Risk Factors of Alzheimer's Disease

By Dr. Brandon Colby MD, a Personalized Preventive Medicine specialist and expert in clinical genomics.

Alzheimer's disease is one of the leading causes of cognitive disability in the modern world. As life expectancy increases globally, the incidence of Alzheimer's and other forms of dementia rises with it. The condition places a significant burden on patients, families, caregivers, and healthcare systems.

Fortunately, years of clinical research have allowed scientists to identify the key risk factors for Alzheimer's disease. Understanding them is the foundation of any meaningful prevention strategy.

What Causes Alzheimer's Disease

One of the primary mechanisms of Alzheimer's is the accumulation of beta-amyloid, a peptide that collects in the extracellular space between brain cells and forms amyloid plaques that impede normal brain function. Tau proteins also accumulate intracellularly, forming neurofibrillary tangles. Over time, these processes lead to significant loss of neurons and synapses, and certain areas of the brain visibly shrink as the disease progresses.

Alzheimer's is a multifactorial disease, meaning it develops as a consequence of multiple interacting genetic and environmental factors. This is why risk varies so widely between individuals.

Environmental Risk Factors

Cardiovascular Disease

Heart health and brain health are closely connected. Hypertension, coronary heart disease, atherosclerosis, and stroke all increase the risk of Alzheimer's and vascular dementia. Preventive measures include maintaining a healthy weight, exercising regularly, managing cholesterol and triglycerides, and following a heart-healthy diet such as the Mediterranean or MIND diet.

Traumatic Brain Injury

Repetitive or severe traumatic brain injuries significantly increase risk. Research involving NFL players has shown that TBIs increase biomarkers for amyloid-beta and tau protein deposits. Protective measures include wearing a helmet during contact sports and cycling, always wearing a seatbelt, and avoiding distracted or impaired driving.

Mild Cognitive Impairment (MCI)

MCI is an intermediate stage between normal cognition and dementia. Approximately 40 percent of seniors with MCI develop dementia within three years. Building cognitive reserve through mental stimulation, brain exercises, and social engagement can help reduce this risk.

Substance Use

Heavy alcohol consumption and tobacco smoking increase risk of Alzheimer's and can compound other risk factors such as heart disease.

Genetic Risk Factors

The APOE Gene

The APOE gene produces apolipoprotein E, a protein that helps clear amyloid-beta from the brain. Its three alleles affect this function differently. APOE2 is protective, increasing apolipoprotein E production. APOE3 is generally neutral but may increase risk when combined with other genetic variants. APOE4 reduces apolipoprotein E production and is the primary known genetic risk factor for Alzheimer's disease. Inheriting even one APOE4 copy elevates risk. Two copies elevates it further. Other risk genes include ABCA7, GAB2, PICALM, SORL1, and TOMM40.

Is Alzheimer's Inherited?

The genes associated with Alzheimer's risk are not linked to sex chromosomes, so they can be inherited from either parent. Risk genes increase the likelihood of disease but do not determine it. Alzheimer's is neither dominant nor recessive in the classical sense, because it is not a single-gene condition.

Early-Onset Familial Alzheimer's Disease

Early-onset familial Alzheimer's disease (EOFAD) is an autosomal dominant condition. Inheriting one copy of the mutated gene from either parent causes the disease. The genes associated with EOFAD are APP, Presenilin 1 (PS1), and Presenilin 2 (PS2). EOFAD is extremely rare, representing less than 1 percent of all Alzheimer's cases, and affects a few hundred families worldwide. Even in cases where the disease cannot be prevented, early identification enables earlier onset of preventive measures, which can delay progression and reduce symptom severity.

Can You Prevent Genetic Alzheimer's?

Carrying a genetic risk factor for Alzheimer's does not mean the disease is inevitable. Preventive measures taken throughout life are the most effective tool currently available to reduce risk. For the rare individuals with EOFAD mutations, prevention may not be possible, but proactive management can meaningfully influence when and how the disease presents.

Genetic Testing for Alzheimer's Risk

Whole Genome Sequencing can identify your APOE variant and assess risk across all genes associated with Alzheimer's disease. Single-gene testing for APOE alone leaves out many other contributing genetic factors. WGS from Sequencing reads 100% of your DNA across over 30,000 genes, providing a complete risk profile alongside insights into other health areas.

References

1. What Happens to the Brain in Alzheimer's Disease? NIH National Institute on Aging.
2. What are complex or multifactorial disorders? MedlinePlus.
3. Colby MD, B. Outsmart Your Genes. 2010.
4. Stern RA, et al. Tau PET in Former NFL Players. NEJM. 2019.
5. Mild Cognitive Impairment. Weill Institute for Neurosciences.
6. Alzheimer's genes: Are you at risk? Mayo Clinic.
7. Is Alzheimer's Genetic? Alzheimer's Association.
8. Wu L, et al. Early-onset familial Alzheimer's disease. Can J Neurol Sci. 2012.
9. Can Alzheimer's Disease Be Prevented? Alzheimer's Association.

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