Early-Onset Alzheimer’s: The Symptoms Beyond Memory Loss

The symptoms of early-onset Alzheimer’s disease don’t always begin with the memory changes that many people associate with dementia. For some, the first signs may involve vision, language, decision-making, behavior, or changes in daily functioning.

Dr. Gil Rabinovici, professor of neurology and radiology at the University of California, San Francisco and behavioral neurologist at the UCSF Edward and Pearl Fein Memory and Aging Center, explains why Alzheimer’s can look different in people who develop symptoms before age 65. His research focuses on using brain imaging and other biomarkers to improve dementia diagnosis, better understand neurodegenerative diseases, and support the development of new treatments.

In this Live Talk with Being Patient founder Deborah Kan, Rabinovici discussed how early-onset Alzheimer’s may first appear through changes in executive function, language, visual processing, or personality, and why those symptoms can sometimes lead to confusion or delayed diagnosis. He also explains how advances in PET scans, spinal fluid testing, and emerging blood tests are helping clinicians detect the biology of Alzheimer’s during life, while new antibody treatments and future combination therapies are beginning to reshape what diagnosis and care may look like for patients and families.

Being Patient: Let’s talk a little bit about early onset Alzheimer’s. We talk to a lot of people who are diagnosed in their 60s, some even earlier. Is there a different classification in terms of diagnosing early onset Alzheimer’s versus later stage Alzheimer’s?

Dr. Gil Rabinovici: Early onset refers to the age at which people develop symptoms. We know that most people with Alzheimer’s develop symptoms at an older age. But some people develop symptoms younger. The threshold that we use for defining early onset disease is age 65 or younger. This is actually based on the German retirement age. Some of the early papers on early onset came out of Germany, so it’s an absolutely arbitrary threshold. Of course, people can develop symptoms beginning in midlife all the way to late life. 

Now, early-onset Alzheimer’s is not synonymous with dominantly inherited Alzheimer’s. About 1 percent of all people who develop Alzheimer’s develop it because they have a gene mutation in one of three genes: APP, presenilin 1, presenilin 2. Those people tend to have young-onset disease. But actually, most people who develop symptoms before age 65 do not carry those mutations. Over 95 percent of people who develop symptoms at a young age do not have a purely genetically driven form of Alzheimer’s disease. 

It’s estimated that about 5 percent of all people with Alzheimer’s develop symptoms at a younger age. So, if we think about 7.2 million Americans currently living with Alzheimer’s disease, that translates into roughly 360,000 people in the U.S. living with early-onset.

Being Patient: If you have the gene, that’s pretty much deterministic, I think we’ve learned, right? Presenilin 1, or 2, those folks usually have a very heavy familial component. Are you saying, though, just a small portion of what’s classified as early-onset are actually genetic and the rest are not?

Rabinovici: That’s right. I think people often think synonymously about early-onset and genetically driven. And I think it’s really important to make that distinction. Ninety-five percent of people who develop Alzheimer’s symptoms before age 65 do not have one of the mutations that causes the gene. They may have a predisposition, for example, the APOE4 risk gene, but they don’t have one of the gene mutations that causes the disease. 

It’s a bit of a mystery actually why people develop Alzheimer’s disease at a young age because they don’t have the major risk factor, which is older age. They don’t have a genetic mutation that causes the disease. Only about 50 to 60 percent have even a single copy of the APOE4 risk gene. And so, most people who develop symptoms at a young age, we don’t really understand the reasons why they’re developing symptoms so early in life.

Being Patient: Does the presentation of symptoms look different? 

Rabinovici: It is true that people can present with symptoms that don’t involve memory. The most common are probably symptoms related to what we call executive functions: judgment, reasoning, processing complicated information, being able to plan ahead, being able to multitask, being able to focus and concentrate. Because a lot of people are still working when they develop symptoms at this younger age, the manifestation can be difficulty with some of those really higher-order cognitive tasks that people might have in their jobs. That’s a very common story. 

