Genetic heart health and the brain: the genes that affect both

APOE: the gene that links cholesterol to Alzheimer's

Apolipoprotein E carries cholesterol and fats in the blood and in the brain. The ε4 form is the strongest common genetic risk factor for Alzheimer's disease and also raises LDL cholesterol and heart-disease risk modestly; ε2 is protective against Alzheimer's but can raise triglycerides. 23andMe reports ε4 only, as explained on the 23andMe page. Carrying two copies of ε4 is now argued to be a distinct genetic form of the disease, with near-universal amyloid pathology by the mid-sixties. For ε4 carriers, every vascular factor on the heart health page still applies, and midlife hypertension raises dementia risk by the same proportion as in non-carriers.

Familial hypercholesterolaemia

Mutations in LDLR, APOB or PCSK9 cause lifelong very high LDL cholesterol and early heart attacks in about 1 person in 250. Diagnosis is clinical and by sequencing; a chip-based consumer test covers only a small fraction of the thousands of known variants, so a "variant not detected" result does not exclude the condition. People with familial hypercholesterolaemia share the vascular dementia risk that goes with decades of high LDL, and early statin treatment is standard. The Family Heart Foundation (see other sites) is the patient organisation.

Lipoprotein(a)

Lp(a) levels are 80 to 90 percent genetically determined, set largely by the number of kringle IV type 2 repeats in the LPA gene, and they barely respond to diet or statins. About one person in five has a level high enough to raise heart-disease risk. As the heart page explains, the largest study to date found no continuous association with dementia, though small isoforms were linked to a 25 percent higher Alzheimer's risk in the Copenhagen cohorts. The LPA repeat count is not readable from a consumer chip; a blood test is the way to know your level.

MTHFR, homocysteine and the vitamin B12 pathway

The MTHFR enzyme converts folate into the form the body uses to recycle homocysteine, with vitamin B12 as a cofactor. The common C677T variant (rs1801133), carried in two copies by roughly 10 percent of people of European ancestry and more in some other groups, reduces enzyme activity by about 70 percent and raises homocysteine modestly, mainly when folate intake is low. High homocysteine is associated with stroke, heart disease, brain atrophy and dementia, and the B-vitamin trial VITACOG showed that B12, folate and B6 slowed brain atrophy in people with mild cognitive impairment who had raised homocysteine.

Consumer tests often report MTHFR status, and a whole industry sells supplements on the strength of it. The evidence supports something simpler: if homocysteine is high, or B12 is low, treat the deficiency. Routine MTHFR testing is not recommended by medical genetics bodies because the variant does not change management on its own. The metabolism page covers B12 in detail.

Polygenic scores for heart and brain

Beyond single genes, thousands of common variants each nudge risk a little. Summed into a polygenic risk score, they predict coronary disease reasonably well and Alzheimer's disease modestly. In the UK Biobank, a coronary polygenic score raised dementia risk by about 10 percent per standard deviation, mostly through vascular dementia, and a healthy lifestyle cut the risk in every genetic tier. Machine-learning versions of Alzheimer's scores reach an AUC of roughly 0.72 to 0.85 only when age and APOE are included, and perform worse outside European ancestry. No polygenic Alzheimer's score is FDA-authorised, and none is offered by 23andMe.

What a consumer genotype can and cannot show

Genetic results can affect life, disability and long-term care insurance, which the US Genetic Information Nondiscrimination Act does not cover. Think about this before you look up a result you cannot un-know.