Alzheimer’s disease is not a normal part of aging, but aging is the biggest risk factor. As we age, biological processes can become dysfunctional and contribute to Alzheimer’s. Research into how Alzheimer’s develops is ongoing, but we know it has multiple, interrelated causes that result in a cascade of dysfunction. These include inflammation, misfolded proteins, mitochondrial dysfunction, vascular disease, synaptic loss, and eventually loss of our neurons (i.e. brain cells). Because of this, we believe that a combination of treatments targeting more than one of these causes will be most effective.
Inflammation can be both protective and harmful. It’s part of our normal immune response and helps prevent infection. But chronic inflammation can damage our neurons. When we are young, inflammation ramps up and then subsides quickly. But as we get older, it takes longer to reset, meaning we stay inflamed even when our bodies are healthy.
Damage to the body’s blood vessel network can limit the brain’s supply of oxygen and vital nutrients needed for cells to work properly. Neurons are particularly vulnerable due to their significant energy needs. Hypertension and cardiovascular disease are major risk factors for Alzheimer’s because of their negative impact on our vasculature.
Familial Alzheimer’s disease (also known as early-onset) is a very rare form of the disease caused by a gene mutation inherited from a parent. It involves single gene mutations on chromosomes 1, 14, or 21. There are no genetic “causes” of the more common late-onset form of Alzheimer’s. Though genes such as APOE4 (apolipoproteinE4) can increase a person’s risk of developing Alzheimer’s, they don’t mean you will get it. Epigenetic factors, which influence how much or how little our genes are expressed, can also contribute by turning up “bad” genes or turning down “good” ones.
Proteins are critical to our survival, as they carry out most functions in our cells. Proteostasis is the “quality control” system for our proteins, which is responsible for their correct formation and for recycling them after they are no longer needed. Both sides of this system are more likely to malfunction as we get older, resulting in an excess of toxic, misfolded proteins such as beta-amyloid and tau that, respectively, accumulate into plaques and tangles. Other proteins that can be involved in Alzheimer’s include alpha-synuclein (a component of Lewy bodies), and TDP-43.
Our brains account for about 2% of our body weight but use 20% of our body’s energy. This energy comes from glucose, and brain’s ability to process and use it can become less efficient with age, which starves our neurons. Some of this can stem from dysfunction in our mitochondria, which are the engines that power our cells. Diabetes exacerbates this problem, which is why it is a major risk factor for Alzheimer’s.
During our lives, we are exposed to various things in the environment that can damage our DNA and proteins. Free radicals, the sun, pollution—these all contribute to oxidation and cellular stress. Our ability to repair such cellular damage wanes as we get older.
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