X chromosome, sex affect cognition, tau pathology in aging, AD

Increased expression of various X chromosome genes had different impacts on tau burden and cognition in men and women with and without Alzheimer’s disease, according to a study in JAMA Neurology.

“The X chromosome represents 5% of the genome in women and men and is understudied in aging and [AD],” Emily J. Davis, PhD, of University of California’s department of neurology and biomedical sciences graduate program in San Francisco, and colleagues wrote. “In the brain, more genes are expressed from the X chromosome than from any other single autosome; however, analytic challenges posed by X hemizygosity in male individuals, random X inactivation and baseline X escape in female individuals, shared sequences between the X and Y, and limited representation of the X in genome-wide association studies, have largely led to its exclusion in studies.”

Davis and colleagues analyzed data of 508 participants (62% women; 98.2% non-Hispanic white) without dementia who enrolled in joint cohorts between 1994 and 2017 and who had longitudinal follow up data for a mean of 6.3 years. They profiled X chromosomes in the dorsolateral prefrontal cortex of autopsied individuals through RNA sequencing.

At death, 197 participants (38.8%) had clinical AD and 293 (58.2%) had pathological AD. Incidence of no cognitive impairment (32.7%), mild cognitive impairment (24.4%), clinical AD (34.1%), mixed mild cognitive impairment (1.8%), mixed AD (4.7%) and other types of dementia (2.4%) did not differ between sexes.

For women, 29 X chromosome genes were significantly associated with cognitive change, with 19 (65.5%) having a positive beta score correlated with slower cognitive decline. X genes in men were not significantly associated with cognitive change, although they had similar cognitive decline compared with women (beta = 0.18).

Conversely, three X chromosome genes were associated with neurofibrillary tangle (NFT) burden in men but not in women, even though NFT burden was lower in men (beta = 0.06; P = .07).

“Sex-specific findings of X gene expression in aging and AD were observed at the genome-wide level, including statistical correction for all autosomal and X genes detected,” Davis and colleagues wrote. “Thus, our results represent strong biological signals comparable with studies reporting autosomal gene associations. Sex stratification likely increased accuracy and resolution of findings because sex-specific biology governs X expression.”

Despite this strength, researchers noted study limitations included racially homogenous participant sample, focus on dorsolateral prefrontal cortex only and non-specificity of cell types in gene expression.

Moving forward, Davis and colleagues suggested future study of X factors will help further understanding of their impacts on cognition and tau pathology.