Early-onset Alzheimer’s disease (AD) is a rare form of dementia affecting individuals younger than 65. It accounts for approximately 5% to 10% of all Alzheimer’s cases. Understanding its contributing factors is important, as its presentation and progression can differ from late-onset AD.
Understanding Early-Onset Alzheimer’s
Early-onset Alzheimer’s disease is typically diagnosed between the 30s and early 60s. This form of AD often progresses more rapidly than late-onset AD, and its initial symptoms can be atypical. While late-onset AD usually begins with memory loss, those with early-onset AD might first experience visual symptoms, such as impaired depth perception or difficulty recognizing faces, or language difficulties, like trouble finding words.
The distinct characteristics of early-onset AD, including its earlier age and varied initial symptoms, often lead to diagnostic challenges. It is sometimes referred to as “younger Alzheimer’s” to differentiate it from “early-stage Alzheimer’s disease,” which refers to the initial phase of the condition regardless of age of onset. Both early-onset and late-onset forms of Alzheimer’s disease share similar underlying brain changes, involving the abnormal buildup of amyloid and tau proteins.
The Primary Genetic Drivers
The leading cause of familial early-onset Alzheimer’s disease is dominant genetic mutations. Three main genes have been identified: Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2). Mutations in these genes are highly penetrant, meaning if a person inherits one of these altered gene variants, they are very likely to develop the disorder. These genetic changes account for a significant portion of familial early-onset AD cases, with PSEN1 mutations being the most common, responsible for 70% to 80% of autosomal dominant early-onset AD cases.
The APP gene on chromosome 21 provides instructions for creating amyloid precursor protein. Mutations in APP can lead to an increased amount or a longer form of the amyloid-beta peptide, a fragment of the APP protein. Similarly, mutations in PSEN1 (chromosome 14) and PSEN2 (chromosome 1) disrupt the normal processing of APP. These presenilin genes encode proteins that are part of the gamma-secretase complex, an enzyme that cleaves APP into amyloid-beta peptides. When altered, they lead to the overproduction or improper processing of amyloid-beta protein, particularly the more aggregation-prone amyloid-beta 42.
The accumulation of amyloid-beta protein forms dense clumps in the brain known as amyloid plaques. These plaques are a hallmark of Alzheimer’s disease pathology and trigger events that damage nerve cells in the brain. This cellular damage contributes to progressive cognitive decline in early-onset AD.
The Unique Case of Down Syndrome
Down syndrome, also known as Trisomy 21, is a significant contributing factor to early-onset Alzheimer’s disease. Individuals with Down syndrome have an extra copy of chromosome 21, which includes an additional copy of the APP gene.
This extra copy of the APP gene leads to an overexpression of amyloid precursor protein. This results in the overproduction of amyloid-beta protein, accelerating its accumulation in the brain. Almost all individuals with Down syndrome develop the neuropathological hallmarks of Alzheimer’s disease, including amyloid plaques, by middle age.
While the APP gene is a primary driver, research indicates that other genes on chromosome 21, beyond APP, may also contribute to the Alzheimer’s-like brain pathology and cognitive impairments observed in individuals with Down syndrome. This broader genetic influence from the extra chromosome 21 explains the high prevalence of early-onset AD in this population. The accelerated development of amyloid pathology in Down syndrome highlights the link between APP gene dosage and Alzheimer’s disease onset.