There can be more unusual presentations, however. People can present with trouble with their language abilities, their ability to think of words, retrieve words. Everyone, every now and then, has a tip-of-the-tongue problem, when you’re thinking of that word, but it just isn’t coming to you. That’s very common. That’s not a concerning symptom. But when it happens very, very often, and when people are having trouble retrieving even very common words that they use in day to day, that can be an early manifestation of a language presentation of Alzheimer’s disease. 

People can have trouble with their vision and spatial function. They may have trouble navigating to familiar places. When they’re reading, they might have trouble following a line on the page that they’re trying to read or locating things that are right in front of them, recognizing faces. Alzheimer’s disease can involve the visual system. 

Occasionally, people can also have changes in their behavior and personality. Something that looks very much like what we call frontotemporal dementia, which is a whole other category of dementia that presents with changes in personality and behavior. Occasionally, that clinical presentation can also be due to Alzheimer’s disease. 

Memory loss is most common, but some of these other more unusual symptoms can be the earliest and presenting symptoms of early-onset Alzheimer’s. It is true that these unusual presentations — executive function problems, language problems, visual problems — are more common in early-onset than in later-onset Alzheimer’s, where the vast majority of older people, the disease does present with memory loss specifically.

“Memory loss is most common, but some of these other more unusual symptoms can be the earliest and presenting symptoms of early-onset Alzheimer’s.”

Being Patient: My mom passed away last December of Alzheimer’s, and we donated her brain to science, to UCSF. And what the result showed us was really three different types of dementia: there was presence of vascular, Alzheimer’s, and LATE dementia, which is a newly discovered dementia that has been categorized without plaque, but very symptomatic, like Alzheimer’s. I’m wondering if it’s possible that we have called Alzheimer’s, but maybe it’s different dementias that are starting under the umbrella of dementia that we’re just naming Alzheimer’s. Where are you on all of that? I think there’s a lot of debate within the industry as to classifications, what comes before what. What is your opinion of really how we define where disease starts and really identifying and parsing out different types of dementias?

Rabinovici: It’s a really important point. The way I think about classification is: how are we ultimately going to have treatments that are effective against these different disorders? I think the diagnosis really needs to be grounded in the biology — not what are the symptoms, but what is the underlying biology that’s driving the symptoms? 

The symptoms come from where different pathologies accumulate in the brain. If there’s pathology in memory areas, people have memory problems. If there’s pathology in language areas, people have language problems. But I think when we’re thinking about future therapies and even current therapies now, we really should be thinking about: what are the pathologies in those areas that are driving the disease? 

Alzheimer’s disease is currently defined by the deposition of these two toxic proteins in the brain called amyloid plaques and tau tangles. And it’s the combination of these two proteins — the plaques accumulating around nerve cells, the tangles accumulating inside nerve cells — that are really driving the symptoms of the disease. We now have therapies that can target the amyloid plaques specifically. We’re going to hear a lot about therapies that are targeting the other bad actor, the tau tangles. And so I do think that our diagnosis should be grounded in biology. And all these different symptoms that I’ve described — memory symptoms, executive function problems, visual or language problems — in Alzheimer’s disease, we call it Alzheimer’s because they are driven by plaques and tangles that are accumulating. 

The difference is: where in the brain do they start accumulating? In most people, especially the tangles, the location of the tangles is really very closely related to what the symptoms are. And we know that there are different areas in the brain that are specialized for different functions. In typical Alzheimer’s disease, and in most people with late-onset or older people with Alzheimer’s, the tangles start in an area of the brain called the temporal lobes, which are areas that are very important for recent memory, short-term memory, making and retrieving new memories. 

But especially in early-onset, and for reasons we can speculate on but don’t fully understand, in some people, the tangles early on are depositing in other brain areas that are important for executive functions: reasoning, higher-order thinking, cognitive problems. 

In some people, they’re really depositing on the left side of the brain, which is the language part of the brain. And therefore, people present with language symptoms. And then in others, they’re depositing in areas in the back of the brain that are really important for our visual brain, on the right side of the brain especially. So it really is where the Alzheimer’s changes, especially the tau tangles that are accumulating early on, that define what kind of symptoms people are going to have.

