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. 2021;79(3):1297-1305.
doi: 10.3233/JAD-200944.

Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes

Ira Driscoll  1   2   3 , Yue Ma  2 , Catherine L Gallagher  4   5 , Sterling C Johnson  1   2   4 , Sanjay Asthana  1   2   4 , Bruce P Hermann  1   2   5 , Mark A Sager  1   2 , Kaj Blennow  6   7 , Henrik Zetterberg  6   7   8   9 , Cynthia M Carlsson  1   2   4 , Corinne D Engelman  1   2   10 , Dena B Dubal  11 , Ozioma C Okonkwo  1   2   4
Affiliations

Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes

Ira Driscoll et al. J Alzheimers Dis. 2021.

Erratum in

Abstract

Background: Identification of new genetic variants that modify Alzheimer's disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset.

Objective: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk.

Methods: Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET).

Results: In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14).

Conclusion: Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.

Keywords: Alzheimer’s disease; biomarkers; cerebrospinal fluid; executive function; memory.

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Figures

Figure 1.
Figure 1.. Age differentially associates with CSF tau measures as a function of KL-VS status.
Bar graphs depicting group differences (M(SE)) in tau between Younger (black) and Older (white) individuals. Among KL-VSNC, Older age was associated with worse levels of A) total tau (tTau), B) phosphorylated tau (pTau), and their respective ratios to Aβ42 (C & D). This age-related pattern of associations with CSF tau biomarkers was abated in KL-VSHET. Abbreviations: M=mean; SE=standard error; Aβ42 = β-amyloid42; tTau = total tau; pTau = phosphorylated tau; KL-VSNC = KL-VS non-carriers; KL-VSHET = KL-VS heterozygotes.
Figure 2.
Figure 2.. Age differentially associates with measures of episodic memory and executive function as a function of KL-VS status.
Bar graphs depicting group differences (M(SE)) in cognition between Younger (black) and Older (white) individuals. KL-VSNC exhibited age-related deficits in memory (A & B) and executive function (C & D), which were attenuated in KL-VSHET. Abbreviations: M=mean; SE=standard error; RAVLT = Rey Auditory Verbal Learning Test (total trials); TMT = Trail Making Test (time in seconds); KL-VSNC = KL-VS non-carriers; KL-VSHET = KL-VS heterozygotes.
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