Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

Abstract

Objective: The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer's disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition.

Design: Clinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium.

Methods: We used multivariable logistic regressions to model outcomes [Aβ plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE ε4 (allelic discrimination assay), older age (≥50 years), Aβ plaques, and their two-way interactions] and comorbid factors.

Results: Isocortical Aβ deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00, 95% CI 1.41-638.63, P = 0.029, n = 15), but not in non-ε4 carriers (n = 57).

Conclusion: The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally, Aβ plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimer's disease brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND patients who could benefit from Aβ-targeted therapies.

Fig. 1. β-Amyloid (Aβ) and phospho-Tau (p-Tau) pathology in the middle frontal cortex of HIV-infected adults

Immunohistochemical staining with anti-Aβ antibody (clone 4G8) shows diffuse plaques of focal (a, arrows) or widespread (b) density in the cortex; scale bars 500 μm. Immunohistochemical staining with anti-p-Tau antibody (clone AT8) shows scattered neurites (c, arrows), an intraneuronal neurofibrillary tangle (d, arrow), and a cluster of dystrophic neurites, consistent with a neuritic plaque, (e, arrow); scale bars 30 μm.

Fig. 2. The apolipoprotein E (APOE)ε4 genotype and older age (≥50 years) independently predicts cerebral β-amyloid (Aβ) plaque deposition in HIV-infected adults

There is no significant interaction effect of the APOE ε4 and older age on the presence of Aβ plaques. The probability of Aβ plaques is increased either with the APOE ε4 (adjusted odds ratio [OR] 10.16 [95% confidence interval (CI) 2.89–35.76], P=0.0003) or older age (adjusted OR 5.77 [95% CI 1.91–17.48], P=0.0019). Shown in parentheses is the number of cases with Aβ plaques out of the total number of cases with and without Aβ plaques in each of the four APOE ε4–age subgroups.

Fig. 3. The interaction effect of apolipoprotein E (APOE)ε4 genotype and cerebral β-amyloid (Aβ) plaque deposition on HIV-associated neurocognitive disorders (HAND)

The probability of HAND is increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted odds ratio [OR] 30.00 [95% confidence interval (CI) 1.41–638.63], P=0.029), but not in non-ε4 carriers (adjusted OR 1.30 [95% CI 0.24–7.09], P=0.76). Shown in parentheses is the number of HAND cases out of the total number of HAND cases and cases with normal cognition in each of the four APOE ε4–Aβ plaque subgroups.