Alzheimer's disorder might have a higher hereditary occurrence than previously understood, as per a fresh investigation that offers clearer insights into a gene long associated with the typical form of cognitive decline.
The researchers of this study, published Monday in Nature Medicine, propose that this might be perceived as a distinctive, inherited variation of the ailment, hinting at the necessity for diverse approaches to examination and therapy.
Among individuals diagnosed with Alzheimer's, scientists distinguish between familial and sporadic cases of the disorder. While the majority of cases are believed to be sporadic and emerge later in life, familial cases, triggered by mutations in three specific genes, usually manifest earlier and are acknowledged to be rare, constituting approximately 2% of all Alzheimer's diagnoses, or roughly 1 in 50 cases.
Under this fresh perspective, 1 out of every 6 Alzheimer's cases could be deemed inherited or familial.
This evolving understanding of hereditary susceptibility, researchers assert, stems from a deeper comprehension of the involvement of a fourth gene responsible for producing a lipid-transporting protein known as apolipoprotein E, or APOE. APOE facilitates the transport of cholesterol throughout the body and brain, potentially influencing the accumulation or clearance of adhesive beta-amyloid plaques, a key characteristic of Alzheimer's.
There exist three variants of the APOE gene that an individual may carry. One variant, APOE2, is presumed to offer protection against Alzheimer's development. APOE3 is thought to confer a neutral risk for the disorder.
In contrast, APOE4 presents a concerning scenario. It has long been established that individuals carrying at least one copy of the APOE4 gene face an elevated risk of Alzheimer's onset, while those with two copies face an even higher risk.
Now, researchers propose that APOE4 should not solely be recognized as a risk factor; rather, it should be viewed as an inherited manifestation of the ailment, essentially ensuring that individuals possessing two copies will exhibit the biological markers associated with Alzheimer's in their brains.
Deciphering the role of genes in Alzheimer's
In their recent study, researchers from Spain and the United States compared individuals participating in clinical studies who possessed two copies of the APOE4 gene with those carrying other forms of the APOE gene.
Moreover, they contrasted individuals with two copies of APOE4 with those having other inherited variants of the disorder: early-onset autosomal dominant Alzheimer's disease (ADAD) and Down syndrome-associated Alzheimer's disease (DSAD). The study encompassed data from nearly 3,300 brains archived at the National Alzheimer's Coordinating Center, along with data from another 10,000 individuals involved in five clinical trials.
Not only were individuals with two copies of the APOE4 gene significantly more prone to developing the biological hallmarks of Alzheimer's, akin to those with other genetic forms of the disorder, but they were nearly guaranteed the diagnosis: Almost 95% of individuals in the studies possessing two copies of the APOE4 gene exhibited the biological traits of Alzheimer's by the age of 82.
The study authors highlight that while APOE4 consistently triggers the biological alterations associated with the ailment—the formation of beta-amyloid plaques in the brain—possessing one or two copies of this gene does not invariably lead to cognitive decline. In some rare instances, individuals carrying APOE4 may have substantial beta-amyloid presence in their brains but remain asymptomatic, perhaps due to other genetic or environmental factors shielding their brains concurrently. For instance, among the extensive dataset of nearly 3,300 brains maintained by the National Alzheimer's Coordinating Center, 273 individuals possessed two copies of the APOE4 gene, and 240, or 88%, were diagnosed with dementia.
When individuals with two copies of APOE4 do exhibit symptoms, they tend to manifest them earlier than others. On average, they develop Alzheimer's roughly 10 years earlier—around the age of 65—than individuals with other APOE gene variants. Researchers also observed that the buildup of beta-amyloid and tau proteins in their brains followed a trajectory similar to that noted in individuals with other inherited forms of the ailment, with more severe manifestations occurring earlier in life.
Across all inherited forms of Alzheimer's, "there are remarkable similarities in disease progression and symptomatic presentation," remarked lead study author Dr. Juan Fortea, a neurologist and director of the Memory Unit at Hospital de la Santa Creu i Sant Pau in Barcelona, during a news briefing.
Fortea and his colleagues argue that due to these factors, having two copies of the APOE4 gene should be classified as a genetic manifestation of the ailment, rather than merely a risk factor.
