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ApoA1 Levels Tied to Risk of Progression to Dementia

January 16, 2017

By Marilynn Larkin

NEW YORK—In individuals with subjective cognitive decline (SCD) and the APOE-e4 genotype, higher ApoA1 levels in cerebrospinal fluid (CSF) and lower levels in plasma are associated with an increased risk of progression to dementia, researchers in the Netherlands say.

"HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-beta aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer's disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD," write Dr. Rosalinde Slot of VU University Medical Center in Amsterdam and colleagues in the Journal of Alzheimer's Disease, online December 30.

To investigate, the team analyzed data from the Amsterdam Dementia Cohort on 206 adults (average age, 61) with SCD and 223 with mild cognitive impairment (MCI; average age, 67).

Patients were considered to have SCD if they presented with memory complaints, but their cognitive functioning was normal and they did not meet the criteria for MCI, dementia, or any other neurological or psychiatric disorder known to cause cognitive decline.

Mini-Mental State Exam (MMSE) scores averaged 28 for those with SCD and 27 for those with MCI. Participants had yearly follow-up visits during which cognitive tests and physical and neurological exams were repeated and diagnoses were re-evaluated.

During a mean 2.5 years followup, 117 patients (27%) progressed clinically. Clinical progression was defined as progression from SCD to MCI or AD, and from MCI to AD.

The researchers adjusted for age, gender, MMSE score and plasma cholesterol levels, and stratified results of their analyses by diagnosis and presence of the APOE e4 allele, an established AD risk factor.

In those who progressed, one standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio, 1.3), and the effect seemed to be attributable to the APOE e4 carriers with SCD (HR 3.3).

Lower plasma ApoA1 levels also were associated with an increased risk of clinical progression in APOE e4 carriers with SCD (HR 5.0).

No significant associations were found between either CSF or plasma ApoA1 and clinical progression alone.

Dr. Slot told Reuters Health by email, "We continue to study the possible influence of apolipoproteins in the pre-dementia stages of AD, as these stages seem to be of great of interest to help understand the disease. Further research is needed to determine the significance of these findings for the risk of developing Alzheimer's disease."

Dr. Slot acknowledged that although the main focus of her work is SCD, "this concept is not entirely accepted, since memory complaints in cognitively healthy individuals can be caused by several other factors, such as stress, mood disorders, anxiety, vitamin B-levels, etc."

"Therefore, much more research is needed in this area to determine when individuals with memory complaints really are more at risk to develop AD," she concluded.

Dr. Demetrius Maraganore, medical director of the NorthShore Neurological Institute and director of the Center for Brain Health at NorthShore University HealthSystem in Chicago, Illinois, commented, "While APOE genotyping to risk stratify the population is potentially very helpful, plasma apolipoprotein A1 testing to early detect Alzheimer's in symptomatic individuals is, in my opinion, dispensable."

"CSF testing is not pragmatic," he told Reuters Health by email. "So: good paper, but I doubt this is going to lead to a shift in clinical practice."

"I would encourage the authors and other investigators in the field to focus on the discovery of plasma biomarkers (ApoA1, others) in an APOE genotype-dependent fashion (i.e., blood sample-based testing), in order to move the field forward clinically," he said.

"The predictive value of the test is APOE genotype-dependent. If APOE genotyping is not affordable and reimbursable and supported by policy-setting agencies such as the American College of Medical Genetics, then ApoA1 plasma testing is a nonstarter," he added.

Dr. Maraganore concluded, "We need to change policy to support APOE genetic testing routinely (and with third-party reimbursement). Assuming APOE genotyping were sanctioned, or otherwise affordable as an out-of-pocket test . . . then I would envision plasma ApoA1 testing as an additional biomarker of Alzheimer's trajectory, but only in a very small segment of the population (APOE e4/e4 genotype and subjectively or objectively mildly symptomatic)."


J Alzheimers Dis 2016.

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