Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?
Abstract
:1. Introduction
2. Risk Factors: Early-Onset vs. Late-Onset Alzheimer’s Disease
2.1. Genetics Factors
2.2. Non-Genetic Factors
2.3. Other Factors
3. Pathological Mechanisms
3.1. Amyloid Plaques
- Non-amyloidogenic pathway: In this pathway, APP is cleaved by α-secretases, such as ADAM10, resulting in the generation of a soluble fraction of alpha-APP (sAPPα) and a carboxy-terminal fragment (CTF-α). Subsequently, γ-secretase also acts on CTF-α, producing the P3 fragment. Importantly, P3 is a soluble peptide that lacks the propensity to aggregate, unlike Aβ [54].
- Amyloidogenic pathway: APP can also be cleaved at the β-site by a β-secretase (BACE1), resulting in the production of a soluble beta-amyloid precursor protein (sAPPβ) and a carboxy-terminal fragment composed of 99 amino acids (known as CTF-β or C99). Subsequently, γ-secretase acts on CTF-β, releasing the Aβ, which can vary in size (primarily Aβ40, Aβ42, and Aβ43), depending on enzymatic cleavage. The pathway described above leads to the accumulation of Aβ protein and, consequently, the formation of amyloid plaques. Although the 42-amino acid form (Aβ42) is suspected to be a causative agent in AD, the molecular basis of its neurotoxicity remains unknown. However, amyloid plaques can induce synaptic dysfunction and an inflammatory response that ultimately triggers neurodegeneration. In a healthy individual, the non-amyloidogenic pathway predominates, while in a patient with AD, Aβ clearance is lower than its production through the amyloidogenic pathway [55,56].
3.2. Neurofibrillary Tangles
3.3. Differences of Pathological Mechanisms between EOAD and LOAD
4. Diagnosis and Assessment
4.1. Neuroimaging
4.1.1. Positron Emission Tomography (PET)
4.1.2. Magnetic Resonance Imaging (MRI)
4.2. Cognitive Assessment
4.3. Biomarkers
5. Treatments and Therapeutic Approaches
5.1. Conventional Treatments
5.1.1. Cholinesterase Inhibitors
5.1.2. NMDA Receptor Inhibitor
5.2. Emerging Treatments
5.2.1. Monoclonal Antibodies
5.2.2. Hybrid Molecules with Dual Affinity
5.2.3. Gamma-Secretase Modulators
6. The Effect of ApoE
6.1. Effects of ApoE on LOAD
6.1.1. Effect of ApoE on Cognition
6.1.2. Effect of ApoE on Aβ
6.1.3. Effect of ApoE on Neuroinflammation
6.1.4. Effect of APOE on Blood–Brain Barrier
6.1.5. Effect of ApoE on Tau
6.2. Effect of ApoE on EOAD
7. Future Perspectives
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Characteristics | EOAD | LOAD |
---|---|---|
Age at onset | <65 years | ≥65 years |
Sex distribution | Female = male | Female > male |
Atypical signs and symptoms | Higher prevalence of dysexecutive symptoms and atypical presentations | Uncommon |
Episodic memory loss | Early (late in atypical cases) | Early |
Genetic contributions | Probably polygenic and autosomal dominant in some cases | Probably polygenic |
Heritability | 92–100% | 60–80% |
Neuropathological hallmarks | Plaques and tangles | Plaques and tangles |
Initial PET signal evidence | Precuneus and mesial temporal region | Mesial temporal region |
Initial Aβ accumulation | Neocortex (striatal in some autosomal dominant cases) | Neocortex |
Rate of brain atrophy | Fast | Low |
Tau burden | Higher in cortical and stratum areas | Higher in limbic areas |
Effect of APOE genotype | APOEε4: Accelerates/diminishes cognitive decline depending on other factors [140,167,168,169,175,176,177]. APOEε2: Significantly delays the age of onset [178]. APOEε3: Further research is needed, although a rare variant has been described to exert a protective effect [133]. | APOEε4: Accelerates cognitive decline and especially promotes the appearance of amnesic phenotypes [129,130,131,132,134,135,136,137]. APOEε2: Slows general cognitive rate decline [132,142]. APOEε3: Is considered a neutral risk factor for AD development. |
Pharmacological therapy | Therapies focus on the underlying pathological mechanisms of the disease. Patients may benefit from gene-based therapies aimed at reducing the production or aggregation of Aβ [179] | Therapies primarily focus on managing symptoms and improving cognitive function rather than targeting the underlying disease process as well as Gamma-Secretase modulators. In these patients, a gene-based therapy may not be very useful [100,102,103,104,105,106,107,108,109,110] |
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Valdez-Gaxiola, C.A.; Rosales-Leycegui, F.; Gaxiola-Rubio, A.; Moreno-Ortiz, J.M.; Figuera, L.E. Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin? Diseases 2024, 12, 110. https://doi.org/10.3390/diseases12060110
Valdez-Gaxiola CA, Rosales-Leycegui F, Gaxiola-Rubio A, Moreno-Ortiz JM, Figuera LE. Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin? Diseases. 2024; 12(6):110. https://doi.org/10.3390/diseases12060110
Chicago/Turabian StyleValdez-Gaxiola, César A., Frida Rosales-Leycegui, Abigail Gaxiola-Rubio, José Miguel Moreno-Ortiz, and Luis E. Figuera. 2024. "Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?" Diseases 12, no. 6: 110. https://doi.org/10.3390/diseases12060110
APA StyleValdez-Gaxiola, C. A., Rosales-Leycegui, F., Gaxiola-Rubio, A., Moreno-Ortiz, J. M., & Figuera, L. E. (2024). Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin? Diseases, 12(6), 110. https://doi.org/10.3390/diseases12060110