APOE genotype can significantly affect the rate of clinical progression of Alzheimer's disease

Introduction: APOE genotype can significantly affect the rate of clinical progression of AD.
A milestone in Alzheimer's disease (AD) clinical trials is the addition of PET imaging and CSF biomarkers to exclude AD analogs and even preclinical AD1 subjects Design secondary prevention trials.

However, the success of a trial still depends on the change in the rate of cognitive decline between the test treatment and the placebo, which is hindered by the huge difference in the rate of clinical progress between participants.

Given the adverse effects of APOEε4 and ε2 alleles on AD risk, age at onset of symptoms, and AD neuropathological changes (ADNC), a potential contributor to this heterogeneity is the APOE genotype.

Previous longitudinal clinical studies after the onset of symptoms have reported conflicting results-APOEε4's acceleration, neutralization, and mitigation effects, while APOEε2's mitigation effects may be at least partly due to the suboptimal accuracy of clinical AD diagnosis (suboptimal).
accuracy).

Another driving factor is the coexistence of one or more brain lesions, each of which may independently cause cognitive impairment and is also affected by the APOE genotype.

Therefore, it can be speculated that APOE alleles have different effects on cognition.

In this way, Jing Qian and others of the University of Massachusetts conducted a study on this issue: They: 1) Choose a sample of the National Alzheimer's Coordination Center (NACC), and there are enough ADNCs to prove it.

Currently recruiting for therapeutic clinical trials based on biomarkers.

2) Apply a new anti-time longitudinal model to link the autopsy results with the cognitive change process.

3) Controlling the effects of ADNC on cognitive decline rate and comorbidities.
They analyzed 1,102 autopsy-proven AD subjects from the NACC Neuropathology Database (moderate/frequent nerve plaques and Braak tangles ≥ III) CDR-SOB (Clinical Dementia Rating Scale Sum of Boxes) and MMSE score.

The trajectories of common outcome measures in these two AD clinical trials are similar to those of mild to moderate AD participants in therapeutic clinical trials.

The results showed that the increase rate of CDR-SOB in APOEε4 carriers was ≈1.
5 times that of APOEε3/ε3 carriers, and the increase rate was ≈1.
3 times that of APOEε2 carriers, while the difference between APOEε2 and APOEε3/ε3 was not statistically significant.

APOEε4 carriers’ MMSE declined ≈1.
1 times faster than APOEε3/ε3 subjects, and ≈1.
4 times faster than APOEε2 carriers, while APOEε2 carriers’ decline speed was ≈1.
2 times slower than APOEε3/ε3 subjects.

After controlling the effects of AD neuropathological changes on the rate of cognitive decline and the existence and severity of comorbid lesions, these trends remained basically unchanged.

The important significance of this study is that it is found that compared with the reference genotype of APOEε3/ε3, APOEε2 and ε4 alleles have opposite effects on the rate of cognitive decline (reduction and acceleration, respectively), which are clinically relevant and basically independent The different effects of APOE alleles on AD and combined pathology.

Therefore, APOE genotype affects the heterogeneity of the rate of clinical progression of AD.

Original source: Association of Gyrification Pattern, White Matter Changes, and Phenotypic Profile in Patients With Parkinson DiseaseXie Tang, Yuanchao Zhang, Daihong Liu, Yixin Hu, Lingli Jiang, Jiuquan ZhangNeurology Mar 2021, 10.
1212/WNL.
0000000000011894; DOI: 10.
1212/WNL .
0000000000011894