Genetic Associations Identified Between Midlife Depression and Alzheimer Disease

Thomas Wingo, MD

Data from the population-based Health and Retirement Study cohort found that genetic predisposition to Alzheimer disease (AD), demonstrated by higher polygenic risk scores (PRSs), contributed to the likelihood of midlife depression. Whether there is a shared genetic basis between midlife depression and AD merits further study, the investigators concluded.¹

After adjusting for sex, 10 genetic principal components, and genotyping array, those with higher AD PRSs were more likely to experience depression after age 50 years (P = 1.5 x 10^-4; permuted P = .003; GWAS P threshold = .0583501). This association remained significant after adjusting simultaneously for sex, age, education, 10 genetic principal components, and the genotyping array (β = 1627; P = .00086; GWAS P threshold = .0583501).

"These findings suggest that depression manifesting at or after age 50 in cognitively normal persons may represent one of the early signs of prodrome for future cognitive decline and may signify an increased risk for subsequent development of AD," lead investigator Thomas Wingo, MD, assistant professor, Emory University School of Medicine, and colleagues, concluded. "Furthermore, it raises an important question of whether treating depression manifesting after age 50 in cognitively normal persons can alter the risk for subsequent development of AD."

The analysis consisted of 6656 participants with normal cognition at baseline and available genotyping who were followed for a median of 16 years (range, 2-21). Patients had cognitive functioning assessed using a modified Telephone Interview for Cognitive Status (mTICS) and depressive symptoms assessed and validated using the 8-item Center for Epidemiologic Studies of Depression (CES-D) scale, every 2 years.

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Over the course of 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 by the last visit. Consistent with previous natural history data, 9.4% of the participants met the criteria for clinically significant depression throughout the follow-up duration.

To calculate the PRS for AD, investigators used the AD large genome-wide association studies (GWAS) in 21,982 AD cases and 41,944 cognitively normal controls of European ancestry, which had 11,480,633 single-nucleotide polymorphisms (SNPs), as the base data. Because the goal of the study aimed to investigate the association between AD genetic burden and depression manifesting at or after age 50 years among cognitively normal persons, Wingo et al excluded participants with both depression and cognitive impairment from the analysis.

Among cognitively normal participants, those with a higher depression PRS were more likely to experience depression after age 50 years after accounting for the effects of sex and population structure (P = 6.2 x 10^-11; permuted P = 1.0 x 10^-4; GWAS P threshold = .0131001). Furthermore, higher AD PRS were more likely to develop cognitive impairment–either probable mild cognitive impairment or dementia—during the follow-up years, after accounting for the effects of sex, age, education, and population substructure (β = 17.8; P = 7.5 x 10^-10; permuted P = 1.0 x 10^-4).

Presence ofapolipoprotein E (APOE)ε4 allele, the strongest genetic risk factor for AD, was not associated with depression (P = .08) despite being correlated with the AD PRS (correlation ρ = 0.14; P = 1.0 x 10^-30). Notably the AD PRS and depression PRS were modestly correlated (ρ = 0.03; P = .008). The study investigators wrote that “together, these results suggest that the cumulative genetic liability for AD contributes to depression after age 50 in cognitively normal persons independent of their genetic liability for depression."

To determine the specificity of the association between depression and AD PRS, the investigators examined the association between depression and genetic liability for other neurologic and psychiatric traits, including amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), intracranial aneurysm, and neuroticism. There were no association between the ALS PRS and depression (P = .05; permuted P = .41), no association between PD PRS and depression (P = .05; permuted P = .42) and no association between intracranial aneurysm PRS and depression (P = .01; permuted P = .13). Notably, there was a strong association between neuroticism PRS and depression (P = 9.3 x 10^-8; permuted P = 9.9 x 10^-5), which the investigators noted was expected because neuroticism is a personality trait that predisposes to depression.

REFERENCE
1. Wingo TS, Gerasimov ES, Canon SM, Lah JJ, Levey AI, Wingo AP. Alzheimer’s disease genetic burden is associated with mid-life depression among persons with normal cognition. Published online June 21, 2022. doi:10.1002/alz.12716