Apolipoprotein-4 (APOE-4): bad for the brain and bad for the heart

At some point while I was a medical student in the 1970s, I had my cholesterol checked. I think it was part of a pedagogical exercise, and as I recall, only the total cholesterol was measured. Surprisingly, the cholesterol level was near the upper limit of normal.  Too many burgers and fries said my wife, Lois.  I laughed it off.  There wasn’t much heart disease in the family.  One of my grandfathers died of a heart attack, but he was in his mid 70s. I was in my 20s and invincible. As I grew older, my cholesterol levels, especially the LDL cholesterol, crept higher, and the upper limits of normal were revised down so that by the time I was in my 40s, my cholesterol was unambiguously elevated.  By the time I was in my 50s, I was taking medications to keep my cholesterol levels and blood pressure under control. As the years went by the doses of these medications continued to climb.  My hyperlipidemia and hypertension have always been a bit of a puzzle to me, but they have both been managed well with medications and diet.

As I previously mentioned in A Tattoo on my Brain, I inadvertently learned that I have two copies of the APOE-4 allele in 2012 while pursuing DNA testing for genealogical purposes. Apolipoprotein E is an important carrier protein for cholesterol in the blood. The gene coding for apolipoprotein comes in three isoforms, APOE-2, APOE-3 and APOE-4. (By convention, the gene is written in italics, and the protein produced by translation of that gene is written in normal script.) Having one copy of the APOE-4 allele increases risk of getting Alzheimer’s disease by about 3-fold, and having two copies increases risk by about 12-fold, although one study in which the diagnosis of Alzheimer’s was confirmed at autopsy suggests that the risk of Alzheimer’s due to APOE-4 is actually much higher. APOE-3, the most common allele, confers neutral risk, and APOE-2, a relatively rare allele, confers protection against Alzheimer’s, especially when two copies are present.

But why should a gene coding for a cholesterol-carrying lipoprotein have anything to do with the risk of getting Alzheimer’s?  When Dr. Allen Roses and his team at Duke first reported this connection in the 1990s, his work was initially dismissed. It did not fit the paradigm of the time. He had trouble getting research funding, so he was forced to take out a loan secured by his home to support his research. Eventually he was vindicated, and APOE-4 is now recognized as the most important genetic risk factor for Alzheimer’s disease aside from rare mutations in one of three genes – amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2)  – that cause early-onset, autosomal dominant Alzheimer’s.

It turns out that cholesterol bound to apolipoprotein circulating in the blood cannot get into the brain because it cannot cross the blood brain barrier.  However, cholesterol is synthesized in the brain, primarily in astrocytes, and it is transferred to other cell types including neurons by apolipoprotein in the brain. This brain cholesterol is closely regulated. It is needed for normal brain activity, but too much can interfere with functions of several types of brain cells including microglia, the inflammatory cells of the brain, and oligodendrocytes, cells that make the myeline sheaths around nerve axons.  APOE-4 causes dysregulation of cholesterol metabolism in the brain, and this is thought to be at the core of increased risk of developing Alzheimer’s disease.

Not surprisingly, carrying the APOE-4 allele, especially two copies, increases risk for cardiovascular disease. In a recent meta-analysis of 33 studies looking at the role of the various apolipoprotein isoforms on risk for myocardial infarction, MI is more likely in those with at least one copy of APOE-4 (compared to APOE-3-associated risk) and less likely in those carrying the APOE-2 allele. Research subjects carrying APOE-4 have higher baseline LDL cholesterol and triglycerides, and they have a reduced response to the cholesterol-lowering effects of statins.

Bottom line? The APOE-4 gene is a risk factor for both heart and brain disease. Carrying the APOE-4 gene, especially two copies, increases the risk of Alzheimer’s and cardiovascular disease, but it doesn’t mean that you will get them. It is possible to reduce these risks by adopting heart and brain healthy lifestyle modifications.  Get daily aerobic exercise. Eat a Mediterranean-style diet like the MIND diet. Stop smoking. Get at least seven hour of sleep per night.  Control hypertension, diabetes, sleep apnea, and hyperlipidemia if present. And specifically for Alzheimer’s prevention, stay socially and intellectually engaged.