Being Patient: Is it only Alzheimer’s that has beta-amyloid and tau? Or are there other types of dementia that also have those biomarkers?

Rabinovici: Amyloid beta and tau are proteins. And in Alzheimer’s disease, they’re accumulating in the brain. Tau can accumulate in a lot of different disorders. It’s a really complicated group of diseases that are called tauopathies, or diseases that are driven by tau. Alzheimer’s disease is one of the diseases that presents with tau, and it really is the co-occurrence of plaques and tangles and the way the tangles look under the microscope that differentiates the tau of Alzheimer’s from the tau of CTE, which tends to accumulate in brain areas that are exposed to repeated trauma. Or to the tau disorders that present with frontotemporal dementia — accumulation of tau in brain areas that are important for behavior, personality, without amyloid, just tau. And the tau looks a little different. The pathologist can tell the difference when they look under the microscope. 

Then there’s a whole other category of diseases that present with movement as well as cognitive changes, Parkinsonism, like we see in Lewy body disease. But the symptoms, the movement changes, are different than Lewy body, and it’s a different protein. It is tau underlying some of these Parkinson’s-like syndromes called progressive supranuclear palsy, corticobasal degeneration. Anyway, there’s a whole other topic, but there’s so many different diseases. Tau seems to be very central, in general, causing neurodegeneration, or progressive loss of brain tissue, and causing dementia in late life. 

But it is important to understand that the tau is different, it looks different under the microscope. Now we have this amazing technique called cryo-electron microscopy, which allows us to see tiny, tiny little structures with high resolution. And what we’ve learned is that the tau is folding in different ways, say, in Alzheimer’s disease versus in some of these Parkinson’s-like tauopathies versus CTE versus frontotemporal dementia. 

So there are differences in the biology that underlie tau. Even though it’s the same protein that’s accumulating, it’s probably driven by different mechanisms. What we don’t know is whether it will require different treatments. If a treatment is working for tau and Alzheimer’s, will it work for other tauopathies? That’s still an open question.

Being Patient: Can you see that type of misfolding when the person is still alive in a scan, or is this only post-mortem right now?

Rabinovici: For so many years, the only way to diagnose Alzheimer’s was after someone had passed away. The only way to be sure was after someone had passed away and to do a brain autopsy. We could guess that someone had Alzheimer’s based on their symptoms. And we could rule out other things like strokes and simple hormone changes and things like that. And then we could say, well, we’ve ruled out other things. It’s probably Alzheimer’s disease. And it turns out that even experts, when they made that diagnosis when people had dementia, were wrong about 20 to 30 percent of the time. 

We’ve just talked about all the different complicated ways that Alzheimer’s disease can present. So you can see how hard it would be to accurately diagnose it based just on symptoms. If someone has language problems, it could be Alzheimer’s disease, but it could be a different form of tau disorder. Maybe it’s TDP-43, that bad protein that’s in LATE disease. All of these different proteins can cause language problems. 

To really make progress in therapies, we needed a way of detecting these bad proteins, not after someone passed away, but during life. Of the major breakthroughs that occurred about 20 years ago was the ability to image these proteins with a special kind of brain scan called a PET scan. The first PET scans allowed us to see amyloid plaques in living people. That was about 2004, where the first studies on amyloid PET scans allowed us to quantify and detect plaques in living people. And then about 10 years later, there was new technology that also, with a special PET scan, allowed us the tangles. 

And so now for Alzheimer’s disease, we can detect plaques and tangles in living people with brain scans. There are other ways to do it. We can measure the concentrations of the amyloid and tau proteins in spinal fluid. And one of the most amazing developments is the development of blood tests that can, with 90 percent accuracy, determine whether people have plaques and tangles in their brain just by measuring the concentrations of these proteins in the blood. 

That to me is unbelievable because PET scans are not accessible to most people, certainly in low- middle-income countries, but even in the United States. Only major urban areas, academic centers, etc., have access to amyloid or tau PET scans. In most of the country, there’s no way to get access to that technology. Spinal fluid was a good alternative, but now just a simple blood test can help us make the diagnosis with very high accuracy, and that’s a real game changer.

