Data from the population-based Health and Retirement Study cohort revealed that genetic predisposition to Alzheimer’s disease (AD), demonstrated by higher polygenic risk scores (PRS), contributed to the likelihood of midlife depression. Whether there is a shared genetic basis between midlife depression and Alzheimer’s disease deserves further study, the researchers concluded.1
After adjusting for sex, top 10 genetic components, and genotyping matrix, people with higher AD SRPs were more likely to have depression after age 50 (P = 1.5×10-4; swapped P = 0.003; GWAS P threshold = 0.0583501). This association remained significant after simultaneous adjustment for sex, age, education, the 10 main genetic components and the genotyping table (β = 1627; P = 0.00086; GWAS P threshold = 0.0583501).
“These results suggest that depression onset at age 50 or later in cognitively normal people may represent one of the earliest prodrome signs of future cognitive decline and may signify an increased risk of later development of Alzheimer’s disease,” said lead researcher Thomas Wingo, MD, assistant. professor, Emory University School of Medicine, and colleagues, concluded. “Furthermore, it raises an important question whether treating depression onset after age 50 in cognitively normal people can alter the risk of later development of AD.”
The analysis included 6656 participants with normal cognition at baseline and available genotyping who were followed for a median of 16 years (range, 2-21). Patients’ cognitive functioning was assessed using a Modified Telephone Interview for Cognitive Status (mTICS) and depressive symptoms were assessed and validated using the Center for 8-item scale. epidemiological studies on depression (CES-D), every 2 years.
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During the study, 1.3% and 2.0% of participants developed cognitive impairment at the first and second follow-up visit, respectively, and cumulatively, 15.6% developed cognitive impairment during from the last visit. Consistent with previous natural history data, 9.4% of participants met criteria for clinically significant depression throughout the duration of follow-up.
To calculate the PRS for AD, the investigators used the large genome-wide association studies (GWAS) of AD in 21,982 AD cases and 41,944 cognitively normal controls of European ancestry, who had 11,480,633 single nucleotide polymorphisms ( SNP), as basic data. Since the aim of the study was to investigate the association between the genetic burden of Alzheimer’s disease and depression onset at or after age 50 in cognitively normal people, Wingo et al excluded from the analysis participants with both depression and cognitive impairment.
Among cognitively normal participants, those with a higher depression SRP were more likely to experience depression after age 50 after controlling for the effects of gender and population structure (P = 6.2 x 10-11; swapped P = 1.0 × 10-4; GWAS P threshold = 0.0131001). Additionally, higher AD SRPs were more likely to develop cognitive impairment – either probable mild cognitive impairment or dementia – over the years of follow-up, after controlling for the effects of gender, age , education and population substructure (β = 17.8; P = 7.5 x 10-ten; swapped P = 1.0 × 10-4).
Presence of apolipoprotein E (APOE)ε4 allele, the most important genetic risk factor for AD, was not associated with depression (P = 0.08) although it is correlated with AD PRS (correlation ρ = 0.14; P = 1.0 × 10-30). In particular, PRS AD and PRS depression were moderately correlated (ρ = 0.03; P = 0.008). The study investigators wrote that “together, these results suggest that cumulative genetic responsibility for AD contributes to depression after age 50 in cognitively normal people, independent of their genetic responsibility for depression.”
To determine the specificity of the association between depression and AD PRS, the researchers examined the association between depression and genetic responsibility for other neurological and psychiatric traits, including amyotrophic lateral sclerosis (ALS), the disease disease (PD), intracranial aneurysm and neuroticism. There was no association between ALS PRS and depression (P = 0.05; swapped P = 0.41), no association between PD PRS and depression (P = 0.05; swapped P = 0.42) and no association between PRS intracranial aneurysm and depression (P = 0.01; swapped P = .13). Notably, there was a strong association between PRS neuroticism and depression (P = 9.3 x 10-8; swapped P = 9.9 x 10-5), which the investigators said was expected because neuroticism is a personality trait that predisposes to depression.