TY  - JOUR
Y1  - 2021/02/02/
KW  - Alzheimer?s disease
KW  -  biomarkers
KW  -  cerebrospinal fluid
KW  -  executive function
KW  -  memory
IS  - 3
ID  - discovery10120636
SP  - 1297
A1  - Driscoll, I
A1  - Ma, Y
A1  - Gallagher, CL
A1  - Johnson, SC
A1  - Asthana, S
A1  - Hermann, BP
A1  - Sager, MA
A1  - Blennow, K
A1  - Zetterberg, H
A1  - Carlsson, CM
A1  - Engelman, CD
A1  - Dubal, DB
A1  - Okonkwo, OC
TI  - Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
UR  - https://doi.org/10.3233/JAD-200944
N2  - 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?=?63ą8, 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-? (A?)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.
VL  - 79
EP  - 1305
JF  - Journal of Alzheimer's Disease
AV  - public
ER  -