“Now for Alzheimer’s disease, we can detect plaques and tangles in living people with brain scans.”

Being Patient: The blood tests are looking for these different deposits in our bloodstream, right? Tell us exactly what it means to have these protein deposits in the blood? Does that mean we definitely have them in the brain because it circulates everywhere? Or is it possible it’s early enough detection so that the pathology hasn’t really started in your brain, but you’re at high risk? What does it mean as someone diagnosing patients?

Rabinovici: It’s important to understand that the deposits represent deposits of many proteins together. The amyloid and the tau protein, they’re sticky proteins, one sticks to another. They form these big deposits that you can see under the microscope or you can see with a PET scan. 

What we’re measuring in blood is not deposits per se. It’s just the concentration of the proteins that form these deposits. And what that tells us, however, with pretty high accuracy — if someone has a high concentration of p-tau217, that’s tau with a specific change at position amino acid number 217, that’s why it’s called 217. If someone has a high value of that on their blood test, that means that they are very likely to be depositing plaque in their brain. 

It doesn’t mean that they are going to get dementia, necessarily. It doesn’t mean that they have symptoms, but what it does mean is that with very high likelihood, these deposits are beginning in the brain. That is going to be very important if we have treatments that we can take to try to reduce those deposits if they are detected early on. Just like we measure our cholesterol level, and if it’s high, we take a medication to lower it before we get a heart attack or a stroke. 

The hope is that in the future, we’re able to really diagnose people very early based on a blood test or a panel of blood tests. And then, ideally, we would be able to give medications that could reduce or prevent these deposits from spreading and delay or hopefully prevent people from ever developing symptoms. The availability of blood tests to do that is really going to democratize diagnosis. It’s going to make it much more accessible across the country and across the world. 

Being Patient: Take us through what a diagnosis looks like today. So let’s take someone coming in to you saying, “I’m 55 years old. I’m starting to experience memory problems, beyond forgetting the occasional keys or things. Now, with changes in diagnostics, changes in treatments and medications, what is the right course?”

Rabinovici: The first thing we do when someone comes in is we take a really detailed history. We ask a lot of questions. Our new patient appointments at UCSF can be an hour and a half or two hours long. So if people come, just expect it’s going to be a long appointment because we ask very detailed questions about different elements of cognitive function. What we’re really trying to understand is which brain areas are involved, and that helps us with the diagnosis, as we discussed.

We ask about medical history, we ask about lifestyle habits, we look at medications. Could there be some medications side effects that could be contributing if not causing memory loss or other cognitive symptoms? We do some simple blood tests to look for things that are easily treatable that can impact memory and cognition, like low thyroid levels or low vitamin B12 levels. And we do a brain MRI scan to look for evidence of strokes or other things in the brain that could explain some of the symptoms. 

And then the next stage, if we suspect it may be Alzheimer’s disease, is we often start with a blood test, a p-tau217, the test you mentioned, to see if that is elevated as a first step towards diagnosis. And then, depending on the results and depending on the patient, we may proceed to do more advanced diagnostics like PET scans. 

In some people, they may be candidates for these new drugs. These are people who are at the early stages of their symptoms. So either mild cognitive impairment, meaning they have symptoms but are still independent, or early dementia, meaning they may have some trouble with some of the more complicated daily tasks like doing the finances, the taxes, but are independent with basic things. And in those individuals, we do discuss the possibility of being on an antibody treatment. 

