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

Area of Science:

• Genetics
• Neuroscience
• Aging Research

Background:

• Dementia is not an inevitable consequence of aging.
• Investigating factors that confer resilience is crucial.
• The KLOTHO gene is a putative aging suppressor with a functionally advantageous KL-VS variant.

Purpose of the Study:

• To examine if the KL-VS variant of the KLOTHO gene attenuates age-related cognitive decline.
• To investigate if the KL-VS variant reduces deleterious biomolecular changes associated with aging and Alzheimer's disease (AD).

Main Methods:

• Compared cognitive function trajectories (memory, executive function) in middle-aged and older adults.
• Analyzed cerebrospinal fluid (CSF) Alzheimer's disease biomarkers (amyloid beta 42, total tau, phosphorylated tau).
• Compared KL-VS non-carriers and heterozygotes from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center studies.

Main Results:

• Memory and executive function declined with age (p < 0.001).
• CSF levels of total tau, phosphorylated tau, and their ratios with amyloid beta 42 increased with age (p < 0.004).
• KL-VS heterozygotes exhibited an attenuated rate of phosphorylated tau accumulation (p = 0.03).

Conclusions:

• KL-VS heterozygosity may confer resilience to age-related cognitive decline.
• KL-VS heterozygosity may protect against Alzheimer's disease-associated biomolecular changes.