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Study Provides New Insight Into Relationship Of Beta Amyloid And APOE4 To Cognitive Decline

April 29, 2016

neurology In the continuing search for the underlying causes of Alzheimer’s disease, two biomarkers consistently demonstrate their significance; the levels of beta amyloid (Aβ) in the brain and the presence of the Apolipoprotein E (APOE) ε4 allele genotype.

Previous studies have shown that in cognitively normal older adults, the combination of high levels of Aβ with the APOE ε4 allele will increase the risk of mild cognitive impairment and often lead to Alzheimer’s disease, even though researchers are not sure how these two interact.

In those studies, over 54 months, older adults with high Aβ but not ε4 show no cognitive decline while ε4 carriers suffer from early deficits, especially in episodic memory. In fact, research shows that the absence of ε4 delays the onset of dementia by approximately 8 years.

In a new study published in Neurology, a population of 423 cognitively normal adults participating in the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) underwent Positron Emission Testing (PET) to detect Aβ and APOE genotyping. They also completed comprehensive neuropsychological assessments at baseline, 18, 36, 54, and 72 months.

Researchers confirmed that this group had not had a previous diagnosis of schizophrenia, Parkinson disease, sleep apnea, depression, or cancer in the last 2 years, or symptomatic stroke or uncontrolled diabetes or current alcohol abuse.

Neuropsychological assessments included testing for episodic memory, executive function, language and attention.

From the PET scans and genotyping, the population was divided into four groups; Aβ positive (+) and ε4 carrier (+), Aβ+ and ε4-, Aβ- and ε4+, and Aβ- and ε4-.

It was hypothesized that those adults that were ε4 carriers would show greater cognitive decline and higher rates of progression to mild cognitive impairment (MCI) compared to non-carriers over 72 months, regardless of the presence of Aβ.

Indeed, the results of the neuropsychological tests showed that, compared to the Aβ- ε4- group, the Aβ+ ε4+ group showed the highest rate of decline across all four cognitive domains, with episodic memory exhibiting the most. In fact, the Aβ- ε4- group showed no cognitive decline across the 72 months. And memory decline was greater in Aβ+ ε4+ than in Aβ+ and ε4-.

The presence of beta amyloid alone was still a concern as both of the Aβ+ groups showed an increase in decline over the Aβ- ε4- group. Interestingly, carrying the ε4 allele without a corresponding presence of Aβ did not affect cognitive performance over the six year study period. Despite previous studies showing cognitive decline associated with the ε4 allele, the presence of Aβ was not controlled for in that research, suggesting that it is the combination of the two that creates early cognitive impairment.

“The important aspect of the data from this study is that it shows for the first time the nature and rate of amyloid related decline in cognitively normal older people who do not carry any APOE ε4 allele,” said Paul Maruff PhD, Chief Science Officer at Cogstate and co-author of the study.

“Surprisingly, before this publication, amyloid related cognitive decline in cognitively normal older adults had been observed only in those who also carried at least one APOE ε4 allele.  This finding therefore illustrates the extent to which carriage of APOE ε4 hastens cognitive decline and ultimately clinical disease stage progression.  This information may allow us to plan more accurately the expected rate of cognitive decline in studies, including clinical trials, of preclinical AD.”

Questions or comments?  Please contact Dan Peterson