray colors indicate individuals with heterozygous (N = 55) or non-heterozygous KL-VS alleles (N = 174). Memory was measured by an established composite score, ADNI-MEM, based on test performance across multiple different memory tests. Statistical result of the main effect of KL-VS^het on memory was derived from multiple linear regression analysis, controlled for age, sex, diagnosis, education, and ApoE ε4 carrier status. Boxplots show the 25th percentile, median, 75th percentile (box), 95% confidence intervals of the median (notch), and 1.5× IQR (whiskers).

Fig. 4. Lower tau-PET levels mediate the beneficial association of KL-VS heterozygosity and memory in individuals with the elevated amyloid-PET burden.

Path diagram of the mediation model (assessed only in amyloid-positive participants, N = 229), showing that the association between KL-VS^het and better memory performance is mediated via lower global tau-PET uptake. Memory is measured by ADNI-MEM, i.e., an established memory composite score. Path-weights are displayed as standardized beta values. All paths are controlled for age, sex, diagnosis, education, ApoE ε4 carrier status, and continuous global amyloid-PET levels. The significance of the indirect effect was determined using bootstrapping with 10,000 iterations as implemented in the mediation package in R.