Skip to content

Early Brain Changes Predict Alzheimer's Disease in Individuals at Genetic Risk

In This Article

  • Researchers at Massachusetts General Hospital's Familial Dementia Neuroimaging Laboratory have identified some of the earliest brain changes predictive of developing Alzheimer's Disease
  • Investigators have been studying individuals from the world's largest kindred known to have approximately 1,500 carriers of the PSEN1 gene mutation, which is associated with familial Alzheimer's disease
  • Using neuroimaging, the team observed abnormalities in the brain of carriers as young as 9 years old
  • Using blood biomarkers, the team observed abnormalities in the plasma of carriers in their early 20s, which predicted memory loss decades later. These biomarkers may lead to early detection and treatment of individuals who have yet to develop symptoms
  • The team is expanding their research to study individuals at increased risk for sporadic late-onset Alzheimer's disease in the Boston area Latino/a/x population

Researchers at Massachusetts General Hospital are following an extended family group of 6,000 individuals in Colombia with a known Alzheimer's disease genetic mutation. Their work is revealing key details about the genetics and early brain changes associated with Alzheimer's disease (AD).

"In my lab, we are studying these individuals decades before they have cognitive symptoms to predict who may develop the disease in the future. 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," says Yakeel Quiroz, PhD, clinical neuropsychologist, director of the Multicultural Assessment and Research Center, the Multicultural Alzheimer's Prevention Program and the Familial Dementia Neuroimaging Laboratory in the Department of Psychiatry at Mass General.

COLBOS Project Focuses on Colombian Kindred With PSEN1 Mutation

There are two types of Alzheimer's disease­­—the more common late-sporadic onset and rarer familial Alzheimer's disease (FAD). According to Dr. Quiroz, FAD accounts for less than 1% of Alzheimer's disease cases. Cognitive symptoms of FAD typically appear earlier than age 65, though disease onset may actually occur in the 30s, 40s or 50s. There are three genes linked to familial Alzheimer's disease: amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2).

Since 2015, Dr. Quiroz has collaborated with colleagues at Fundación Universidad de Antioquia, Colombia, on the COLBOS (COLombia-BOSton) research project, which follows the largest known extended family with one of these genetic mutations. The family of 6,000 individuals in Antioquia, Colombia, includes approximately 1,500 carriers of the PSEN1 E280A mutation, all of whom have a near-certain chance of developing FAD in their forties. They travel to Boston every two years, where Dr. Quiroz and her team collect biomarker data and perform advanced neuroimaging, including:

  • Functional magnetic resonance imaging (fMRI)
  • Structural magnetic resonance imaging (sMRI)
  • Positron emission tomography (PET)
  • Diffusion tensor imaging (DTI)
  • Optical coherence tomography (OCT)
  • Blood samples

COLBOS findings to date have enabled the researchers to characterize the Alzheimer's disease course among cognitively unimpaired PSEN1 carriers.

"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. This kindred is very homogenous. Through these ongoing studies, we have found brain abnormalities in carriers as early as 9 years of age," says Dr. Quiroz. "Using MRI and fMRI we saw that carriers of the PSEN1 mutation had hyperactivation in medial temporal lobe regions of the brain and less activation of the parietal regions of the brain compared to noncarriers, even though they had no cognitive difficulties."

Researchers also observed higher plasma neurofilament light chain (NfL) concentrations in carriers of the mutation (published in The Lancet Neurology). Concentrations began to differentiate between carriers and non-carriers around 22 years of age. "This supports that NfL could be a useful biomarker tool to detect risk for Alzheimer's disease before symptoms appear," Dr. Quiroz says.

The Impact of Amyloid and Tau Accumulation

In addition to early changes in brain functions and elevated plasma NfL, investigators found the brains of carriers of PSEN1 mutation accumulate more amyloid and tau proteins, two hallmark pathologies of Alzheimer's disease (published in JAMA Neurology). The team detected the increase in amyloid and tau years before the individuals showed symptoms of 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," explained 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."

In mutation carriers, researchers observed that an increase in amyloid accumulation was associated with an increase in tau pathology. Additionally, tau pathology was always accompanied by amyloid and tau directly correlated with a decline in the individual's memory function.

"Tau pathology was first observed in the entorhinal cortex and other areas of the brain associated with memory. This accumulation of tau among carriers was associated with lower outcomes on cognitive assessments, such as the Mini-Mental State Examination and CERAD Word List Delayed Recall," says Dr. Quiroz.

Most recently, researchers showed that in mutation carriers, amyloid and tau pathologies relate to distinct patterns of brain functional connectivity and episodic memory (published in Proceedings of the National Academy of Sciences).

Researching Protective Factors Against Dementia

Dr. Quiroz and her team have identified a few COLBOS study participants who have remained cognitively unimpaired despite carrying the PSEN1 mutation. These rare occurrences have given the researchers insights into potential protective factors against the neuropathogenesis of Alzheimer's disease and possible avenues for therapeutic targets.

One of these participants was a woman in her 70s who began showing signs of Alzheimer's disease 30 years after the expected age of clinical onset (published in Nature Medicine). "Her brain imaging showed that she had the highest levels of amyloid in the family, but she had very limited levels of tau pathology compared to other carriers, even those with MCI" says Dr. Quiroz.

Using genome sequencing, researchers discovered the woman had two copies of the APOE Christchurch mutation, which prevents APOE from binding to the heparan sulfate proteoglycans (HSPG), a process investigators believe triggers tau accumulation in the brain.

"This indicates that the Christchurch mutation may be a protective factor against the development of Alzheimer's disease," explains Dr. 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."

Boston Latino Aging Study

In 2021, Dr. Quiroz and her colleagues leveraged their work and findings on COLBOS to begin the Boston Latino Aging Study (BLAST), which uses a similar biomarker research protocol to study the Latino/a/x population in Boston. Unlike the COLBOS work, BLAST is looking at individuals older than 55 to identify biomarkers for the most common type of Alzheimer's disease—sporadic late-onset.

"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. We are now leveraging all of that to study the Latino/a/x population in Boston," explains Dr. Quiroz.

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

Dr. Quiroz and colleagues hope that combined with the results from COLBOS, the BLAST study will deepen their understanding of Alzheimer's disease and possibly develop tools to prevent cognitive decline in the Latino/a/x population through culturally informed interventions, brain imaging and novel memory assessments.

"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," she says.

Learn more about research in the Department of Psychiatry

Learn more about Mass General's Department of Psychiatry


By measuring neurofilament light chain in a uniquely large, homogeneous cohort over an unprecedented age range, researchers have confirmed the promise of its use as a marker of preclinical Alzheimer's disease.


Researchers at Massachusetts General Hospital observed differences in the kinetics of tau aggregation across brain tissue samples from individuals with sporadic Alzheimer's disease, confirming and extending the concept of patient-specific characteristics of tau in this disease.