New insights into Apolipoprotein E and Alzheimer’s Disease

ApoE4 may exert neurodegenerative effect via tau

ApoE4 is a well-known genetic risk factor for developing Alzheimer’s Disease (AD).  Dave M. Holtzman, MD (Washington University, USA) explained that there is evidence that tau may mediate the effects of ApoE4.

A recent study in transgenic mice showed that animals expressing both human tau and ApoE4 develop significant neurodegeneration compared with ApoE knockout mice that showed no damage.¹ The tau/ApoE4 mice also showed considerable neuronal loss and atrophy in the hippocampus. As these animals age, there is a shift in expression from soluble to insoluble forms of tau, and by 9 months these mice show different patterns of phosphorylated tau staining compared with mice expressing ApoE2 or ApoE3, suggesting that ApoE4 may change the form or pattern of distribution of tau.

ApoE4 may change the form or pattern of distribution of tau

ApoE4 also appears to promote a stronger inflammatory response in the presence of tauopathy, with increased activation of inflammatory microglial and astrocyte genes and increased neurodegeneration – an effect which seems to be blocked in the absence of ApoE.¹

ApoE4 is associated with amyloid burden

These findings support ApoE4 reduction as a potential therapeutic target.

Imaging biomarkers reveal insights into the role of ApoE in Alzheimer’s Disease

Beth C Mormino, PhD (Massachusetts General Hospital, USA) explored the associations between ApoE and imaging biomarkers of AD. It has been known for a number of years that ApoE4 is associated with amyloid burden and that this effect is ‘dose-dependent’, with two alleles leading to increased amyloid deposition compared to that of one allele.^{2, 3} In contrast, ApoE2 is protective showing decreased amyloid burden.⁴

In patients with AD, ApoE4 carriers tend to present with a pattern of atrophy in the medial temporal lobe, in contrast to non-carriers who show cortical atrophy.⁵ Consistent with this, ApoE4 carriers have more deficits in memory and non-carriers have deficits in non-memory functions. ApoE4 is also a risk factor for cognitive decline, particularly in the presence of amyloid-beta (Aβ).^{6, 7}

ApoE4 seems to exert some effects independent of the Aβ pathway

Early longitudinal increases in amyloid have been shown in positron emission tomography (PET) imaging of patients with dementia carrying the ApoE4 allele.⁸  However, ApoE4 seems to exert some effects independent of the Aβ pathway.

ApoE4 appears to influence tau burden. ApoE4 is more strongly associated with neurofibrillary tangles in older individuals with Aβ deposition than in those without Aβ.⁹ Interestingly, a recently published study has shown that increased levels of tau phosphorylation in ApoE4-expressing human neurons was independent of Aβ.¹⁰ An exploratory PET study showed that ApoE4 carriers with AD have elevated tau PET compared with non-carriers, irrespective of Aβ status.¹¹ ApoE genotype also appears to influence the distribution of tau PET in the brain.¹²

ApoE4 carriers with AD have elevated tau PET

Other studies have shown Aβ-independent effects of ApoE4. Older ApoE4-positive individuals show disrupted connectivity on functional magnetic resonance imaging in the absence of Aβ.¹³ The reduction in brain glucose metabolism by ApoE4 is also unaffected by Aβ.¹⁴

Better biomarkers will improve our understanding of the interactions between ApoE4, Aβ, and tau.

Apo E influences the differences in risk of Alzheimer’s Disease between men and women

Among individuals with one ApoE4 allele, the risk of AD is approximately 1.5 times greater in women than in men. New data have shown that women have increased levels of tau in their cerebrospinal fluid compared with men and that there is a stronger association between ApoE4 and tau (total and phosphorylated) among women than men.¹⁵

There is a stronger association between ApoE4 and tau (total and phosphorylated) among women than men

Arthur W. Toga, PhD (Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, USA) explained that the Global Alzheimer’s Association Interactive Network (GAAIN; www.gaain.org), a searchable database of research data, was used to further investigate the role of ApoE in the sex differences seen in AD. Although men and women with the ApoE3/E4 genotype have similar odds of developing AD between 55 and 85 years of age, women have a significantly higher risk than men at younger ages (between 65 and 75 years). There is a similar pattern for the risk of developing mild cognitive impairment (MCI), with women at higher risk between 55 and 70 years of age. Women appear to benefit from the protective effect of the ApoE2/E3 genotype on AD risk to a greater degree than men. However, although the ApoE4/E4 genotype confers an increased risk of AD compared with the ApoE3/E4 genotype, this does not differ between men and women.

Maternal AD increases the risk for MCI/AD conversion while paternal AD does not

GAAIN has also been used to investigate the role that the sex of an individual’s parents has in developing MCI. Data from 741 ApoE3/E3 individuals (55-85 years of age) suggest that maternal AD increases the risk for MCI/AD conversion while paternal AD does not.