Early Signs of Alzheimer’s in People With Genetic Risk

Alzheimer’s disease (AD) is a brain disorder that’s the most common cause of dementia in older adults. The disease slowly destroys memory and thinking skills. Over time, people with Alzheimer’s disease lose the ability to carry out the simplest tasks.

Mass General Brigham is at the forefront of Alzheimer’s research. Our investigators have discovered promising insights into the genetics and early brain changes associated with the condition. These findings may one day help doctors and scientists prevent Alzheimer’s disease, diagnose the disease earlier, delay symptom onset, and develop new treatments.

Yakeel Quiroz, PhD, a Mass General Brigham clinical neuropsychologist and neuroimaging researcher, is the principal investigator of one such landmark study, the Colombia-Boston (COLBOS) biomarker study. Dr. Quiroz’s team and colleagues at the Universidad de Antioquia, Colombia, are studying the largest known family with early-onset Alzheimer’s disease. This family has about 1,500 carriers of the presenilin-1 (PSEN1) E280A mutation.

COLBOS findings have deepened the understanding of Alzheimer’s disease, documented signs of early onset years before symptoms arise, and helped lay the foundation for the Boston Latino Aging Study.

"Discovering these early brain changes associated with Alzheimer's disease can be key to early detection and diagnosis of the disease and hopefully, it will lead to novel ways to improve care for all patients," Quiroz says.

There are two types of Alzheimer’s disease:

1. Familial Alzheimer’s disease (FAD): This early-onset form of the disease runs in families with genetic risk of Alzheimer’s disease. People with FAD typically first develop symptoms before the age of 65. Disease onset may occur in the 30s, 40s, or 50s. Familial Alzheimer’s is very rare, making up less than 1% of Alzheimer’s disease cases. There are three genes linked to early-onset Alzheimer’s: Amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2).
   
   
2. Late-onset Alzheimer’s: Most people with Alzheimer’s have late-onset symptoms that first appear in their mid-60s. Researchers have not found a specific gene that directly causes late-onset Alzheimer's disease. However, having a genetic variant of the apolipoprotein E (APOE) gene on chromosome 19 does increase a person's risk of developing Alzheimer’s. The APOE gene helps make a protein that carries cholesterol and other types of fat in the bloodstream.

The COLBOS study began in 2015. Quiroz’s team and colleagues in Colombia began bringing members of an extended family group of 6,000 individuals with the known PSEN1 mutation to Boston for advanced examinations. During these visits, Mass General Brigham researchers collect biomarker data and perform advanced neuroimaging to study changes in the brain.

“We are studying these individuals decades before they have cognitive symptoms to predict who may develop the disease in the future,” explains Dr. Quiroz. “The goal is to identify biomarkers of AD in these individuals who are destined to develop dementia to use that information to delay or prevent the clinical onset of Alzheimer’s disease.”

"Since we have been studying these families for so long, we have established a timeline where we can predict disease progression according to their age,” she adds. “Through these ongoing studies, we have found brain abnormalities in carriers as early as 9 years of age.”

The team also has reviewed blood biomarkers. A biomarker is a biological molecule found in blood, other body fluids, or tissues. It’s a sign of a normal or abnormal process, or of a condition or disease.

The team found abnormalities in the plasma of carriers in their early 20s. This finding predicted memory loss decades later. These biomarkers may lead to early detection and treatment of people who haven’t yet developed symptoms.

Mass General Brigham researchers also found that brains of PSEN1 mutation carriers accumulate more amyloid and tau proteins. These proteins can form abnormal protein clumps in the brain (called amyloid plaques) and tangled bundles of fibers (called tau tangles). Plaques and tangles in the brain are the main features of Alzheimer’s disease. The team detected the increase in amyloid and tau proteins years before the carriers showed symptoms of mild cognitive impairment (MCI).

"Carriers start accumulating amyloid in their brains around age 29. This is 15 years before the average onset of MCI at age 44 in this kindred," explains Dr. Quiroz. "Tau accumulation in medial temporal regions of the brain was observed around the age of 38. Then, we see a sharp increase of tau pathology when they start showing symptoms of MCI."

Quiroz and her team have identified a few COLBOS study participants who remained without memory problems until their 70s, even though they carry the PSEN1 mutation. This has helped the team glean insights into potential protective factors against Alzheimer's disease and possible treatments. One such participant was a woman in her early 70s who began showing signs of Alzheimer's disease almost 30 years after the expected age of clinical onset.

"Her brain imaging showed that she had the highest levels of amyloid in the family, but she had very limited levels of tau pathology or atrophy compared to other carriers, even those with MCI," says Quiroz.

Researchers performed genome sequencing and learned the woman had two copies of the APOE Christchurch mutation. This mutation prevents the APOE gene from binding to the HSPG gene, a process researchers believe triggers tau build-up in the brain.

"This indicates that the Christchurch mutation may be a protective factor against the development of Alzheimer's disease," explains Quiroz. "We have developed an antibody to mimic the function of Christchurch mutation by preventing that binding between APOE and HSPG. We are currently testing if such an antibody can be used someday as a therapeutic."

Dr. Quiroz and colleagues built upon their COLBOS research to start the Boston Latino Aging Study (BLAST) in 2021. BLAST researchers use a similar research protocol to study the Latino/a/x population in Boston. However, BLAST differs from the COLBOS project in that researchers are studying people older than 55 to identify biomarkers for sporadic late-onset Alzheimer’s, rather than early-onset Alzheimer’s.

Patients are eligible for the study if they are:

• Over the age of 55
• Latino/a/x
• Speak English and/or Spanish
• Have no cognitive impairment

"Since we work with Colombians, all our study materials are translated into Spanish, most of our cognitive measures are culturally adapted for Spanish-speaking participants, and almost all of the members of my research team are bilingual,” explains Dr. Quiroz.

The team hopes the collective work of COLBOS and BLAST will advance the understanding of Alzheimer’s disease to prevent cognitive impairment in those at risk of developing the condition.