Depressive Symptoms Not Tied to Amyloid Pathology in Adults with Normal Cognition

Wietse A. Wiels, MD

Credit: Vrije Universiteit Brussel

In a recent study, depressive symptoms were not consistently linked to a greater frequency of amyloid pathology in older individuals with normal cognition.¹ However, participants with mild cognitive impairment were associated with a lower likelihood of amyloid pathology.

“These findings suggest that mechanisms other than amyloid accumulation may underlie the presence of depressive symptomatology in late life,” wrote investigators, led by Wietse A. Wiels, MD, from Vrije Universiteit Brussel in Belgium.

Depressive symptoms are associated with cognitive decline in older adults, but the underlying mechanism of this link remains uncertain, hindering diagnostic and therapeutic efforts. Research has indicated that late-life depression may be primarily mediated by nonamyloid pathologies, with one study showing a lack of associations between late-life depression and amyloid deposition.²

Investigators conducted a large-scale cross-sectional study from December 2022 to February 2024 to assess the association between depressive symptoms and amyloid pathology in older adults without dementia, taking into consideration age, sex, education, and APOE genotype.¹ The team leveraged data from the Amyloid Biomarker Study which pooled 49 research, population-based, and memory clinic studies from 95 centers.

The study included 9746 individuals with normal cognition (mean age, 68.6 years; 58.2% female; 34% APOE carriers) and 3023 participants with mild cognitive impairment (mean age, 70.2 years; 49% female, 44.8% APOE carriers) aged 34 – 100 years. Participants were included if they had data on age, amyloid biomarkers, and the presence of depressive symptoms.

The primary outcomes were the presence or absence of amyloid pathology, determined by amyloid- β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans, and the presence of depressive symptoms. The presence of depressive symptoms was determined based on either validated depression rating scale scores, current clinical diagnosis of depression, or self-reported depressive symptoms.

Among patients with normal cognition, 27.2% had amyloid pathology and 9.6% had depressive symptoms. The presence of depressive symptoms in patients with normal cognition was not linked to amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90 – 1.40; P = .29).

“…the lack of significant associations in individuals with [normal cognition] must be interpreted in the light of a relatively low burden of depressive symptoms (9.6%) in this group,” investigators wrote. “…this finding may suggest that amyloid pathology—that is, preclinical AD—does not play a major role in explaining subsyndromal or mild depressive symptoms in older adults with normal cognitive test scores.”

Conversely, among patients with mild cognitive impairment, 55.8% had amyloid pathology and 27.3% had depressive symptoms. For these patients, the presence of depressive symptoms was linked to a lower likelihood of amyloid pathology (OR, 0.73; 95% CI, 0.61 – 0.89; P = .001). This suggests depressive symptoms are not generally caused by amyloid pathology.

After considering age, sex, education, and APOE genotype, the study found the presence of depressive symptoms in individuals with normal cognition was associated with a greater frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95fi confidence interval [CI], 1.0 – 9.0; P = .02). The same finding was not true for individuals with normal cognition who were APOE ε4 carriers nor those with mild cognitive impairment.

“Overall, depressive symptoms were not consistently related to amyloid pathology in persons with NC in this study, although possible differences by APOE ε4 carriership status, biomarker modality, and depression rating scale and cutoffs used warrant further exploration,” investigators concluded.

References

1. ^{Wiels WA, Oomens JE, Engelborghs S, et al. Depressive Symptoms and Amyloid Pathology. JAMA Psychiatry. Published online January 22, 2025. doi:10.1001/jamapsychiatry.2024.4305}
2. ^{Takamiya A, Vande Casteele T, Koole M, De Winter FL, Bouckaert F, Van den Stock J, Sunaert S, Dupont P, Vandenberghe R, Van Laere K, Vandenbulcke M, Emsell L. Lower regional gray matter volume in the absence of higher cortical amyloid burden in late-life depression. Sci Rep. 2021 Aug 5;11(1):15981. doi: 10.1038/s41598-021-95206-0. PMID: 34354136; PMCID: PMC8342521.}