AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes

Ira Driscoll; Yue Ma; Sarah R Lose; Catherine L Gallagher; Sterling C Johnson; Sanjay Asthana; Bruce P Hermann; Mark A Sager; Kaj Blennow; Henrik Zetterberg; Cynthia M Carlsson; Corinne D Engelman; Dena B Dubal; Ozioma C Okonkwo

doi:10.1002/dad2.12383

AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes

Alzheimers Dement (Amst). 2022 Dec 7;14(1):e12383. doi: 10.1002/dad2.12383. eCollection 2022.

Authors

Ira Driscoll^{1

2

3}, Yue Ma², Sarah R Lose^{1

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 Dubal¹¹, Ozioma C Okonkwo^{1

2

4}

Affiliations

¹ Wisconsin Alzheimer's Disease Research Center University of Wisconsin-Madison Madison Wisconsin USA.
² Wisconsin Alzheimer's Institute Madison Wisconsin USA.
³ Department of Psychology University of Wisconsin-Milwaukee Milwaukee Wisconsin USA.
⁴ Geriatric Research Education and Clinical Center William S. Middleton VA Hospital Madison Wisconsin USA.
⁵ Department of Neurology University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.
⁶ Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Göteborg Sweden.
⁷ Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden.
⁸ Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK.
⁹ UK Dementia Research Institute at UCL London UK.
¹⁰ Departments of Population Health Sciences University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.
¹¹ Department of Neurology and Weill Institute for Neurosciences University of California California San Francisco USA.

Abstract

Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor KLOTHO gene attenuates age-related cognitive decline and deleterious biomolecular changes.

Methods: Trajectories of change in memory and executive function (N = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aβ)42, total tau (t-tau), phosphorylated tau (p-tau) (N = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies.

Results: Memory and executive function declined (p's $\leq$ 0.001) and CSF t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42 levels increased (all p's $\leq$ 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03).

Discussion: KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.

Keywords: Alzheimer's disease; CSF; biomarkers; executive function; memory; tau.

Abstract

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