Is late-life depression associated with Alzheimer's disease? Evidence from epidemiological, neuropsychological, and neuroimaging perspectives

In 2021, the FDA approved Aducanumab (Aduhelm™), an anti-amyloid antibody intravenous (IV) infusion therapy approved for Alzheimer's disease (AD) that is the first treatment shown to ameliorate neuropathological changes due to AD in the brain. It is well-established that depression increases the risk of future cognitive decline and dementia, but whether depression is specifically associated with AD is unclear, because many of the earlier epidemiological studies employed a relatively short interval (< 5 years) between observation of depression and AD diagnosis. Since neuropathological changes in the brain due to AD may occur years prior to onset of clinical memory symptoms and AD diagnosis, depression that begins late in life may thus represent a non-cognitive prodromal feature of AD. Moreover, the association between depression in older adults and AD biomarkers is also unclear, with some studies suggesting that amyloid-beta, one of the main neuropathological hallmarks of AD, may be reduced in older adults with depression. With the availability of a disease-altering treatment for AD and knowledge that the neuropathological process for AD begins years before onset of clinical memory symptoms, a logical next step in the near future will be to examine whether anti-amyloid therapies can prevent development of AD in high-risk populations. Thus, it is timely to clarify the relationship between depression and dementia. Specifically, is depression an independent risk factor for AD, or is depression associated with dementia more generally? What is the evidence for a distinct form of dementia subtype due to depression? This symposium will address the question of whether major depressive disorder is an independent risk factor for dementia due to AD or other dementia subtypes by presenting evidence from the epidemiological, neuropsychological, and neuroimaging literature. Dr. Linda Mah will begin by presenting an overview of the epidemiological data on the association between depression and AD or dementia subtypes, focusing on differences in the strength of the association as a function of measurement of exposure, follow-up interval, and dementia subtype outcome. Dr. Scott Mackin will present recent work comparing neuropsychological and neuroimaging data including cortico-limbic volume and amyloid-beta burden in older adults with depression versus non-depressed older adults, which provides evidence for late-life depression as having distinct neurodegenerative features independent of AD. Dr. Jennifer Gatchel will present results from a multi-modal neuroimaging study in non-demented older adults with major depressive disorder, which demonstrates a relationship between tau pathology and depression symptoms and decreased interest-motivation-drive, while in contrast, mood symptoms were not associated with either amyloid-beta or medial temporal lobe atrophy. Dr. Benoit Mulsant will serve as discussant for the symposium. Drawing upon the PACt-MD study ("Preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression"), Dr. Mulsant will highlight some of the baseline AD biomarker data in the remitted major depressive disorder + mild cognitive impairment group, which suggest that this phenotype may be associated with a distinct dementia subtype. Implications for the clinical management of late-life depression and future research priorities will be discussed.