Dementia
Dementia is defined as the loss of intellectual functions (such as thinking, remembering, and reasoning) severe enough to interfere with a person’s daily functioning. It is not a disease in itself but a group of symptoms that may accompany certain diseases or physical conditions.
Some common types of dementia
- Alzheimer’s Disease: The most common form of dementia, characterized by memory loss and cognitive decline.
- Parkinson’s Disease Dementia: Cognitive decline that can occur in later stages of Parkinson’s disease, impacting thinking and memory.
- Huntington’s Disease: A genetic disorder that causes the progressive breakdown of nerve cells in the brain, leading to cognitive decline.
Genetic biomarkers for neurodegenerative diseases (from Ehrenberg AJ, …, Paterson RW. Alzheimers Res Ther. 2020).
| Gene | Protein | Associated Syndrome(s) | Reference |
|---|---|---|---|
| APP | Amyloid precursor protein | Early-onset Alzheimer’s disease (EOAD) (familial) | Tanzi et al., Science, 1987 |
| PSEN1 | Presenilin 1 | Early-onset Alzheimer’s disease (EOAD) (familial) | Sherrington et al., Nature, 1995 |
| PSEN2 | Presenilin 2 | Early-onset Alzheimer’s disease (EOAD) (familial) | Levy-Lahad et al., Science, 1995 |
| ApoE (ε4 allele) | Apolipoprotein E | Alzheimer’s disease (AD) (risk factor) | Corder et al., Science, 1993; Saunders et al., Neurology, 1993 |
| TREM2 | Triggering receptor expressed on myeloid cells 2 | Alzheimer’s disease (AD) (risk factor) | Guerreiro et al., N Engl J Med, 2013; Jonsson and Stafansson, N Engl J Med, 2013 |
| MAPT | Microtubule-associated protein tau | Behavioral variant frontotemporal dementia (bvFTD) | Hutton et al., Nature, 1998; Poorkaj et al., Ann Neurol, 1998 |
| HTT | Huntingtin | Huntington’s disease (HD) | The Huntington’s Disease Collaborative Research Group, Cell, 1993 |
| GBA | β-glucocerebrosidase | Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) | Sidransky and Lopez, Lancet Neurol, 2012 |
| SNCA | α-synuclein | Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) | Kruger et al., Nat Genet, 1998 |
APOE4 is associated with earlier AD onset, higher Aβ and tau toxicity, and increased microglial inflammation.
TREM2 is a transmembrane receptor found on microglial cells that is involved in a wide array of physiological processes. One of its key functions is the phagocytosis of amyloid-beta (Aβ), which is crucial for the progression of Alzheimer’s disease (AD). The R47H mutant variant of TREM2 has been shown to elevate the risk of AD by disrupting the binding between TREM2 and Aβ.
Notably, APOE is a ligand of microglial TREM2, and the R47H risk variant impairs APOE binding, potentially contributing to its disease risk.
The GBA gene primarily encodes the lysosomal enzyme glucocerebrosidase (GCase), which catalyzes the hydrolysis of glucosylceramide (GlcCer) into glucose and ceramide. Mutations in the GBA gene are now identified as the most significant and prevalent risk factors for the development of Parkinson’s disease (Sidransky and Lopez, 2012).