Depression in Alzheimer's disease : biomarkers and treatment

Depression and Alzheimer’s disease (AD) are among the most common clinical diagnosis in older people. The relation between depression and AD is complex: depression has been shown to be a risk factor, prodromal symptom and a consequence of AD. Increased understanding of the underlying mechanisms of depression in AD may lead to early detection and differential diagnosis, and is crucial for development of novel and mechanism-based treatments.

The first two studies of this doctoral thesis are exploring the associations between depressive symptoms and biomarkers of amyloid deposition and neuronal injury in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD. The aims of the third study were to describe the use of antidepressants in patients with dementia and to explore the association between mortality risk and the use of antidepressants 3 years before the dementia diagnosis.

CAIDE Dementia Risk Score is taking into account midlife risk and protective factors; age, educational level, gender, systolic blood pressure, body mass index, cholesterol level and physical activity and APOE genotyping, and can predict dementia over 20 years. The last study was focused on exploring the associations between CAIDE Dementia Risk Score and biomarkers of amyloid deposition, neuronal injury and small vessel pathology in SCI and MCI patients. Additionally we explored the capacity of CAIDE Dementia Risk Score to predict dementia in a memory clinic population.

Data were obtained from Memory Clinic Karolinska University Hospital Huddinge Sweden (Study I, II and IV). In study III, two large national registries were merged: the Swedish Dementia Registry (SveDem) and the Swedish Prescribed Drug Register.

In study I, analysis of the three different cerebrospinal fluid biomarkers; amyloid beta (CSF Aβ), total-tau (CSF t-tau), and phosphorylated-tau did not support the hypothesis that more severe amyloid or tau pathologies are associated with more severe depressive symptoms. In contrast, SCI and AD patients with depressive symptoms tended to have lower CSF p-tau levels and, in particular, lower CSF t-tau levels than those without depression, indicating less severe neuronal injury. In study II, we used two different analysis methods of MRI to measure medial temporal lobe atrophy and hippocampus volume. Using manual tracing of the hippocampi we found smaller left hippocampus volume in SCI patients with depressive symptoms compared to those without depressive symptoms. In contrast, AD patients with depressive symptoms had less medial temporal lobe atrophy compared with those without depressive symptoms.

In study III, 20,050 patients with incident dementia diagnosed in memory clinics and registered in SveDem were included. Information on the total number of medication and all antidepressants dispensed at the time of dementia diagnosis and at the first, the second and the third year prior to dementia diagnosis was obtained from the Swedish Prescribed Drug Register. During a median follow up of 2 years, 5168 (25.8%) dementia patients died. At the time of dementia diagnosis, 5,004 (25.0%) patients were on antidepressant treatment. Use of antidepressant treatment for 3 consecutive years prior to a dementia diagnosis was associated with a lower mortality risk for all dementia disorders in general and particularly in AD.

In study IV, a higher CAIDE Dementia Risk Score was associated with higher CSF t-tau levels, more severe medial temporal lobe atrophy and more severe white matter changes. For the CAIDE score including APOE, a score above 9 points was associated with lower CSF Aβ, more severe medial temporal lobe atrophy and more severe white matter changes. CAIDE Dementia Risk Score (version with APOE) performed better at predicting AD compared with CAIDE Dementia Risk Score without APOE.

Conclusion: We found that depressive symptoms in patients with AD and SCI are not associated with more amyloid deposition nor more neuronal injury compared with AD and SCI patients without depressive symptoms. Thus our results are consistent with the hypothesis that the mechanisms underlying depression differ between older people with and without AD. Our results have shown that use of antidepressants in prodromal AD stages is associated with a lower mortality risk. Further longitudinal studies are needed to better understand the associations between the use of antidepressants and mortality risk in dementia.

List of scientific papers

I. Kramberger MG, Jelic V, Kareholt I, Enache D, Eriksdotter Jönhagen M, Winblad B, Aarsland D. Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease. Dement Geriatr Cogn Dis Extra. 2012, 2:48-56.
https://doi.org/10.1159/000334644

II. Enache D, Cavallin L, Lindberg O, Farahmand B, Kramberger MG, Westman E, Jelic V, Eriksdotter M, Ballard C, Winblad B, Wahlund L-O, Aarsland D. Medial Temporal Lobe Atrophy and Depressive Symptoms in Elderly Patients With and Without Alzheimer Disease. Journal of Geriatric Psychiatry and Neurology 2015, 28:40-8.
https://doi.org/10.1177/0891988714541873

III. Enache D, Fereshtehnejad SM, Cermakova P, Garcia-Ptacek S, Kåreholt I, Johnell K, Religa D, Jelic V, Winblad B, Ballard C, Aarsland D, Fastbom J, Eriksdotter M. Antidepressants and mortality risk in a dementia cohort- data from SveDem, the Swedish Dementia Registry. [Submitted]

IV. Enache D, Solomon A, Cavallin L, Kåreholt I, Kramberger MG, Aarslad D, Kivipelto M, Eriksdotter M, Winblad B, Jelic V. CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic patients without dementia. [Submitted]