By the time that the symptoms of dementia emerge in Alzheimer's disease, tissue damage is well underway in the brain. Now, scientists propose that specific psychiatric symptoms—such as depression, anxiety, sleep disruption, and loss of appetite—may serve as markers of very early brain changes in Alzheimer's.

Working with the Brazilian Biobank for Aging Studies (BBAS) at the University of São Paulo, investigators at the University of California in San Francisco (UCSF) studied results of postmortem brain tissue tests and compared them with psychiatric symptoms obtained from detailed interviews conducted with people who knew the deceased well, such as relatives and carers.

They suggest that their study—a paper on which now features in the Journal of Alzheimer's Disease—reveals that psychiatric symptoms are not the cause of Alzheimer's, but more likely early indicators of the disease.

Such markers could help doctors to diagnose Alzheimer's disease much earlier and thus increase opportunities for slowing its progress, they note.

Better understanding of Alzheimer's

The authors also propose that the findings could alter our understanding of how the biology of Alzheimer's leads to psychiatric symptoms in people who develop the disease.

"The discovery," says senior study author Dr. Lea T. Grinberg, who is a principal investigator and associate professor in neurology at UCSF, "that the biological basis for these symptoms is the early Alzheimer's pathology itself was quite surprising."

"It suggests these people with neuropsychiatric symptoms are not at risk of developing Alzheimer's disease—they already have it," she explains.

There are around 5.7 million people with Alzheimer's disease living in the United States. This figure is likely to reach almost 14 million by 2050.

If doctors could diagnose the disease more accurately, and earlier, it could save the nation trillions of dollars in care and medical costs.

Alzheimer's is the leading cause of dementia and has some specific biological features. The main hallmarks are two types of abnormal proteins found inside and around the brain cells in people who have died with the disease.

The abnormal proteins found inside the brain cells are known as tau tangles and the ones found between the cells are called beta-amyloid plaques.

Brain samples from a large cohort

For their study, Dr. Grinberg and colleagues used brain tissue samples from the BBAS. The BBAS is a large and unique bank that stores the brain tissue that scientists retrieve during postmortems in São Paulo, where an autopsy follows every death.

This allowed them to study autopsied brain tissue from 1,092 adults aged over 50 who died between 2004 and 2014 and who were representative of São Paulo's general population.

In addition, the BBAS records included data from "postmortem interviews with reliable informants" on the psychiatric symptoms and mental capacity of the deceased.

The team excluded 637 brain samples that showed abnormalities that were not related to Alzheimer's disease. This left 455 samples from people who either had signs of Alzheimer's disease, such as beta-amyloid plaques and tau tangles, or no signs of neurodegeneration.

To assess the amount of Alzheimer-related neurodegeneration, researchers evaluated each sample using a method called "Braak staging" to measure tau tangle burden, and a "CERAD neuropathology score," to measure beta-amyloid burden.

The investigators evaluated psychiatric symptoms using a "12-item neuropsychiatric inventory" and cognitive status using a tool called the "CDR-SOB score."

They then analyzed the psychiatric and cognitive evaluations against the measures of Alzheimer-related neurodegeneration for all of the 455 brains.

Improved diagnosis of Alzheimer's

The results showed significant links between psychiatric and cognitive measures and patterns of tau tangle burden, but no links to beta-amyloid burden.

Symptoms of anxiety, agitation, depression, sleep disruption, and appetite changes, for example, had links to early-stage Alzheimer's in which tau tangles appear in the brain stem. The link was present even though the individuals concerned had shown no noticeable changes in memory capacity before they died.

As Alzheimer's progresses, tau tangles start to build up in the outer cortex of the brain. Samples from individuals in which there were signs that this process had begun had links to a higher risk of agitation.

Also, samples from individuals in which tau tangles had already progressed to the outer cortex, were linked to dementia symptoms that are typical of Alzheimer's disease, such as a decline in memory and thinking ability and delusions.

The team suggests that the findings could impact trials for drugs that target early Alzheimer's disease in which there is a need for measurable outcomes in addition to cognitive decline.

The results could also be added to screening—alongside brain scans and blood tests—for improving the diagnosis of early-stage Alzheimer's.

"If we could use this new knowledge to find a way to reduce the burden of these conditions in aging adults, it would be absolutely huge."

–Dr. Lea T. Grinberg

—Catharine Paddock, PhD