Depression is recognized as a symptom often associated with Alzheimer's disease (AD), frequently reported by caregivers1. It has been found that around 38% to 40% of individuals with dementia exhibit depressive symptoms2.
Depression is recognized as a symptom often associated with Alzheimer's disease (AD), frequently reported by caregivers1. This link has prompted numerous studies to investigate the relationship further. It has been found that around 38% to 40% of individuals with dementia exhibit depressive symptoms2. Several pieces of research support the notion that depression may precede the onset of AD, a conclusion supported by meta-analysis3.
Specifically, individuals experiencing more than three depressive symptoms faced a 45% higher risk of developing dementia over a 5.5-year follow-up period compared to those with fewer symptoms4.
Specifically, individuals experiencing more than three depressive symptoms faced a 45% higher risk of developing dementia over a 5.5-year follow-up period compared to those with fewer symptoms4. Moreover, preclinical studies have identified shared genetic factors between depression and AD5.
Extensive database searches have revealed five genetic variants common to both depression and AD, including APOE*ε3, APOE*ε4, CLU rs11136000 T allele, MTHFD1L rs11754661 A allele, and GSK3β rs334558 T allele6-11.
Extensive database searches have revealed five genetic variants common to both depression and AD, including APOE*ε3, APOE*ε4, CLU rs11136000 T allele, MTHFD1L rs11754661 A allele, and GSK3β rs334558 T allele6-11. These findings suggest a shared pathophysiology between the two conditions, indicating that they may have common underlying mechanisms. The genetic variants APOE*ε3, APOE*ε4, and CLU genes are implicated in the regulation of neuronal cholesterol, which is essential for the normal function of amyloid-beta (Aβ) and the development of high-density lipoprotein (HDL) (Figure 1)6. The formation of an Aβ-APOE-APOC1 complex has been suggested as a mechanism for Aβ clearance in the central nervous system. CLU, in particular, is critical for the development of HDL in cooperation with apolipoprotein A-I (apoA-I) and APOE, which plays a significant role in cholesterol metabolism and Aβ clearance6.
The MTHFD1L gene is involved in immunity regulation, specifically in neuroinflammation and the regeneration of methionine from homocysteine. Abnormalities in MTHFD1L can lead to hyperhomocysteinemia, which contributes to AD risk through increased oxidative stress (Figure 1). This process underscores the importance of proper methionine-homocysteine metabolism in brain health and its potential impact on Alzheimer's disease progression6.
GSK3β gene is involved inthe production of Aβ through two primarymechanisms: the increased expression of amyloid precursor protein (APP) and the activation of betasecretase 1 (BACE1). Additionally, GSK3β plays a role in the phosphorylation of tau, a protein that, when abnormally modified, forms tangles inside neurons, a hallmark of AD pathology (Figure 1)6. These genetic variants lead to aberrant functions in their respective pathways, contributing to the pathophysiology of AD. The disruption in neuronal cholesterol regulation, increased oxidative stress due to hyperhomocysteinemia, and enhanced Aβ production and tau phosphorylation collectively underline the complex genetic and molecular basis of AD, highlighting the interplay between genetic factors and the disease's development6.
Figure 1. Genetic Overlap Influencing Alzheimer's Disease and Depression. The genes APOE*ε3, APOE*ε4, and CLU play a critical role in managing neuronal cholesterol levels, crucial for Aβ functionality and the synthesis of HDL. This process is vital for maintaining amyloid-beta's normal operations and fostering the development of HDL. The MTHFD1L gene is key in controlling immune responses, particularly focusing on neuroinflammation and the conversion of homocysteine into methionine. Defects in MTHFD1L can lead to elevated homocysteine levels, escalating the risk of Alzheimer's disease by promoting oxidative stress. Furthermore, the GSK3β gene is implicated in Aβ production via two main routes: enhancing APP levels and activating BACE1. GSK3β is 5 © Confidential 2017 also involved in the phosphorylation of tau protein. Abnormal phosphorylation of tau results in the formation of neurofibrillary tangles, a critical feature of Alzheimer's pathology.