These treatments aren’t for everyone. They’re not a cure, but they do, I think, meaningfully slow the progression of the disease. And the earlier we start them, the greater the clinical response that people will get. They are associated potentially with some significant side effects as well. And so, if people are in that window disease where they may benefit from the drugs, we sit down and we have a very detailed discussion. This is usually not in the first appointment. It might be the second or third appointment, or closely thereafter, after we’ve made the diagnosis, where we talk about therapy options, including the new antibodies, including some more established drugs. And we have a nuanced conversation about that, engage in what we call shared decision making: What are the patients’ values? What does the patient want? What does the family want? What do I recommend as a doctor? What are the potential benefits? What are the potential risks? And then we come up with a conclusion around: are these monoclonal antibodies right for this person? Maybe Aricept, one of the simpler drugs, is the better place to start, et cetera. There’s a lot more we can do now. We can nail the diagnosis with high accuracy, and we can intervene and are starting to intervene on the biology of the disease. 

I think about these antibody drugs as just the beginning of a new era of treatment. These are the first drugs that are actually changing the biology of Alzheimer’s disease, clearing the plaques. An analogy I often make is to relate it to the HIV epidemic. The first drug to treat HIV was AZT. If people remember, that drug was really toxic. It had nasty side effects, and the efficacy was so-so, it wasn’t the most effective drug, but it opened the door to new combinations of therapies that now allow people to live with HIV for decades and to live healthy and meaningful lives. 

I think about these new antibodies as our AZT. They’re not as effective as we would want, though. New ones are quickly following. They’re more toxic than we would like, but they do represent the beginning of a new era for everyone with Alzheimer’s, early-onset, late-onset. 

For many years, this was really an understudied area of Alzheimer’s disease, early-onset Alzheimer’s disease. In 2018, we launched a study across the United States called the Longitudinal Early Onset Alzheimer’s Disease Study, or LEADS. It’s led by Dr. Liana Apostolova at Indiana University. Co-led by myself, Dr. Brad Dickerson at Harvard, and Dr. Maria Carrillo from the Alzheimer’s Association. And in this study, we are recruiting individuals with early-onset Alzheimer’s disease from around the country at 18 different clinical sites. And we are doing detailed cognitive tests, blood tests, spinal fluid for those who consent, PET scans. We return the results to everyone, all the results. And for many people, participation in this study can actually be the gateway to diagnosis. 

And so, if anyone is having trouble getting a diagnosis, if they’re worried about early onset Alzheimer’s disease, look up the LEADS study at Indiana University. And there are sites across the country. And that might be a really good way for people to get a definitive diagnosis and to understand what their options are for future therapy.

Interestingly, in that study, about 75 percent of people do have Alzheimer’s disease, but 25 percent don’t, based on the PET scan results. And so they may either have a different type of dementia, or in some of them we think it might actually be something reversible like a mood disorder, a sleep disorder, or something else that’s causing their symptoms. And so whether or not it turns out to be Alzheimer’s disease, it’s really important to get that accurate diagnosis. 

Through the LEADS study, we are studying tools to measure disease progression, to understand, is the disease faster in younger people, as you mentioned? And we are hoping to actually use that as a scaffold in the future for clinical trials that are specifically looking at this population. People with early-onset Alzheimer’s sometimes aren’t even candidates for clinical trials because they are too young. Some of these trials have limits, like you have to be over 60, or they have requirements about memory loss. And so, if people have non-memory symptoms, they may not be able to access clinical trials. We’re going to change that with LEADS.

Being Patient: Is there a therapy we should keep our eyes out for in terms of like the HIV type of treatment. So we’re starting with amyloid. How far away are we from a tau drug? And how game changing would that be if we had one?

Rabinovici: I think it would be game changing. As we discussed, the symptoms of Alzheimer’s disease are much more closely linked to the tau tangles than they are to the amyloid plaques. We really think the spread of tangles is what’s driving brain dysfunction and ultimately symptoms.

I would say there’s been a lot of progress with tau therapies, and I think many of us, just like in HIV, when we have combination therapies that are attacking different parts of the virus’s biology — I think many of us believe that in Alzheimer’s disease, ultimately, we’re going to fall on combination therapies, therapies that are addressing different parts of the biology of the disease, the plaques, the tangles, the inflammation, the changes in brain metabolism, the synaptic dysfunction, all of these different things. And it’s going to be different treatments for different patients. We’re going to have to understand what’s driving things in an individual patient. That’s the future. That’s where we’re headed.