Sex-, and neurodegeneration-dependent effect modification in the association between thyroid function and cognitive impairment in non-depressed, non-demented elderly

IntroductionUnderstanding the particularities of thyroid-cognition interactions in the elderly is crucial in assessing the risks and evaluating therapeutic options. MethodsCross-sectional analyses where participants from Alzheimers Disease Neuroimaging Initiative (ADNI) with mild cognitive impairment (MCI) and healthy controls (HC), with complete neurocognitive tests, thyroid stimulating hormone (TSH) <10 {micro}IU/mL, and geriatric depression scale (GDS) <5 were eligible. Linear and logistic regression models, including testing for non-linearity, were performed. Sex and neurodegeneration-related stratifications were explored. ResultsOf the total 1845 participants, with a median age of 73 (IQR: 68, 78); 887 (48%) were females, and 1056 (57%) had MCI. The median TSH level was 1.70 {micro}IU/mL (IQR: 1.15, 2.40). There was a significant association between TSH and cognition only in males (adj. {beta}Males: -0.40; 95% CI: -0.74, -0.07; p-value: 0.019). The odds of being diagnosed with MCI at baseline decreased with higher TSH levels in the total study population (adj. ORTotal: 0.87; 95% CI: 0.79, 0.95; p-value: 0.002), and in males (adj. ORMales: 0.80; 95% CI: 0.70, 0.92; p-value: 0.001). The median TSH value was a significant cutoff in this association. ConclusionsThe association between thyroid function and cognitive decline in the elderly is subject to a sex-driven effect modification and depends on a cutoff value. Plain English summaryThe thyroid-brain association starts at very early stages of the nervous system development and plays a central role in cognition. During the aging process, the thyroid maintains an important role in modulating mental health well-being and associated risks. Older persons are at higher risk of hypothyroidism (lower functioning of thyroid hormone), which is a risk factor for reversible cognitive impairment and dementia. The current study explored the association between thyroid stimulating hormone, a central biomarker of thyroid function, and cognitive function in the elderly. People with dementia, depression, and overt hypothyroidism were excluded to better assess the risks beyond those well-established risk factors. Using different advanced statistical methods, a significant association between thyroid function and cognitive impairment was observed only in males but not females. The association was particularly relevant in older males with lower TSH levels under the median TSH value. Sex-related mechanisms and the reversibility of the association after appropriate intervention are still unclear. It is therefore important to explore thyroid-brain interactions in males and females separately and use methods testing for non-linear associations. The study design based on a cross-sectional analysis of baseline data does not imply causation and randomized longitudinal studies are needed. HighlightsO_LIADAS13 total score was negatively correlated with TSH levels in a statistically significant manner only in males. C_LIO_LIHigher TSH levels predicted significantly lower ADAS13 scores only in males. C_LIO_LILower TSH levels were significantly associated with higher odds of mild cognitive impairment only in males. C_LIO_LIThe median TSH value was a significant cutoff point in the association between thyroid function and mild cognitive impairment. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/24309827v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@10a6486org.highwire.dtl.DTLVardef@14dd678org.highwire.dtl.DTLVardef@13b86e7org.highwire.dtl.DTLVardef@115da96_HPS_FORMAT_FIGEXP M_FIG C_FIG