Summary: Middle-aged adults who carry the APOE ε4 genetic variant and report depressive symptoms may be at increased risk for developing tau protein deposits in brain regions involved in emotion and memory.
Source: UT Austin
Researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and collaborating institutions report that middle-aged individuals with depressive symptoms who also carry the apolipoprotein E (APOE) ε4 allele show an association with elevated tau protein accumulation in brain regions governing emotional processing and memory. The findings highlight a potential midlife biomarker pattern that could inform future studies of risk and prevention for Alzheimer’s disease.
The study, published in the June 2021 print issue of The Journal of Alzheimer’s Disease, analyzed depression assessments together with positron emission tomography (PET) imaging results from 201 participants in the multigenerational Framingham Heart Study. The average age of participants was 53 years, making this one of the imaging studies focused on a younger cohort than is typical in neurodegeneration research.
PET imaging decades before clinical diagnosis
PET scans are commonly performed in older adults or in individuals already showing cognitive decline; in contrast, this study uses PET imaging in midlife people who were cognitively normal at the time of scanning. According to Mitzi M. Gonzales, PhD, the study’s lead author and a neuropsychologist at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio, the midlife focus provides an opportunity to identify early patterns of protein accumulation and behavioral symptoms long before any clinical dementia diagnosis might occur.
“Studying participants at midlife gives us a clearer window into potential early processes associated with later neurodegeneration,” Dr. Gonzales said. “Because these participants were mostly decades away from any likely dementia diagnosis, the results may help identify early biological correlates of mood symptoms that relate to Alzheimer’s pathology.”
No link found between depression and amyloid beta
The study examined two hallmark proteins of Alzheimer’s disease: amyloid beta (amyloid-β) and tau. Researchers found no statistically significant associations between depressive symptoms and amyloid-β deposition in this midlife cohort. The only observed relationship was between depressive symptoms and increased tau accumulation, and that association was limited to participants who carried at least one copy of the APOE ε4 allele. Approximately one-quarter of the sample (47 of 201 participants) were APOE ε4 carriers.
It is well established that carrying a single copy of APOE ε4 increases an individual’s risk of developing Alzheimer’s disease by roughly two- to threefold compared with non-carriers, although the presence of the allele does not guarantee that dementia will occur. “APOE ε4 increases risk, but many carriers remain cognitively healthy into advanced age,” Dr. Gonzales emphasized. “An APOE ε4 result should be interpreted as a risk marker rather than a deterministic diagnosis.”
Depressive symptoms and clinical depression were assessed using the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging and again using data from assessments conducted eight years earlier. The research team evaluated the relationship between depressive measures and PET imaging outcomes at both time points while adjusting analyses for age and sex.
Associations localized to emotion and memory centers
Analyses revealed that depressive symptoms among APOE ε4 carriers were associated with greater tau deposition in two brain regions in particular: the entorhinal cortex and the amygdala. The entorhinal cortex is a critical hub for memory consolidation and is often one of the earliest sites for Alzheimer’s-related protein deposition. The amygdala plays a central role in emotional processing and regulation. The researchers stressed that these associations are correlational: the data do not show that tau accumulation causes depressive symptoms, nor that depression causes tau buildup. Rather, both features were observed concurrently among ε4 carriers in this cohort.
“We cannot infer causality from these cross-sectional findings,” Dr. Gonzales said. “However, the localized association of tau with mood symptoms in entorhinal and amygdala regions raises important questions about how emotional regulation and subtle memory changes might relate to early pathological processes in at-risk individuals.”
The investigators call for longitudinal follow-up studies to track how depressive symptoms, APOE genotype, and regional protein accumulation evolve over time and whether these midlife patterns predict later cognitive decline. Such prospective studies could help clarify timing and directionality, and potentially guide early interventions targeting mood, lifestyle, or other modifiable risk factors.
About this neuroscience research news
Source: UT Austin
Contact: Will Sansom – UT Austin
Image: The image is in the public domain
Original Research: The study will appear in Journal of Alzheimer’s Disease