Dr. Charles Bernick, associate medical director of the Cleveland Clinic Lou Ruvo Center for Brain Health, noted that the study demonstrates the potent influence of possessing two copies of the APOE4 gene.
"It significantly propels the disease process," remarked Bernick, who was not involved in the study.
Evolution of genetic risk comprehension
The researchers speculate that the robust role of APOE4 in Alzheimer's development wasn't previously acknowledged because APOE4 also plays a crucial role in cardiovascular health, and they suspect that many individuals with two copies of the gene likely succumbed to cardiovascular issues before Alzheimer's manifested. Earlier studies had estimated that 30% to 35% of individuals with two copies of the APOE4 gene would develop mild cognitive impairment or dementia.
Researchers also note a gene-dosage effect. While possessing two copies of APOE4 guaranteed the accumulation of beta-amyloid and tau proteins in the brain, having only one copy of the gene also heightened the risk—albeit not to the same extent as possessing two copies.
This suggests that the APOE4 gene exhibits semi-dominance, as Fortea highlighted. Other diseases showcasing semi-dominant inheritance include sickle cell anemia and hypercholesterolemia. For instance, in sickle cell anemia, possessing two copies of the gene results in the disease, whereas having one copy leads to sickle cell trait. Individuals with sickle cell trait typically remain asymptomatic, but they may be more susceptible to heat stroke or muscle breakdown during vigorous exercise and may experience pain crises under specific conditions.
Designating APOE4 as an inherited form of Alzheimer's carries significant implications. Initially, it implies that a substantially greater proportion of Alzheimer's cases stem from genetic factors than previously understood.
Before the recognition of APOE4, the only genetic alterations associated with Alzheimer's were linked to early-onset forms of the disorder and Down syndrome. These accounted for roughly 2% of Alzheimer's cases, equating to approximately 1 in 50 cases.
Individuals with two copies of the APOE4 gene constitute about 15% of those diagnosed with Alzheimer's, or 1 in 7 cases of the disorder.
Approximately 2% of the general population carries two copies of the APOE4 gene, potentially making it one of the most prevalent inherited disorders.
Dr. Constantine Lyketsos, director of the Memory and Alzheimer's Treatment Center at Johns Hopkins, emphasized that Alzheimer's should not be perceived as a homogeneous condition. Rather, it underscores the presence of diverse forms of the disorder necessitating personalized treatment.
"The key point is that we need to embrace precision medicine and dissect it. Initiate with genetics," Lyketsos remarked, not involved in the study.
Gene testing's evolving role
The study is also likely to impact how individuals carrying the APOE4 gene are diagnosed and managed.
While tests exist to determine an individual's APOE4 status, they are not routinely recommended for diagnosis. This may necessitate reconsideration, the study authors suggest.
"The current consensus and guidelines do not advocate testing for APOE4, largely due to the belief that it doesn't aid in diagnosis," Fortea noted.
APOE testing is advised for patients being assessed for new amyloid-clearing medications like lecanemab.
Given that Alzheimer's patients with two copies of the APOE4 gene face heightened risks of severe side effects such as brain swelling from these medications, some treatment centers have opted against offering them the drugs, noted study author Dr. Reisa Sperling, director of the Center for Alzheimer's Research and Treatment at Brigham and Women's Hospital.
"I find this problematic, given these findings," she remarked, suggesting the importance of investigating whether safer dosing or treatments could be identified for this demographic.
"For me, this underscores the need for earlier intervention," Sperling added, "and this research strongly indicates that we should initiate treatment quite early, at a younger age, and at an early stage of pathology because we know they are very likely to progress to impairment rapidly."
Dr. Sterling Johnson, a study author leading the Wisconsin Registry for Alzheimer's Prevention at the University of Wisconsin, emphasized the significance of considering participants' APOE4 status in clinical trials.
"We might need to start categorizing these individuals as a distinct group in our research publications so that we can truly comprehend the relationship between amyloid, tau, and symptoms in individuals with two copies of the APOE4 gene, something we haven't been able to do before," Johnson remarked during the news briefing.
